Polyvalent Catalysts Operating on Polyvalent Substrates: A Model for Surface-Controlled Reactivity

Article abstract of DOI:10.1002/anie.201602797

Unusually fast rates of nucleophilic catalysis of hydrazone ligation were observed when polyvalent anthranilic acid catalysts operating on polyvalent aldehyde substrates were used with PAMAM dendrimers as the common platform. When presented in this way, t

Full text of DOI:10.1002/anie.201602797

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International Edition: DOI: 10.1002/anie.201602797
German Edition: DOI: 10.1002/ange.201602797
Catalysis on Dendrimers
Polyvalent Catalysts Operating on Polyvalent Substrates: A Model for
Surface-Controlled Reactivity
Craig S. McKay and M. G. Finn*
Dedicated to K. Barry Sharpless on the occasion of his 75th birthday
Abstract: Unusually fast rates of nucleophilic catalysis of
hydrazone ligation were observed when polyvalent anthranilic
acid catalysts operating on polyvalent aldehyde substrates were
used with PAMAM dendrimers as the common platform.
When presented in this way, the catalyst has a strong accel-
erating effect at concentrations 40–400 times lower than those
required for similar monovalent catalysts and displays unique
kinetic parameters. We attribute these properties to polyvalent
engagement between the dendrimer surface groups, and
a potential “rolling” effect leading to fast interparticle kinetic
turnover. The phenomenon is sensitive to the density of
functional groups on each dendrimer, and insensitive to factors
that promote or inhibit nonspecific particle aggregation. These
findings constitute a rare experimental example of an under-
appreciated phenomenon in biological and chemical systems
that are organized on interacting surfaces.
turn, exhibit the expected properties of high local concen-
tration, which can be profound if the reaction mechanism
requires the cooperative action of more than one molecular
component for optimal catalytic function. Yet the interaction
of polyvalent catalysts with polyvalent substrates seems to
have escaped intensive attention so far. Only polynucleotide
phosphodiester hydrolysis by gold-nanoparticle- or micelle-
supported catalysts has been repeatedly explored from this
[
5,17–21]
point of view.
Significant advantages in rate and
processivity have been identified, although most quantitative
measurements have been reported for a monovalent model
substrate.
We describe herein the first exploration of polyvalent
catalyst–substrate reactivity in which a bond-forming event,
rather than an irreversible cleavage reaction, is monitored.
[
11,22]
Like others,
we think it likely that nature takes advantage
of the principle in as yet unrealized ways, since living cells are
full of surfaces decorated with all manner of functionality.
Figure 1A shows the overall kinetic scheme that inspired
the experiments described below. The initial formation of
a catalyst–substrate complex is followed by its dissociation or
by capture/conversion to form a catalyst–product complex.
We suggest that the overall catalytic rate can be greatly
P
olyvalent binding is a powerful control element in biology
and in laboratory-engineered molecular systems designed to
[
1–3]
engage biological surfaces.
Polyvalency may be regarded
as a tool for the transfer of molecular information, such as by
the induction of cellular signaling events to give a wide
spectrum of responses. Chemical catalysis is another mech-
anism by which polyvalent recognition events can be magni-
fied in their effect. Although polyvalent catalysts have been
intensively investigated for practical reasons in synthetic
increased if dissociation of the catalyst–product complex (k ,
À4
or off-rate) is relatively slow as compared to the rate of
association of an adjacent catalytic site with an adjacent
[
4–12]
chemistry
—for example, to increase activity by virtue of
substrate unit (k ). If this “rolling” process (analogous to the
5
[23]
high local concentration and recyclability by virtue of easier
recovery—they have only rarely been tested as a vehicle for
information transfer in model systems.
However, interesting and illustrative examples of “coop-
erative” or “interfacial” catalysis involving polyvalent sub-
strates do exist (see the Supporting Information). In several of
these cases, the importance of the catalyst moving from one
substrate to a nearby substrate (“scooting” or “hopping”) is
“scooting” of Berg, Jain, and co-workers or the “hopping”
[
24]
of Dawson, Medintz, and co-workers ) occurs efficiently, the
catalyst and substrate would not be separated, and diffusion
limitations would be largely eliminated. If the scaffold is rigid,
we expect the rolling effect to be most pronounced when
catalytic residues are spaced over similar dimensions as the
substrates. If the scaffold is flexible, more than one catalyst–
substrate complex could be formed at the same time. This
possibility does not invalidate the essential nature of poly-
valent–polyvalent catalysis, as simultaneous catalyst–sub-
strate engagement represents an extreme form of rolling.
To create this type of system, we employed poly(amido-
amine) (PAMAM) dendrimers as conveniently modifiable
[
13]
[14–16]
highlighted.
At the risk of oversimplification, these
studies have revealed that multiple copies of substrates are
operated on by monovalent (solution-phase) catalysts in
a manner sensitive to the average two-dimensional “concen-
tration” (density) of the substrate. Polyvalent catalysts, in
[
25,26]
polymer scaffolds.
ture reagent) with aldehydes (substrate) under the catalysis of
The condensation of hydrazines (cap-
[*] C. S. McKay, M. G. Finn
[27]
anthranilic acid derivatives
(catalyst, Figure 1B) was
School of Chemistry and Biochemistry
Georgia Institute of Technology
chosen as the test reaction because it is capable of generating
a chromogenic signal and, at moderate catalyst concentra-
tions, involves rate-limiting Schiff base formation, followed
by rapid transimination with the aryl hydrazine to yield the
901 Atlantic Drive, Atlanta, GA 30332 (USA)
E-mail: mgfinn@gatech.edu
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201602797.
[28,29]
hydrazone product.
Such a kinetic scheme, as opposed to
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(
missing arms and intramolecular loops) that are more
[
37]
severe for successive generations.
Besides varying the scaffold size, we changed the
surface character of the functionalized G4 dendrimers by
the installation of different linkers (propargyl versus
tetraglyme) between the triazole and substrate/catalyst
moieties to provide particles of different surface polarity
proximity. Finally, the average number of substrate or
catalyst units per dendrimer (functional-group density) was
also varied by mixing functional (aldehyde or anthranilate)
and nonfunctional (alcohol) components in the synthetic
steps with precise control of the average composition (see
the Supporting Information). Monovalent and divalent
analogues of the aldehyde substrate (S, S ), anthranilate
2
catalyst (C, C ), and hydrazone (P, P ) were also prepared
2
2
for comparison (Figure 2).
[38]
Reactions with the nitrobenzoxadiazole hydrazine H
gave rise to chromogenic hydrazone adducts, and reaction
progress was monitored by absorbance at 520 nm as
a function of time in a microtiter plate reader. Substrate
and hydrazine concentrations were in the 25–100 mm range,
and the reactions were performed at pH 5, near the optimal
[
27]
pH value for anthranilate catalysis,
in 0.1m NaOAc
buffer. Hydrazone and oxime ligations at the micromolar
level are customarily performed with concentrations of an
aniline-derived nucleophilic catalyst of 1 mm or greater, but
much lower concentrations of the polyvalent catalysts were
required in this study. The observed reaction profiles were
fit to the equation derived by Dawson and co-workers that
Figure 1. Polyvalent catalysis of polyvalent substrates. A) Overall catalytic
scheme. Key: C=catalyst; S=substrate; R=capturing reagent, such as
takes into account catalysis of both forward and reverse
nitrobenzoxadiazole hydrazine in the present case; P=product; k , k
:
[30,31]
1
À1
reactions.
At the concentrations used, completion was
initial association/dissociation rate constant; k : product-forming step;
3
reached at less than 100% conversion of the limiting
k
=catalyzed product-decomposition step; k : escapeꢀk ; k : poly-
À3
À4
À1
5
4
reagent, corresponding to K values in the range of 2 ꢀ 10 ,
eq
valent association rate constant (“rolling” rate). Letter designations (k ,
3
a
[31]
as expected. Representative data are shown in Figure 3
and Table 1 (see the Supporting Information for detailed
experimental methods and results, including all kinetic runs
and fits).
k , etc.) denote the rates of the same fundamental step; these rates may
3
b
differ in different cycles, probably only slightly at early stages of the
reaction. Accelerated substrate transformation may occur if “rolling” (k5)
is much faster than diffusion-controlled steps (k , k ). B) Intermediates in
À4
1
the nucleophilic catalysis of hydrazone formation by monovalent or
polyvalent anthranilic acid. In gray is shown the concomitant anthranilate-
In the absence of a catalyst, the reaction of monovalent
aldehyde S with H under these conditions proceeded at
catalyzed hydrolysis of the hydrazone that establishes Keq.
À1 À1
a rate of approximately 0.14m s . The presence of
a monovalent catalyst at a low concentration of either 25
or 100 mm increased the reaction rate by a factor of
approximately 3. Aldehydes displayed on dendrimers were
rate-limiting reagent capture, should be best suited to the
generation of a polyvalent catalytic effect. The catalyst
accelerates the dehydration step by a combination of
better substrates than others: In the absence of an added
À1 À1
catalyst, background rates of 1.3–6.6m
s
were observed,
[
28,30–33]
nucleophilicity
and intramolecular proton assis-
the rate of the uncatalyzed reaction is also
enhanced by a lowering of the pH value of the reaction
depending on which dendrimer scaffold was used. This effect
is probably due to the high local concentration of aldehyde
[
27,34,35]
tance;
groups on these structures, but other examples of anomalous
[
36]
[39]
medium.
reactivity have been described.
Again, a monovalent
Polyvalent benzaldehyde substrates and anthranilate
catalysts based on second-, third-, and fourth-generation
amine-terminated PAMAM dendrimers were prepared by
a two-step acylation/CuAAC procedure (see the Supporting
Information). These fully loaded scaffolds displayed an
average of 16, 31, and 61 functional groups, respectively
catalyst at 25 or 100 mm improved these reactions very little,
increasing the rates threefold at most.
In contrast, the use of the dendrimer-supported poly-
valent catalysts resulted in much faster reactions with
polyvalent, but not monovalent, substrates (Table 1). Rate
À1 À1
constants of approximately 30–400m
s
were observed for
(
Figure 2). The latter two values were less than the nominal
the G2, G3, and G4 dendrimer systems, corresponding to 13–
28-fold rate enhancements relative to the rate of hydrazone
formation from a polyvalent substrate with a monovalent
catalyst, and approximately 90–1300-fold relative to the
values of 32 and 64 attachments per dendrimer because
commercial PAMAM samples suffer from generational
(
trailing generations and oligomers) and branching defects
2
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reaction involving a monovalent
substrate with a monovalent
catalyst. The same pattern was
also observed at pH 6; although
the absolute rates of all the
reactions decreased relative to
those at pH 5, the polyvalent
display of the catalyst and sub-
strate afforded the same kinetic
advantage (see Figures S4 and
S8 in the Supporting Informa-
tion).
Similar levels of accelera-
tion (approximately 70-fold)
have been reported with mono-
valent catalysts operating on
monovalent substrates, but far
higher concentrations of ani-
[
30]
Figure 2. Monovalent and dendrimer-based polyvalent substrates and catalysts. Functionalized dendrim-
ers are designated by the following code: G#-Xvalence, where G# is the dendrimer generation (G2, G3, or
G4); X is the functional unit displayed (S is the benzaldehyde substrate with the short propargylamide
linker from 2a, pS is the benzaldehyde substrate with the longer tetraglyme-based linker from 2b, C is
anthranilate with the short propargyl linker from 3a, and pC is anthranilate with the longer tetraglyme-
based linker from 3b); “valence” is the approximate number of substrate or catalyst units attached per
dendrimer.
line
or 5-methoxyanthranilic
were required (10 and
[
27]
acid
1
mm, respectively). The use of
either of these known catalysts
at 25 mm gave similar results to
those described above for mon-
ovalent C (data not shown).
Substrate and catalyst concen-
trations are described here in
terms of the functional groups; for example, when substrate
G4-pS61 was used at an aldehyde concentration of 25 mm, the
concentration of the fully functionalized dendrimer was 25/
Table 1: Rate constants derived from the plots shown in Figure 3A–D.
[H]=25 mm for all experiments.
6
1 = 0.4 mm. Thus, in terms of the concentration of reactive
[
a]
[a]
À1 À1
Figure
no.
Substrate Catalyst kobs [m
s
]
Rate
ratio 1
Rate
ratio 2
particles, the observed reaction rates are far in excess of any
reported so far.
[
b]
[c]
[
[
[
d]
d]
d]
[e]
Although G2, G3, and G4 dendrimer substrates and
catalysts all showed strong rate acceleration in reactions with
each other, the relative rates did not track with size. The G3
dendrimer imparted enhanced reactivity in all cases as
compared to the G2 and G4 platforms (Figure 3B, Table 1),
including as a polyvalent substrate reacting in the absence of
3
3
3
3
A
B
C
D
G2-S16
G2-S16
G2-S16
S
S
S
G2-C
C
none
66.5Æ3.3
511.5
24.6
20.2
8.5
25.6
1.2
1.0
0.8
0.3
0.1
59.2
2.1
1.0
1.2
0.05
0.02
20.1
1.5
1.0
0.4
16
[f]
3.2Æ0.16
2.6Æ0.13
1.1Æ0.05
[
e]
G2-C
C
1
6
[
f]
0.41Æ0.02 3.2
0.13Æ0.01 1.0
391.0Æ15.0 2607
none
G3-C31
G3-S31
À1 À1
a catalyst (6.6 versus 2.6 or 1.5m s ), in the presence of
G3-S31
G3-S31
C
14.0Æ0.7
6.6Æ0.3
8.1Æ0.4
0.3Æ0.02
93.3
44.0
54.0
2.0
À1 À1
monovalent catalyst (14.0 versus 3.2 or 2.3m s ), and as
none
G3-C31
C
none
G4-C61
C
none
G4-C61
C
S
S
S
a polyvalent catalyst with the monovalent substrate (8.1
À1 À1
versus 1.1 or 0.63m s ). As expected from these results, the
0.15Æ0.02 1.0
G3 polyvalent–polyvalent combination was the fastest reac-
G4-S61
G4-S61
G4-S61
30.1Æ1.5
2.3Æ0.11
1.5Æ0.08
231.5
17.7
11.5
À1 À1
tion measured in this study, with a rate constant of 391m
s
in the presence of 100 mm catalyst (3.2 mm of the polyvalent
G3 catalyst particle).
S
S
S
0.63Æ0.03 6.0
0.32Æ0.02 3.2
0.13Æ0.01 1.0
Several lines of evidence were inconsistent with non-
specific aggregation being the key factor in the observed
acceleration of hydrazone formation, rather than a structure-
based polyvalent catalytic effect of the type described in
Figure 1A: 1) No aggregates were observed by dynamic light
scattering for dendrimers bearing the catalyst and the
substrate under the reaction conditions; only at concentra-
tions approximately 100 times greater were aggregates
detected. The minimum aggregate size detected by our
instrumentation is approximately 5 nm. 2) G4 dendrimers
with and without a tetraglyme spacer between the triazole and
0.2
none
0.09
22.3
1.4
1.0
0.5
G4-pS61
G4-pS61
G4-pC61 29.1Æ1.5
223.8
C
none
1.76Æ0.09 13.5
1.30Æ0.08 10.0
G4-pS61
S
S
S
G4-pC61 0.59Æ0.04 4.5
C
none
0.32Æ0.02 2.5
0.2
0.1
0.13Æ0.01 1.0
[
a] The substrate and catalyst were used at a concentration of 100 mm,
unless otherwise noted. [b] Ratio (kcat/kuncat) of the rate of the polyvalent
reaction to that of the reaction [S+H]. [c] Ratio (kcat/kuncat) relative to the
reaction [polyvalent substrate+H]. [d] Concentration: 50 mm. [e] Con-
centration: 12.5 mm. [f] Concentration: 25 mm.
the aldehyde groups (designated G4-S61 and G4-pS ) were
61
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lent, divalent, and G2-based
polyvalent reactants. Pairwise
comparisons of rate (see Fig-
ures S20 and S21) showed that
multivalency had a consis-
tently greater effect for the
substrate than for the catalyst.
Thus, the divalent catalyst
operated on various sub-
strates only 1.5–2.7 times
faster than the monovalent
catalyst, but the divalent sub-
strate reacted 3.8–4.6 times
faster than its monovalent
counterpart in the presence
of different catalysts. Simi-
larly, the rate acceleration
for the polyvalent versus diva-
lent substrate (6.5–26.1-fold)
was much greater than for the
polyvalent versus divalent
catalyst (3.3–7.4-fold).
We suggest that these
results reflect two beneficial
effects of substrate polyva-
lency: enhanced initial bind-
ing to the catalyst (an advant-
age that can be described in
terms of effective molar-
[40,41]
ity
processivity, or “rolling”
Figure 4). Polyvalent cata-
)
and
enhanced
(
Figure 3. Representative data for reactions of species shown in Figure 2. A–D) Reactivity profiles of fully
loaded G2/short linker, G3/short linker, G4/short linker, and G4/long linker polyvalent catalysts and
substrates in the presence of hydrazine H. E–G) Reactions of monovalent, divalent, and G2-polyvalent
substrates with monovalent, divalent, and G2-polyvalent versions of the catalyst. All reactions were
performed with 25 mm hydrazine H; the concentrations of aldehyde and anthranilate groups are indicated in
each panel.
lysts should benefit from the
first but not the second. Over-
all, the intersection of a poly-
valent catalyst and a poly-
valent substrate is highly
effective, especially since the
prepared with the expectation
that they should differ signifi-
cantly in their tendency to
aggregate in aqueous solution.
These scaffolds gave virtually
identical results (Figure 3C
versus D, Table 1), thus suggest-
ing that hydrophobicity of the
dendrimer surface had little
[
18]
effect on polyvalent catalysis.
Figure 4. Schematic representation of two different types of polyvalent advantage in catalysis. “sub”=
3
) The presence of unreactive substrate (aldehyde), “cat”=catalyst (anthranilate), “prod”=product (hydrazone).
hydrophilic or hydrophobic den-
drimers added in excess had no
effect on reaction kinetics (see Figure S10). If nonspecific
aggregation were important, one or both of these added
dendrimers would be expected to change the reaction rate.
To gain a better appreciation of the roles of intramolec-
ular association versus polyvalency, we prepared a divalent
substrate and catalyst as the simplest tethered components.
Figure 3E–G shows comparisons of reactions with monova-
concentrations of catalyst- and substrate-bearing particles are
much less than those of the lower-valent species used in these
comparisons.
Rates of hydrazone formation with G4 dendrimers bear-
ing different numbers of substrate and catalyst units were
measured, with the total concentration of substrate and
catalyst moieties kept constant at 100 mm. Thus, particles
4
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bearing fewer functional units were used in larger amounts.
The observed reaction rate constants were found to be highly
sensitive to the functional-group density on the scaffold
than all reactions involving a similar number of reactive
groups on the larger G4 scaffold (G4-pS + G4-pC ; G4-
1
5
61
pS + G4-pC ; G4-pS + G4-pC ). Similarly, G3-S + G3-
6
1
15
15
15
31
(
Figure 5). Relatively small decreases in rate were observed
C31 was a much faster reaction than reactions involving G4-
when the occupancy of the substrate or catalyst was cut to
three-quarters (61–46 per dendrimer), but a much greater loss
was observed in going from three-quarters to half (46–31 per
dendrimer; Figure 5A,B). The simultaneous variation of both
substrate and catalyst loading produced a dramatic drop in
catalytic rate at both the first and second dilution in func-
tional-group density (Figure 5C). Furthermore, polyvalent
reactions involving 16 and 31 functional units on each scaffold
were highly dependent on the scaffold size (Table 2). Thus,
the reaction of G2-S16 mediated by G2-C16 was much faster
pS31 or G4-pC . In contrast, reactions between any of the
fully loaded dendrimers were all within a factor of 4 of each
other (see Figures S4, S6, and S8 and Tables S1–S3).
31
This observed sharp and nonlinear dependence of reac-
tion rate on functional-group density is significantly different
from that of “cooperative” catalysts, in which two or more
functional groups on the same scaffold combine to produce
a much more effective catalyst than if the functional groups
are on different molecules. In such a case, for example, a two-
armed catalytic assembly would be revealed by a constant
second-order dependence of rate on the density of catalyst–
[11,42]
component groups on the scaffold.
Figure 5 shows
Table 2: Comparison of reactions involving similar numbers of substrate
and catalyst units on different-sized dendrimer scaffolds. Aldehyde and
anthraniliate concentration: 100 mm, unless noted otherwise.
a different scenario in which the magnitude of rate accel-
eration varies across the range of functional-group densities,
thus implicating a structure-dependent phenomenon such as
[
a]
À1 À1
[b]
Figure no. Substrate Catalyst
kobs [m
s
]
Rate incr.
“
rolling”. A simple aggregation effect would be expected to
5
5
5
A
B
C
G4-pS15
G4-pS61
G4-pC61
G4-pC15
1.7Æ0.09
3.7Æ0.19
1.5Æ0.08
1.1
2.5
1.0
95.9
1.8
2.7
1.0
produce a steadier drop in rate as the putative aggregates
were diluted by the addition of more dendrimers bearing
fewer functional groups.
G4-pS15
G4-pC15
S4F
G2-S16
G2-C16 (50 mm) 143.9Æ7.2
The concentrations of polyvalent catalysts and polyvalent
substrates were independently varied to survey the reaction-
rate dependence on these factors (Figure 6). For all three
scaffolds, the rate was found to increase with increasing
catalyst concentration, although in a nonlinear manner (Fig-
ure 6A–C). In contrast, for G4 and G3, but not G2
dendrimers, high substrate concentrations relative to the
catalyst were inhibitory (Figure 6D–F).
5
5
5
3
A
B
C
B
G4-pS31
G4-pS61
G4-pS31
G3-S31
G4-pC61
G4-pC31
G4-pC31
G3-C31
3.3Æ0.17
4.8Æ0.24
1.8Æ0.09
391.0Æ19.6 217.2
[a] The catalyst was used at a concentration of 100 mm, unless noted
otherwise. [b] Factor by which the rate constant increased relative to the
slowest reacting polyvalent scaffolds bearing a similar number of
reactive substrates and catalysts.
Figure 5. Exploration of rate versus density of the substrate and catalyst on PAMAM scaffolds. A) Variation in substrate loading, B) variation in
catalyst loading, C) simultaneous variation in substrate and catalyst loading. Plots of rates derived from these reactions are shown on the right;
values in italics are the ratios of the rate of each reaction to that of the next reaction in the series with lower functional-group density. All
reactions were performed with 100 mm total substrate, 100 mm total catalyst, and 25 mm hydrazine H. Similar results were observed in analogous
experiments with 25 mm catalyst (see Figure S16).
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This striking difference was
reflected in kinetic parameters
obtained by standard Eyring analysis,
albeit over a limited temperature range
(see Figures S13 and S14). Reactions
involving polyvalent substrates with
polyvalent catalysts showed substan-
tially diminished entropic costs (less
negative values of activation entropy),
as expected for polyvalent assistance.
Apparent entropy–enthalpy compensa-
tion was also observed. Although the
compensation is unlikely to be statisti-
[
45,46]
cally significant,
this case is
uniquely interesting: Few studies of
compensation have involved true cat-
alysis (rather than the binding of cata-
lysts), and none have examined activa-
tion parameters versus variations in the
valency of substrates and catalysts.
Finally, the relationship between
solution viscosity and reaction rate
was explored by measuring the rates
of reactions of the polyvalent G3-S31
substrate with hydrazine H in the
presence of different catalysts (G3-C ,
Figure 6. Plots of observed rate constant versus concentration of the fully loaded polyvalent
catalyst (A–C) or substrate (D–F), with G2/short linker, G3/short linker, and G4/long linker
dendrimers. All reactions were performed with 25 mm hydrazine H.
3
1
These varying outcomes in the rate dependence on
catalyst and substrate concentration would not be observed
if each catalyst and substrate moiety was acting independently
as in free solution. Furthermore, the inhibitory behavior of
higher concentrations of the larger substrate dendrimers is
consistent with a potentially deleterious consequence of
polyvalent interactions. As represented in Figure 1, multiple
catalyst and substrate groups on interacting scaffolds can
engage with each other simultaneously. It is possible that
some of the resulting imines may not be processed efficiently,
since not all will be equally accessible to the hydrazine. Such
an inhibitory effect would be expected to be more severe for
larger dendrimers, which should be more prone to simulta-
neous binding over large surface areas. The counterbalancing
of this phenomenon with rate acceleration by rolling should
produce an optimal formulation, represented in this prelimi-
nary study by the significantly faster reactivity of the G3–G3
poly–poly pair compared to G2–G2 and G4–G4.
C , C), in mixtures of a buffer and glycerol (up to 50%) to
2
[47]
increase solution viscosity.
Although all observed rates
were inversely dependent on the glycerol content (see
Figure S23), the polyvalent catalyst was significantly less
sensitive to increasing viscosity than the divalent or mono-
valent catalyst. The significant participation of a “rolling”
interaction that does not require the diffusion-induced
collision of separated particles would be expected to produce
such a result.
The interaction of polyvalent surfaces in a catalytic bond-
forming function was shown herein to be distinctive. It
enabled very rapid anthranilate-catalyzed hydrazone forma-
tion when both the substrate and the catalyst were displayed
in a polyvalent manner, even though particle concentrations
were low. Most interestingly, this type of process was found to
be sensitive to functional-group density, reaction-mixture
viscosity, and temperature in unusual ways, consistent with
the processive “rolling” of catalyst- and substrate-bearing
particles with respect to each other. These findings illustrate
a relatively simple way to enhance surface-based catalytic
reactivity, and suggest the existence of a complex kinetic
landscape with elements of homogeneous and heterogeneous
catalytic features. We believe that additional examples await
the construction of such systems in the laboratory and the
discovery or appreciation of membrane- or biopolymer-
arrayed catalysts and substrates in biology.
Rates of hydrazone formation were also measured at
different temperatures for polyvalent systems versus mono-
valent analogues (see Figure S13 and Table S5). Most of these
reactions, as well as the reaction of a polyvalent substrate
without a catalyst, slowed down at increased temperatures, as
previously observed by Bane and co-workers, and ascribed by
them to the more favorable formation of imine intermediates
[
43]
at lower temperature.
[A similar inverse temperature
dependence and formal negative enthalpy of activation have
been reported for a different organocatalytic reaction (thio-
urea-catalyzed Mannich alkylation of imines) in association
with the formation of key hydrogen bonds in the activated
complex. ] In contrast, the very fast processing of polyvalent
substrates in the G2 and G3 series was invariant with changes
in temperature between 25 and 458C (see Figure S13A,E).
Keywords: dendrimers · hydrazone formation · kinetics ·
polyvalent catalysts · polyvalent substrates
[
44]
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Received: April 1, 2016
30, 7283 – 7297.
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 8
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7
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Angewandte
Communications
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Communications
Catalysis on Dendrimers
C. S. McKay, M. G. Finn*
&&&& — &&&&
Polyvalent Catalysts Operating on
Polyvalent Substrates: A Model for
Surface-Controlled Reactivity
Roll and rock: Fast nucleophilic catalysis
of hydrazone ligation was observed with
polyvalent anthranilic acid catalysts
operating on polyvalent aldehyde sub-
strates with a common dendrimer plat-
form. The rapid catalysis and unique
kinetic parameters observed are attrib-
uted to polyvalent engagement between
the dendrimer surface groups and
a potential “rolling” effect that promotes
fast interparticle kinetic turnover (see
picture).
8
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These are not the final page numbers!