Structure-reactivity relationships in a recognition mediated [3+2] dipolar cycloaddition reaction

Article abstract of DOI:10.1039/b908072d

The [3+2] dipolar cycloaddition between an azide and maleimide can be accelerated by a factor of more than 100 simply by attaching complementary recognition sites to the reactive partners. This rate acceleration derives from the formation of a reactive bi

Full text of DOI:10.1039/b908072d

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Structure–reactivity relationships in a recognition mediated [3+2] dipolar
cycloaddition reaction†
Andrew J. Sinclair, Vicente del Amo and Douglas Philp*
Received 23rd April 2009, Accepted 13th May 2009
First published as an Advance Article on the web 23rd June 2009
DOI: 10.1039/b908072d
The [3+2] dipolar cycloaddition between an azide and maleimide can be accelerated by a factor of more
than 100 simply by attaching complementary recognition sites to the reactive partners. This rate
acceleration derives from the formation of a reactive binary complex between the azide and the
maleimide. The variation of the observed rate acceleration with simple structural changes, such as
adding additional rotors, should be relatively predictable. However, the application of a simple,
rotor-based increment in the systems reported here is insufficient to predict reactivity correctly.
Computational studies suggest that the nature of the available reaction pathways within the binary
complex formed by the reactants is important in determining the reactivity of a given complex.
entropic consequences of adding rotors to the system to rationalise
any subsequent effect on the efficiency of the bimolecular complex.
Here, we report: (i) dramatic acceleration observed for the reaction
between azide dipole 1a and maleimide dipolarophile 2a, mediated
Introduction
A key objective of supramolecular chemistry is the use of
molecular recognition to achieve the acceleration1 and control2 of
chemical reactions. As part of our program3 on the study of self-
by the formation of a [1a·2a] complex and (ii) the effects of the
replicating systems, we have been exploring the consequences of
recognition processes on the acceleration of solution phase Diels–
Alder4 and [3+2] dipolar5 cycloaddition reactions. In previous
additional rotors on the kinetic behavior of these systems.
examples, we have demonstrated that the location of comple-
mentary recognition sites on the components of a [3+2] dipolar
cycloaddition, namely dipole A and dipolarophile B, allows the
association of these reactive partners in a binary complex [A·B].
If, as a result of formation of this complex, the reactive groups
are then oriented in a mutually suitable geometry, the reaction
is rendered pseudo-intramolecular within the [A·B] complex. It is
therefore expected that some of the unfavourable entropic cost
of organising the reactive partners is shifted to the binding event
earlier in the reactive sequence and it is reasonable to expect6
that the formation of the [A·B] complex will effect significant rate
acceleration. In order to apply this concept to the transition metal-
free7 [3+2] dipolar cycloadditions of azides, we designed the azide
dipole 1a based on an amidopicoline moiety, and the maleimide
dipolarophiles 2a, 3a and 4a, based on a carboxylic acid motif.
Intermolecular recognition within Systems I to III (Scheme 1)
was directed by formation of parallel hydrogen-bonded diads8
[1a·2a], [1a·3a] and [1a·4a]. These pre-reactive complexes may be
capable of significant acceleration of the rate of formation of the
corresponding triazoline cycloadducts 5a, 6a and 7a (Scheme 1).
Through employing this range of dipolarophiles with a varying
number of methylene units in the spacer between the carboxylic
acid and maleimide groups, it was intended to investigate the
Results and discussion
Azide 1a was synthesized readily in two steps from commer-
cially available 2-amino-6-picoline in 90% overall yield using
standard synthetic methods. The dipolarophiles 2a through 4a
were prepared9 from the corresponding amino acids in modest or
moderate yield.
In order to assess the magnitude of any rate acceleration arising
from the formation of a reactive binary complex, the rate of the
recognition-mediated reaction must be compared to the rate of
the corresponding bimolecular reaction between the two reaction
partners in the absence of molecular recognition. Accordingly,
the control compounds 1b, 2b, 3b and 4b were designed. These
molecules do not possess the capability of 1a, 2a, 3a and 4a
for molecular recognition, but match their chemical reactivity as
closely as possible. The dipolarophiles were synthesised success-
fully from the corresponding acids 2a, 3a and 4a respectively and
the control dipole 1b was synthesised in a manner analogous to
that used to access dipole 1a.
The reaction mixtures for study were prepared in CDCl3 and
the extent of reaction at 323 K assayed at regular intervals by
400 MHz 1H NMR spectroscopy. Reaction progress was assessed
by monitoring the disappearance or appearance of the appropriate
resonances in the region d 6.80 to 6.99 (maleimide) or d 5.30 to
5.80 (cycloadducts) as a function of time. Product concentrations
1
were calculated from the H NMR spectroscopic data by decon-
Centre for Biomolecular Sciences, School of Chemistry, University of St
Andrews, North Haugh, St Andrews, United Kingdom KY16 9ST. E-mail:
d.philp@st-andrews.ac.uk; Fax: +44 (0) 1334 463808; Tel: +44 (0) 1334
467264
† Electronic supplementary information (ESI) available: Synthetic proce-
dures; determination of association constants; thermodynamic relation-
ships. See DOI: 10.1039/b908072d
volution methods. All kinetic experiments were performed under
thermostatically controlled conditions ( 0.1 ◦C). We did not
observe decomposition of the triazoline products or the formation
of unexpected side products in any of the kinetic experiments
performed.
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Scheme 1
Kinetic results for Systems I to III
[1a·2a] complex (110 M-1 in CDCl3 at 323K as determined10 by 1H
NMR titration experiments) were used to perform simulations of
the kinetic behaviour of the recognition-mediated system. Best-fit
values for the rate constants k3 and k4 (Table 1) are in acceptable
agreement with the experimental data and the calculated time
course based on these parameters is plotted in Fig. 1a. From
these parameters, the kinetic effective molarity (kEM) generated
in the [1a·2a] complex—the ratio k3/k1—was calculated as 3.96 M,
indicating that the presence of the recognition elements on
the reactive partners is capable of lowering the energy of the
transition state for the [3+2] dipolar cycloaddition significantly.
This stabilisation results in an increase of the initial rate11 for the
reaction between the azide and the maleimide of 125-fold (8.1 ¥
10-8 Ms-1 in the control to 1.03 ¥ 10-5 Ms-1 in the recognition
mediated reaction).
In System I, the dipolarophile presents a single methylene rotor
between the recognition site and the maleimide reactive site. The
control reaction between 1b and 2b reveals (Fig. 1a) that, after 16 h
at 323 K in CDCl3 where [1b] = [2b] = 25.0 mM, the conversion to
triazoline 5b was 16%. Kinetic simulation and fitting of this data to
the appropriate bimolecular model (k1 and k2, Scheme 1) afforded
the rate constant for the formation of triazoline 5b, k1 = 1.62 ¥
10-4 M-1s-1. When the control dipole 1b and dipolarophile 2b were
replaced by the recognition-capable dipole 1a and dipolarophile
2a, the rate of formation of triazoline 5a increased dramatically.
After 2 h, the conversion to triazoline 5a was now more than 90%.
In fact, the reaction reaches >90% conversion after 6 hours. At
this point, the control reaction between 1b and 2b has reached only
8% conversion. The kinetic data obtained for the reaction between
the compounds 1b and 2b were used to estimate the bimolecular
rate constants, k1 and k2, for the reaction between azide 1a and
dipolarophile 2a according to the model outlined in Scheme 1.
These estimates, together with the association constant within the
The introduction of an additional methylene unit into the
dipolarophile component of the [3+2] dipolar cycloaddition
reaction affords System II (Scheme 1). The recognition-mediated
reaction between 1a and 3a would be expected to be significantly
slower than that observed for System I as a result of the presence
Table 1 Best-fit kinetic parameters for the three recognition-mediated dipolar cycloaddition reactions studied
System
Dipolarophile
K
assoc/M-1a
k1 /10-6 M-1s-1
k2 /10-6 s-1b
k3 /10-6 s-1c
k4 /10-6 s-1c
kEM/mMd
tEM/mMe
I
II
III
2a
3a
4a
110
45
45
162 0.0001
85.6 0.001
74.2 0.001
5.69 0.02
0.77 0.15
0.012f
642 0.01
43.6 0.01
22.5 0.01
7.23 0.04
7.53 0.14
1.27 0.14
3960
509
303
3120
520
0.51f
a In CDCl3 at 323K. b Best fit values derived from kinetic data acquired from the control reaction between azide 1b and the appropriate control dipolarophile
(2b, 3b or 4b). A simple reversible bimolecular reaction model was used to fit the experimental kinetic data. c Best fit values derived from kinetic data
acquired from the recognition-mediated reaction between azide 1a and the indicated dipolarophile. The kinetic model depicted in Scheme 1 was used
to fit the experimental kinetic data. d kEM = k3/k1. e tEM = k1k4/k2k3. f Because of their small magnitude, these values are associated with significant
uncertainty.
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13 and 21 eu. Once again, the control reaction between azide
1b and dipolarophile 3b at 323 K where [1b] = [3b] = 25.0 mM
was slow—conversion to triazoline 6b reaching 10% after 16 h
(Fig. 1b). Incorporating molecular recognition into this system (1a
and 3a) does result in a faster reaction, however the acceleration
is more modest than that observed in System I. The reaction rates
extracted from the bimolecular reaction between 1b and 3b and
the association constant within the complex [1a·3a] (45 M-1 in
1
CDCl3 at 323 K as determined by H NMR spectroscopy) were
applied, as for System I, to the kinetic model shown in Scheme 1
and best fit values of k3 and k4 were determined. From these kinetic
parameters (Table 1), a kEM13 value of 0.52 M was calculated for
System II.
Placing a CH2CH2CH2 spacer between the carboxylic acid and
the maleimide unit of the dipolarophile generates System III
(Scheme 1). Once again, we studied the kinetics of the reaction
between azide 1a and maleimide 4a in CDCl3 at an initial
concentration of 25 mM for each component and a temperature
of 323 K. The corresponding control reaction between 1b and 4b,
performed under identical conditions, was used to establish the
background rate for the recognition-mediated system. Again, both
reactions were monitored by 1H NMR spectroscopy as described
previously. Deconvolution of the appropriate resonances in the
time course spectra obtained allowed rate profiles for the two
reactions to be constructed (Fig. 1c). As before, the reaction rates
extracted from the bimolecular reaction between 1b and 4b and the
association constant within the complex [1a·4a] (45 M-1 in CDCl3
at 323 K) were applied, to the kinetic model shown in Scheme 1
and best fit values of k3 and k4 were determined. From these kinetic
parameters (Table 1), a kEM value of 0.32 M was calculated for
System III. This value is rather close to that obtained for System
II which possesses one less methylene rotor.
The kinetic data shown in Table 1 can be converted into free
energy profiles (Fig. 2) by application of standard thermodynamic
relationships. These profiles show the relative energies of the
ground states and the transition state energies of the recognition-
mediated reaction between azide 1a and maleimide 2a (Fig. 2a),
as well as the relative energies for the reactions between 1a and 3a
(Fig. 2b) and 1a and 4a (Fig. 2c).
The ground state of product 5a is stabilized significantly
(Fig. 2a) suggesting that the recognition that is used to assemble
the [1a·2a] complex lives on in the product 5a. For the other two
systems studied (Fig. 2b and c ), the transition state stabilization
within the binary complex is not sufficient to offset the free energy
change associated with forming the complex in the first place.
Thus, for both of these cases, the kinetic effective molarity is
<1 M. We were, however, intrigued by the similarity in the kEM
values obtained for Systems II and III. The addition of additional
methylene groups into the spacer between the carboxylic acid
recognition site and the maleimide should affect the rate of
the cycloaddition between the azide and the dipolarophile in a
predictable manner. The incorporation of additional rotors should
introduce12 an entropic penalty of between 13 and 21 eu. This
entropic penalty can be converted readily to differences in rate
by standard transformations allowing us to calculate the expected
rates (Fig. 3) of the reaction between 1a and the dipolarophiles
2a, 3a and 4a. We performed14 this calculation in two ways. We
assumed that the rate of System I is representative and then applied
the entropic correction for the addition of one or two rotors
Fig. 1 Rate profiles at 50 ◦C for the formation of (a) triazoline 5a (ꢀ) or
5b (᭺), (b) triazoline 6a (ꢀ) or 6b (᭺) and (c) triazoline 7a (ꢀ) or 7b (᭺).
In all cases, the starting concentrations of dipole and dipolarophile were
25 mM in CDCl3 solution. In all cases, the solid lines represent the best
fit of the experimental data to the appropriate kinetic model (Scheme 1)
obtained using the COPASI package.21 See ESI† for further details of the
kinetic models used.
of the extra methylene rotor in the dipolarophile 3a. The presence
of this extra rotor would be expected to have an adverse effect on
the entropy of activation as it must be frozen in order to reach the
transition state. The magnitude12 of this effect should be between
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Fig. 2 Energy profiles for the formation of (a) triazoline 5a, (b) triazoline 6a and (c) triazoline 7a. All energies are relative to the starting materials and
are in kJ mol-1.
(Fig. 3a). Alternatively, we assumed that the rate of System III
is representative and then applied the entropic correction for the
removal of one or two rotors (Fig. 3b). The dashed lines in Fig. 3
represent the boundaries for the range (13 to 21 eu) of the entropic
rotor increment. From the data presented in Fig. 3, it is clear that
System II appears to be unusually unreactive no matter which
system (I or III) we take as our baseline.
In order to probe the reasons behind these reactivity differences
in systems which are apparently very similar in a structural sense,
we turned to computational methods. Firstly, we decided to probe
the low energy conformations occupied by cycloadducts 5a, 6a
and 7a. We reasoned that, since the transition state for the azide
cycloaddition is relatively late, we could use this conformational
mapping to detect interactions which might stabilize or destabilize
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Fig. 3 Comparison of experimental rate profiles as 50 ◦C for the
formation of triazoline 5a (ꢀ), 6a (᭜) and 7a (᭹) and computed rate
profiles based on rotor increments. In both cases, the dashed lines represent
the predicted cou◦rse of the reaction between azide 1a and the appropriate
maleimide at 50 C using a rotor increment of DS‡ = +13 J mol-1 K-1
(upper line) or DS‡ = +21 J mol-1 K-1 (lower line). Plot (a) uses System I
as the basis for the extrapolation to System II and System III (addition of
rotors) whereas plot (b) uses System III as the basis for the extrapolation
to System II and System I (removal of rotors).
the corresponding transition states. Conformational searches were
carried out using Monte Carlo methods and conformations within
50 kJ mol-1 of the global minimum were saved. The results of
these searches are shown in Fig. 4. In Fig. 4, the low energy
conformations of the cycloadducts are plotted as a function of two
=
hydrogen bonding distances—the N–H(Amide) ◊ ◊ ◊ O C(Acid)
distance and the N(Pyridine) ◊ ◊ ◊ H–O(Acid) distance. The shading
of the individual points represents the relative energy of the
conformations—the darker the shading, the lower the energy.
This conformational mapping reveals three distinct families of
low energy conformations. Representative structures from each
family for cycloadduct 6a (System II) are shown in Fig. 5—the
families for both 5a and 7a are very similar (see ESI†). Family
B structures are characterized by a hydrogen bond between the
carboxylic acid proton and the carbonyl group of the amidopy-
ridine. Family C structures are characterized by a hydrogen bond
between the carboxylic acid carbonyl oxygen atom and the N–H
group of the amidopyridine. It seemed unlikely that either of
these conformations had any direct bearing on the reactivity of
the maleimide. However, the structures in Family A contain a
N(Pyridine) ◊ ◊ ◊ H–O(Acid) hydrogen bond and some of them also
contain a hydrogen bond between the amide N–H and the
Fig. 4 Comparison of low energy conformations adopted by triazolines
(a) 5a, (b) 6a and (c) 7a calculated using the OPLS_2005 forcefield and
the GB/SA solvation model for chloroform. In each case, individual
conformations are represented by a square which is shaded according
to its energy relative to the global minimum with black being the global
minimum and white being + 50 kJ mol-1. Conformations are set out as
a function of two hydrogen bonding distances—the pyridine N to acid
proton distance (x axis) and the amide proton to acid carbonyl oxygen
atom distance (y axis).
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Fig. 5 Ball and stick representations of examples of conformations from
each of the three families identified in Fig. 4. Conformations are shown
for 6a only—those adopted by 5a and 7a have the same structural features.
The type of conformation shown for Family A is described as normally
hydrogen bonded in the text. Carbon atoms are shaded black, oxygen
atoms are shaded dark grey, nitrogen atoms are shaded light grey and
hydrogen atoms are unshaded. Dashed lines represent hydrogen bonds.
Fig. 6 Ball and stick representations of examples of conformations from
Family A for (a) 5a, (b) 6a and (c) 7a which do not display a hydrogen bond
between the amide proton and acid carbonyl oxygen atom. The type of
conformations shown in (b) and (c) are described as abnormally hydrogen
bonded in the text. Carbon atoms are shaded black, oxygen atoms are
shaded dark grey, nitrogen atoms are shaded light grey and hydrogen
atoms are unshaded. Dashed lines represent hydrogen bonds.
carbonyl oxygen of the acid—the global minimum is one such
structure. This conformation is the one that we had anticipated
would play a major role in the acceleration of the reaction in our
original design.
Surprisingly, there are, however, a number of low energy
structures which, although they have a hydrogen bond between
the pyridine N atom and the acid hydrogen do not contain a
may be altered15 by hydrogen bond-mediated polarization in the
transition states leading to these products.
=
N–H(Amide) ◊ ◊ ◊ O C(Acid) hydrogen bond. In the case of 5a,
the lowest energy of these conformations (Fig. 6a), although very
close in energy to the global minimum (+8.04 kJ), does not contain
any additional interactions. However, in the case of 6a and 7a, in
the lowest energy of these conformations (+7.41 kJ and +5.69 kJ,
respectively) (Fig. 6b and c) there is an additional hydrogen bond
In order to probe the effect of this interaction further, we turned
to electronic structure calculations. We located transition state
structures linking the binary complexes [1a·2a], [1a·3a] and [1a·4a],
in both the normal and abnormally hydrogen bonded forms, and
the corresponding cycloadducts at the B3LYP/6-31G(d,p) level
of theory. Additionally, we calculated the transition state linking
benzyl azide and N-methylmaleimide and the corresponding
cycloadduct in order to allow comparison with a situation where
recognition is not involved. The results of these calculations
provide some insight into the subtle structural effects which
operate in these systems and help to rationalise the reasons for
the relatively poor performance of System II. The structures of
=
present between the N–H of the amide group and one of C O
groups on the maleimide. Clearly, the short tether length present
in 5a prevents this type of conformation being stable since the
lowest energy conformation which possesses such an additional
interaction is +30.79 kJ higher in energy than the global minimum.
The presence of this hydrogen bond in these conformations in 6a
and 7a opens up the possibility that the reactivity of the maleimide
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the five transition states located—two each for Systems I and III
and one for System II—are shown in Fig. 7.
of System II, only the transition state from the normally hydrogen
bonded complex is accessible. Repeated attempts to locate the
transition state that would be accessed from the abnormally
hydrogen bonded complex in System II resulted in the location
of the transition state accessed by the normally hydrogen bonded
complex instead.
The accessibility of transition states with different structural
types for each complex makes direct comparison of the rel-
ative rates of reaction through these complexes problematic16
using electronic structure methods. Bruice and Lightstone have
demonstrated16 that there is a correlation between rate and the
fraction of low energy near attack conformations (NACs)—the
higher the mole fraction of NACs the faster the reaction. This
analysis is particularly suited to our system as the definition of a
NAC relies only on the relative orientations of the reacting centres
and not on the location of the recognition elements. Accordingly,
we adapted the protocol described by Bruice and Lightstone
to our systems. Stochastic methods were used17 to generate
>25000 conformations for each of the complexes, [1·2a], [1·3a]
and [1·4a]. The generation of these conformations was subject to a
single constraint—the hydrogen bond between the amidopyridine
nitrogen atom and the carboxylic acid proton must be maintained.
After removal of conformations that were not local minima, those
that were >25 kJ mol-1 from the global minimum and duplicate
conformations, a set of low energy conformations for each complex
was created. These sets consisted of 198 conformations for [1·2a],
176 conformations for [1·3a] and 220 conformations for [1·4a].
These sets were then searched for conformations which satisfied
our definition18 of a NAC for the dipolar cycloaddition reaction.
This analysis revealed that of the 198 conformations for [1·2a], 22
were NACs, of the 176 conformations for [1·3a], 11 were NACs
and of the 220 conformations for [1·4a], 25 were NACs. The
locations of the NACs within the energy distribution of the lowest
conformations for each complex are shown in Fig. 8a. Since, in
each case, the NACs are of varying energy with respect to the
global minimum, it is necessary to account for the probability
of a NAC being occupied at 313 K. Thus, for each complex,
the overall Boltzmann-weighted probability of the occurrence
of a NAC was 0.082 for [1·2a], 0.028 for [1·3a], and 0.026 for
[1·4a].
Fig. 7 Ball and stick representations of the transition states accessible to
the complexes (a) [1·2a], (b) [1·3a] and (c) [1·4a]. Carbon atoms are shaded
black, oxygen atoms are shaded dark grey, nitrogen atoms are shaded light
grey and hydrogen atoms are unshaded. Dashed lines represent hydrogen
bonds.
We can immediately rule out any role for a hydrogen bond
=
between the N–H of the amide group and one of the C O
groups on the maleimide in altering the reactivity of the maleimide
=
dipolarophile. In all cases, the N–H ◊ ◊ ◊ O C distance is greater
than 2.50 A. We have shown previously that even two short
15a
˚
There is a reasonable correlation (Fig. 8b) between the com-
puted initial rate of reaction based on the experimentally deter-
mined rate constants and the Boltzmann-weighted probability of
the occurrence of a NAC. Thus, for System I, we would expect
that the high fraction of low energy NACs, coupled with the
higher association constant for the [1·2a] complex, would result in
rapid reaction through this complex. In the case of System III, the
additional flexibility of the three carbon atom spacer connecting
the maleimide to the acid recognition site lowers the fraction of
NACs; however, a substantial fraction of the accessible low energy
conformations are NACs. The anomalous member of this series
would therefore appear to be System II and can be traced to
the relatively low fraction of low energy conformations that are
NACs. The net result is that System II displays reactivity which is
much closer to System III than to System I. Phenomenologically,
these findings mirror the results reported19 by Hamilton and
co-workers—the inclusion of added free rotors in their thiol
transacylase mimic removes the advantage of the close proximity
of the reactive groups to each other.
=
N–H ◊ ◊ ◊ O C hydrogen bonds to a maleimide have a limited
effect on the reactivity of the system in dipolar cycloaddition
=
reactions. Given the long N–H ◊ ◊ ◊ O C distances present here,
we would expect that these contacts play essentially no role. In
all cases where transition states were located successfully, there
are minimal structural differences (Table 2) between the transition
state structure in the hydrogen bonded complex and that for the bi-
molecular reaction between benzyl azide and N-methylmaleimide.
In the case of System I, the lowest energy transition state—by
some 27.6 kJ mol-1—is that accessed from the normally hydrogen
bonded complex. This transition state is the one accessed from
the global minimum conformation. In the case of System III, the
lowest energy transition state—by 5.1 kJ mol-1—is, once again,
that accessed from the normally hydrogen bonded complex, i.e. the
one accessed from the global minimum conformation. Therefore,
in these two cases, two reaction pathways are accessible—one
through the normally hydrogen bonded complex and one through
the abnormally hydrogen bonded complex. By contrast, in the case
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Table 2 Calculated structural parameters for the transition states accessed by Systems I, II and III
System I
Normalb
System II
Normalb
System III
Normalb
Metrica
Abnormalb
Abnormalb
Base TSc
Relative Energy/kJ mol-1
0
+ 27.6
2.072
1.262
1.175
2.221
1.389
137.5
123.8
101.8
0.333
0.332
–
0
+ 5.10
2.113
1.269
1.175
2.147
1.392
138.2
117.7
101.3
0.340
0.361
–
˚
a/A
2.068
1.263
1.174
2.178
1.394
138.0
120.6
102.4
0.347
0.348
2.090
1.261
1.173
2.218
1.380
139.6
122.9
100.6
0.329
0.325
2.086
1.265
1.174
2.195
1.389
138.3
121.7
102.5
0.336
0.344
2.095
1.266
1.174
2.188
1.391
138.2
120.6
102.3
0.331
0.341
˚
b/A
˚
c/A
˚
d/A
˚
e/A
a/◦
b/◦
Hinge angle/◦
Bond Order C–Na
Bond Order C–Na
a From calculation at B3LYP/6-31G(d,p) level of theory. b Normal and Abnormal refer to hydrogen bonding pattern adopted in the transition state. See
Fig. 7 and text for details. c From reaction of benzyl azide with N-methylmaleimide.
and where necessary, stained with iodine, phosphomolybdic acid
Conclusions
(PMA), ninhydrin or potassium permanganate to aid visualisa-
The design of supramolecular systems which can achieve the
tion. Column chromatography was performed using Kiesegel 60
acceleration and control of chemical reactions remains a chal-
(0.040–0.063 mm mesh, Merck 9385) or MP Silica (silica gel,
lenging goal. We have demonstrated that, with a correctly de-
0.032–0.063 mesh). Melting points were determined using an
signed system, such as System I, it is possible to accelerate a
cycloaddition reaction by two orders of magnitude. This level of
Electrothermal 9200 melting point apparatus and are reported
uncorrected. Microanalyses (C, H, N) were carried out at the Uni-
rate acceleration is competitive20 with catalytic antibodies which
versity of St Andrews. Infra-red Spectra (IR) were recorded as KBr
catalyze similar reactions. However, the subtle interplay between
discs or thin films (PTFE plates) using a Perkin-Elmer Paragon
1000 spectrometer. 1H Nuclear Magnetic Resonance (NMR)
spectra were recorded on a Bruker Avance 400 (400.1 MHz),
a Varian Gemini 2000 (300.0 MHz),) or a Varian UNITYplus
500 (500.1 MHz) spectrometer using deuterated solvent as the
lock and the residual solvent as the internal reference in all
cases. 13C NMR spectra using the PENDANT sequence were
recorded on a Bruker Avance 300 (75.5 MHz) spectrometer.
All other 13C spectra were recorded on a Varian Gemini 2000
structure and reactivity is hard to predict even in systems in which
the structural variation is as simple as the examples described
here. Therefore, we expect that significant progress towards the
goal of simple recognition-based approaches to the acceleration
and control of chemical reactions will require the continued and
expanded application of diverse computational methods as well as
synthetic chemistry to the design of recognition-mediated reactive
supramolecular assemblies.
1
(75.5 MHz) spectrometer using composite pulse H decoupling.
All spectra were recorded at 298 K unless otherwise stated. All
Experimental section
coupling constants (J) are quoted to the nearest 0.1 Hz. In the
1
assignment of H NMR spectra the symbols br, s, d, t, q and
General procedures
m denote broad, singlet, doublet, triplet, quartet and multiplet,
respectively.
Chemicals and solvents were purchased from standard commercial
suppliers and were used as received unless otherwise stated.
Tetrahydrofuran (THF) was dried by heating to reflux in the pres-
ence of sodium/benzophenone under an N2 atmosphere and was
collected by distillation. Acetonitrile (CH3CN), dichloromethane
(DCM) and chloroform were dried by heating under reflux over
calcium hydride and distilled under N2. Acetone and triethylamine
were distilled over K2CO3.
Electron impact mass spectrometry (EIMS) and high-resolution
mass spectrometry (HRMS) were carried out on a VG AU-
TOSPEC mass spectrometer on a Micromass GCT orthogonal
acceleration time of flight mass spectrometer. Chemical Ionisation
Mass Spectrometry (CIMS) was carried out on a VG AUTOSPEC
instrument or on a Micromass GCT orthogonal acceleration
time of flight mass spectrometer. Electrospray mass spectrometry
(ESMS) and high-resolution mass spectrometry (HRMS) was
carried out on a Micromass LCT orthogonal time of flight mass
spectrometer.
Thin-layer chromatography (TLC) was performed on alu-
minium plates coated with Merck Kieselgel 60 F254. Developed
plates were air-dried and scrutinised under a UV lamp (366 nm),
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General procedure for kinetic experiments
Stock solutions were prepared by dissolving the appropriate
amount of reagent in CDCl3 using a 2 cm3 (2 cm3 0.02 cm3 ac-
curacy) volumetric flask. Masses of reagents were measured using
a Sartorius BP 211D balance ( 0.01 mg). Stock solutions were
pre-equilibrated to the appropriate temperature in a water bath
for a minimum of 30 minutes. Subsequent experimental samples,
suitable for kinetic experiments, were obtained by mixing a fixed
amount of appropriate stock solutions by using Hamilton gas-
tight syringes in a Wilmad 507PP or 528PP NMR tube, which was
then fitted with a polyethylene pressure cap to minimise solvent
evaporation. Reaction mixtures were monitored systematically
1
by 400 MHz H NMR spectroscopy over 17 hours. The extent
of reaction for kinetic experiments was determined using the
deconvolution tool available in 1D WINNMR (Version 6.2.0.0,
Bruker Daltonik GmbH, Germany, 2000). Kinetic simulation and
fitting of the resultant data to the appropriate kinetic models was
achieved using the parameter optimization mode of COPASI.21
Computational methods
All molecular mechanics calculations were performed on a Linux
workstation and the OPLS_2005 forcefield together with the
GB/SA solvation model for chloroform as implemented in
Macromodel (Version 9.5, Schro¨dinger Inc., 2008). Electronic
structure calculations were carried out using GAMESS22 running
on a Linux cluster. The 64-bit Linux version dated 24 Mar 2007
(Revision 6) was used in all calculations. The transition state for the
reaction between azide and maleimide was located by generation of
an initial guess using the linear synchronous transit (LST) method
and then refinement at the HF/6-31G(d) level of theory within
GAMESS. This model transition state was then used to construct
an initial guess for the transition state leading to the appropriate
cycloadduct. This guess was refined at the B3LYP/6-31G(d,p)
level of theory to a transition state structure possessing single
imaginary vibration that corresponded to the reaction coordinate.
Relative energies are computed using standard methods from
the electronic energies and the results of the vibrational analysis
performed on the structures.
Synthetic procedures
Preparative methods and characterisation data for compounds 1a,
1b, 2a, 2b, 3a, 3b, 4a, 4b, 8, 9 are provided in the ESI.†
1-([N-{6-Methyl-2-pyridyl}-benzamid-3-yl]methyl-4,6-dioxo-
3a,4,6a-tetrahydro-1H-pyrrolo [3,4-d][1,2,3]triazol-5-yl)-2-etha-
noic acid (5a). A solution of 2-maleimidoethanoic acid (2a,
78 mg, 0.5 mmol) and azide 1a (134 mg, 0.5 mmol) in dry
chloroform (5 mL) was heated at 50 ◦C for 24 hours. The resultant
precipitate was removed by filtration and washed thoroughly
with hexane before it was dried under high vacuum to afford
the desired triazoline 5a (163 mg, 77%) as a white solid. Mp =
249–251.5 ◦C; nmax (KBr) (cm-1) = 3470, 3063, 3002, 1703, 1583;
1H NMR (300 MHz, CDCl3) d = 12.12 (1H, bs, NH), 8.41 (1H,
Fig. 8 (a) Distribution of Near Attack Conformations (NACs) within
the sets of low energy conformations identified for (i) [1·2a], (ii) [1·3a] and
(iii) [1·4a]. Each circle represents a low energy conformation, NACs are
coloured black and non-NACs are coloured grey. (b) Correlation between
initial rate and the Boltzmann-weighted probability of the occurrence of
a NAC. The initial rate values are calculated from the rate constants and
equilibrium constants shown in Table 1, assume a starting concentration
of 25 mM and include contributions from both the bimolecular and recog-
nition-mediated pathways. A regression line is provided to guide the eye.
3
d, JHH = 8.5 Hz, ArCH), 8.02–8.00 (2H, m, ArCH), 7.89 (1H,
3
3
dd, JHH = 7.5 Hz, JHH = 7.5 Hz, ArCH), 7.51–7.48 (2H, m,
ArCH), 7.04 (1H, d, 3JHH = 7.5 Hz, ArCH), 5.80 (1H, d, 3JHH
=
3
10.5 Hz, CH), 5.42 (1H, d, JHH = 15.5 Hz, CHH), 4.73 (1H, d,
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3JHH = 15.5 Hz, CHH), 4.46 (1H, d, 3JHH = 17.0 Hz, CHH), 4.38
(1H, d, 3JHH = 10.5 Hz, CH), 4.12 (1H, d, 3JHH = 17.0 Hz, CHH),
2.55 (3H, s, CH3); 13C NMR (75 MHz, d6-DMSO) d = 172.1
(C), 170.8 (C), 168.0 (C), 165.8 (C), 156.8 (C), 151.7 (C), 138.7
(ArCH), 135.9 (C), 134.7 (C), 132.0 (ArCH), 129.0 (ArCH),
128.2 (ArCH), 127.8 (ArCH), 119.4 (ArCH), 111.9 (ArCH), 82.2
(CH), 57.8 (CH), 52.1 (CH2), 40.5 (CH2), 23.7 (CH3); LRMS
(ES): m/z (%) = 423 (100) [M + H]+; HRMS: found 445.1234
[M + Na]+, C20H18N6O5Na requires 445.1236.
Acknowledgements
We thank the EPSRC for financial support (Grant EP/
E017851/1). We thank Prof. G von Kiedrowski for providing us
with his SimFit program.
Notes and references
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to Enzyme Action, Third Edition; Springer-Verlag, New York, 1996;
(e) M. I. Page, Philos. Trans. R. Soc. Lond. B, 1991, 332, 149; (f) A. J.
Kirby, Phil. Trans. R. Soc. Lond. A, 1993, 345, 67; (g) F. M. Menger,
Acc. Chem. Res., 1993, 26, 206; (h) D. Philp, A. Robertson and A. J.
Sinclair, Chem. Soc. Rev, 2000, 29, 141.
1-([N-{6-Methyl-2-pyridyl}-benzamid-3-yl]methyl-4,6-dioxo-
3a,4,6a-tetrahydro-1H-pyrrolo
[3,4-d][1,2,3]triazol-5-yl)-3-pro-
panoic acid (6a). A solution of 3-maleimidopropanoic acid
(3a, 68 mg, 0.4 mmol) and azide 1a (107 mg, 0.4 mmol) in
dry chloroform (4 mL) was heated at 50 ◦C for 24 hours. The
precipitate formed was filtered off and was washed with hexane.
The residue so obtained was dried under high vacuum to give the
cycloadduct 6a (127 mg, 73%) as a white solid. Mp = 260–262 ◦C;
Elemental analysis calcd. (%) for C21H20N6O5: C, 57.79; H,
4.62; N, 19.26; Found: C, 57.78; H, 4.60; N, 19.42; nmax (KBr)
(cm-1) = 3483, 3210, 2992, 1711, 1682, 1556; 1H NMR (300 MHz,
d6-DMSO) d = 10.75 (1H, bs, NH), 8.03–7.98 (3H, m, ArCH),
7.72–7.70 (1H, m, ArCH), 7.53–7.51 (2H, m, ArCH), 7.04 (1H,
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3
3
d, JHH = 7.5 Hz, ArCH), 5.61 (1H, d, JHH = 11.0 Hz, CH),
5.24 (1H, d, 3JHH = 15.5 Hz, CHH), 4.87 (1H, d, 3JHH = 15.5 Hz,
3
3
CHH), 4.35 (1H, d, JHH = 11.0 Hz, CH), 3.58 (2H, t, JHH
=
7.5 Hz, CH2), 2.51 (2H, t, 3JHH = 7.5 Hz, CH2), 2.45 (3H, s, CH3);
13C NMR (75 MHz, d6-DMSO) d = 172.1 (C), 171.7 (C), 170.9
(C), 165.5 (C), 156.5 (C), 151.4 (C), 138.3 (ArCH), 135.7 (C),
134.4 (C), 131.6 (ArCH), 128.6 (ArCH), 127.9 (ArCH), 127.4
(ArCH), 119.0 (ArCH), 111.6 (ArCH), 81.9 (CH), 57.5 (CH),
51.7 (CH2), 34.4 (CH2), 31.1 (CH2), 23.5 (CH3); LRMS (ES):
m/z (%) = 437 (100) [M + H]+, 409 (15); HRMS: found 459.1385
[M + Na]+, C21H20N6O5Na requires 459.1393.
1-([N-{6-Methyl-2-pyridyl}-benzamid-3-yl]methyl-4,6-dioxo-
3a,4,6a-tetrahydro-1H-pyrrolo [3,4-d][1,2,3]triazol-5-yl)-4-n-but-
anoic acid (7a). A solution of 4-maleimidobutanoic acid (4a,
73 mg, 0.4 mmol) and azide 1a (107 mg, 0.4 mmol) in dry
chloroform (4 mL) was heated at 50 ◦C for 24 hours. The resultant
precipitate was removed by filtration and washed thoroughly with
hexane before it was dried under high vacuum to afford the desired
triazoline 6a (129 mg, 72%) as a white powder. Mp = 280.5–
282.5 ◦C; Elemental analysis calcd. (%) for C22H22N6O5: C, 58.66;
H, 4.92; N, 18.66; Found: C, 58.45; H, 4.97; N, 18.62; nmax (KBr)
(cm-1) = 3482, 3252, 3078, 1707, 1666, 1579; 1H NMR (300 MHz,
d6-DMSO) d = 10.77 (1H, bs, NH), 8.01–7.97 (3H, m, ArCH),
7.69–7.65 (1H, m, ArCH), 7.53–7.51 (2H, m, ArCH), 7.03 (1H,
3
3
d, JHH = 7.0 Hz, ArCH), 5.63 (1H, d, JHH = 11.0 Hz, CH),
5.25 (1H, d, 3JHH = 15.0 Hz, CHH), 4.85 (1H, d, 3JHH = 15.0 Hz,
3
CHH), 4.32 (1H, d, JHH = 11.0 Hz, CH), 3.45 (2H, m, CH2),
2.48 (3H, s, CH3), 2.18 (2H, m, CH2), 1.68 (2H, m, CH2); 13C
NMR (75 MHz, d6-DMSO) d = 173.7 (C), 172.6 (C), 171.5 (C),
165.6 (C), 156.6 (C), 151.5 (C), 138.5 (ArCH), 135.8 (C), 134.5
(C), 131.8 (ArCH), 128.7 (ArCH), 128.0 (ArCH), 127.6 (ArCH),
119.2 (ArCH), 111.7 (ArCH), 82.1 (CH), 57.7 (CH), 51.8 (CH2),
37.8 (CH2), 30.6 (CH2), 23.6 (CH3), 22.3 (CH2); LRMS (ES):
m/z (%) = 473 (85) [M + Na]+, 451 (36) [M + H]+, 445 (47), 423
(100); HRMS: found 473.1551 [M + Na]+, C22H22N6O5Na requires
473.1549.
5 (a) C. A. Booth and D. Philp, Tetrahedron Lett., 1998, 59, 6987; (b) H. L.
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Action, M. I. Page Ed., Elsevier, Amsterdam, 1984, p 1; (d) F. M.
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10 See ESI† for further details.
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18 We define a Near Attack Conformation (NAC) for the dipolar
cycloaddition as follows: the azide and the double bond of the
maleimide to be aligned correctly with respect to each other and both
of the two terminal nitrogen atoms of the azide must be located within
˚
4.0 A of the two carbon atoms of the alkene. Additionally, the hinge
angle (see Table 2) must be within 15◦ of the value calculated using
DFT.
11 The reaction does not reach 100% conversion during the time period in
which kinetic data was recorded. This observation is easily understood
when one considers that fact that the Kd for the [1a·2a] complex
is 9.1 mM. Therefore, after the reaction has reached around 65%
conversion, less than half of the remaining reagents are present as
the reactive [1a·2a] complex. The overall rate of formation of 4a slows
dramatically because the concentration of the reactive [1a·2a] complex
drops rapidly above 65% conversion.
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1678.
13 The kinetic effective molarity (kEM) is defined as the rate constant for
the intracomplex reaction divided by the rate constant for the corre-
sponding bimolecular reaction. The equilibrium or thermodynamic
effective molarity (tEM) is defined as the equilibrium constant for
the intracomplex reaction divided by the equilibrium constant for the
corresponding bimolecular reaction. In practice, this can be derived
from the kinetic data by expressing the equilibrium constant (Keq) as
a ratio of the rate constants for the appropriate forward and reverse
processes (kforward /kreverse).
14 Using System II as the baseline system results in both System I and
System III having apparently anomalous reactivity. It therefore seemed
appropriate to apply Occam’s Razor and assume that System II is the
anomalous point in this data set.
ꢀ
C
21 COPASI 4.1 (Build 22). Copyright 2005 by Pedro Mendes, Virginia
Tech Intellectual Properties, Inc. and EML Research, gGmbH.
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