S1
Supporting information for:
Supramolecular Control over Diels-Alder Reactivity by
Encapsulation and Competitive Displacement
Maarten M. J. Smulders and Jonathan R. Nitschke
Department of Chemistry
University of Cambridge
Lensfield Road, Cambridge CB2 1EW (UK)
E-mail: [email protected]
Contents
1. Experimental ................................................................................................................ S2
1.1. General ................................................................................................................. S2
1.2. Synthesis ............................................................................................................... S2
1.3. Kinetic experiments .............................................................................................. S2
2. Supporting graphs and Figures ..................................................................................... S4
2.1. NOESY Spectrum ................................................................................................. S4
2.2. Ka determination for furan ..................................................................................... S4
2.3. Furan + Maleimide in D2O: control reaction .......................................................... S7
2.4. Furan release kinetics at 25 °C .............................................................................. S8
2.5. Diels-Alder kinetics at 25 °C ............................................................................... S10
2.6. Furan release kinetics at 5 °C .............................................................................. S11
2.7. Diels-Alder kinetics at 5 °C ................................................................................. S13
3. References ................................................................................................................. S14
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1. Experimental
1.1. General
All reagents and solvents were purchased from commercial sources and used as supplied.
NMR spectra were recorded on a Bruker Avance DPX400 spectrometer; δH values are
reported relative to the internal standard tBuOH (δH = 1.24 ppm). Mass spectra were provided
by the EPSRC National MS Service Centre at Swansea and were acquired on a Thermofisher
LTQ Orbitrap XL.
1.2. Synthesis
Cage 1 was prepared as the tetramethylammonium salt according to the method reported
earlier by our group.S1
1.3. Kinetic experiments
A J-Young NMR tube was loaded with 0.45 mL of a 4.4 × 10‒3
M solution of 1 dissolved in
D2O. To this NMR tube was added 50 µL of a 3.6 × 10‒2
M of furan in D2O. After addition,
the concentration of 1 was 4.0 × 10‒3
M, while the concentration of furan was 3.6 × 10‒3
M
(i.e. 0.9 equiv. furan per 1). This solution was left to equilibrate overnight at 50 °C. For the
room temperature experiments 3.20 mg (3.3 mmol) maleimide was added to the solution,
while for the experiments at 5 °C 9.71 mg (10 mmol) maleimide was added. To initiate the
reaction 10 µL of benzene-d6 added and the solution was kept at the appropriate temperature.
For the control reaction, the reaction was started directly after the addition of maleimide (i.e.
no benzene-d6 was added).
1.3.1 Monitoring exit kinetics
As hosts with a different guest are in slow exchange on the NMR timescale, simple
integration of the imine peaks corresponding to the empty host 1 and its host-guest complexes
allowed for the determination of these species’ relative proportions as a function of time.
Table S1 gives the imine peak’s chemical shift for each different host species.
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Table S1 Chemical shifts for the imine peaks of cage 1 in different host-guest states.
Guest Chemical shift / ppm
Furan 9.65
Benzene 10.26
Empty 9.35
1.3.2 Monitoring Diels-Alder kinetics
At room temperature or below, the reaction between furan and maleimide leads primarily to
the formation of the kinetic endo product.S2
Hence, the progress of the Diels-Alder reaction
was monitored by following the formation of this product. To quantify the yield of the
reaction, the integrated intensity of the endo product peaks was compared to the internal
standard’s peak. The internal standard used was tBuOH at a concentration of 5.3 × 10‒3
M.
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2. Supporting graphs and Figures
2.1. NOESY Spectrum
Fig. S1 NOESY spectrum of furan⊂1 (4.0 × 10–3
M) in D2O. The highlighted cross peaks
indicate the NOE interactions between the two furan proton resonances (6.30 and 5.62 ppm)
and the inwardly-oriented protons on the cage’s ligand (f (7.20 ppm) and h (5.96 ppm); see
Scheme 1 in the main text for assignment).
2.2. Ka determination for furan
To 5 mL of a 1.0 × 10–3
M solution of 1 in D2O was added 4.0 µL of furan, resulting in a total
furan concentration of 1.1 × 10–2
M. The solution was allowed to equilibrate overnight at 50
°C. Aliquots of this solution were added to 0.50 mL of a 1.0 × 10–3
M solution of 1 in D2O.
After each addition the mixture was equilibrated for 6 hours, after which the 1H NMR
spectrum was recorded (Fig S2). The degree of encapsulation, [HG]/[H]0, was determined by
comparison of the integrals of the imine peaks of empty 1 (at 9.35 ppm) and furan⊂1 (at 9.65
ppm). Plotting the degree of encapsulation as a function of the total concentration of furan
yielded a binding isotherm (Fig S3), which was fitted using a 1:1 binding model we
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previously derived.S3
In this model the degree of encapsulation, [HG]/[H]0, is given by Eq
S1:
0
00
22
0000
0 ][2
][][4)]][]([1[)]][]([1[
][
][
HK
GHKGHKGHK
H
HG −++−++
= (S1)
in which:
K = Binding constant, in M–1
;
[H]0 = Total host concentration, in M;
[G]0 = Total guest concentration, in M.
10 9 8 7 6 5 4 3 2 1
Chemical Shift / ppm
0 eq. 0.13 eq. 0.43 eq. 0.59 eq. 0.80 eq. 1.08 eq. 1.26 eq. 1.38 eq. 1.65 eq. 2.28 eq. 4.65 eq. 6.51 eq.
Fig. S2 1H NMR spectra for 1 in D2O in the presence of increasing equivalents of furan.
Total concentration of 1: 1.0 × 10–3
M.
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0.000 0.002 0.004 0.006
0.0
0.2
0.4
0.6
0.8
1.0
[HG
]/[H
] 0 / M
[Furan]0 / M
ModelOnetoOneBindingREAL (User)
Equation
y = Y0+DY*((Ka*(P+x)+1)-sqrt(((Ka*(P+x)+1)^2)-4*Ka*Ka*P*x))/(2*Ka*P)
Reduced Chi-Sqr6.51693E-4
Adj. R-Square 0.99429Value Standard Error
B
Ka 8254.8754 748.01278P 1E-3 0Y0 0 0DY 1 0
Fig. S3 Degree of encapsulation, [HG]/[H]0, as a function of the total concentration of furan
and corresponding fit of the data to the 1:1 binding model, revealing a binding constant of 8.3
± 0.7 × 103 M
–1.
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2.3. Furan + Maleimide in D2O: control reaction
To 900 µL of a solution of maleimide in D2O (4.2 × 10–2
M) was added 100 µL of a solution
of furan in D2O (2.3 × 10–2
M). After addition, the concentration of maleimide had become
3.7 × 10–2
M, while the concentration of furan had become 2.3 × 10–3
M. The progress of the
Diels-Alder reaction was monitored by 1H NMR spectroscopy by following the
disappearance of the resonances of the furan (at 7.55 and 6.49 ppm).
8 7 6 5 4 3
t = 20 min t = 50 min t = 200 min t = 225 min t = 300 min t = 1265 min t = 1425 min t = 1670 min t = 2715 min
Chemical Shift / ppm
Fig. S4 1H NMR spectra showing the progress of the Diels-Alder reaction between furan
(resonances at 7.55 and 6.49 ppm) and maleimide (6.79 ppm) in D2O. The resonances of the
endo product appear at 6.57, 5.40 and 3.73 ppm, while those of the exo product appear at
6.61, 5.32 and 3.12 ppm.
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0 500 1000 1500 2000 25000.0
0.2
0.4
0.6
0.8
1.0
[Fur
an]/[
Fura
n]0 /
-
Time / min
Model ExpDec1
Equationy = A1*exp(-x/t1) + y0
Reduced Chi-Sqr
2.47586E-4
Adj. R-Square 0.99814Value Standard Error
Gy0 0.07639 0.01073A1 0.93667 0.01447t1 470.46704 24.58263
Fig. S5 Progress of the Diels-Alder reaction between furan and maleimide. The consumption
of furan could be fitted with a mono-exponential decay function, confirming the validity of
pseudo-first order conditions.
2.4. Furan release kinetics at 25 °C
0 50 100 150 200 2500.0
0.2
0.4
0.6
0.8
1.0 Furan 1 Empty 1
Frac
tion
of H
ost /
-
Time / Hr
Model ExpDec1Equation y = A1*exp(-x/t1) + y0Reduced Chi-Sqr 3.80714E-4 3.80714E-4Adj. R-Square 0.99389 0.99389
Value Standard ErrorFuran y0 0.10873 0.01355Furan A1 0.71012 0.0172Furan t1 60.59724 4.18056Empty y0 0.89127 0.01355Empty A1 -0.71012 0.0172Empty t1 60.59724 4.18056
Fig. S6 Release kinetics of furan from cage 1 at 25 °C in the absence of benzene (i.e. the
control reaction). The release of furan was fitted to a mono-exponential decay function,
resulting in a first-order rate constant (inverse of the life time t1) of 1.65 ± 0.11 × 10–2
h–1
.
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0 50 100 150 2000.0
0.2
0.4
0.6
0.8
1.0
Benzene 1 Furan 1Empty 1
Frac
tion
of H
ost /
-
Time / Hr
Fig. S7 Release kinetics of furan from cage 1 at 25 °C. At t = 0 benzene was added to the
sample, leading to an almost instant release of furan from the cage and encapsulation of
benzene. As the release of furan was too fast to be monitored, it could not be fitted to a
mono-exponential decay function. The dotted line is a simulated trace assuming a first-order
rate constant of 10 h–1
, showing that the release of furan upon addition of benzene is at least
three orders of magnitude faster than in the control reaction.
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2.5. Diels-Alder kinetics at 25 °C
0 50 100 150 200 250
0.0
0.2
0.4
0.6
0.8
1.0 Benzene Control
Prog
ress
of D
-A R
eact
ion
/ -
Time / Hr
Model ExpDec1Equation y = A1*exp(-x/t1) + y0Reduced Chi 0.0023 0.00267Adj. R-Squar 0.97712 0.97537
Value Standard ErrControl y0 0.9865 0.03772Control A1 -1.01389 0.04947Control t1 66.91479 8.64006Benzene y0 1.02536 0.03983Benzene A1 -1.00247 0.05676Benzene t1 49.18072 7.03383
Fig. S8 Progress of the Diels-Alder reaction between furan and maleimide at 25 °C. The
formation of the Diels-Alder product was fitted to a mono-exponential growth function,
resulting in a rate constant (inverse of the life time t1) of 1.49 ± 0.19 × 10–2
h–1
for the control
reaction and 2.03 ± 0.29 × 10–2
h–1
for the benzene-initiated reaction. This means that at 25
°C the benzene-initiated Diels-Alder reaction is 36% faster compared to the control reaction.
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2.6. Furan release kinetics at 5 °C
0 50 100 150 2000.0
0.2
0.4
0.6
0.8
1.0 Furan 1 Empty 1
Frac
tion
of H
ost /
-
Time / Hr
Model ExpDec1
Equationy = A1*exp(-x/t1) + y0
Reduced Chi-Sqr
4.71482E-5
Adj. R-Square 0.99718Value Standard Error
Control_Furany0 0 0A1 0.80237 0.00442t1 334.19914 6.09087
Fig. S9 Release kinetics of furan from cage 1 at 5 °C in the absence of benzene (i.e. the
control reaction). The release of furan was fitted to a mono-exponential decay function,
resulting in a first-order rate constant (inverse of the life time t1) of 2.99 ± 0.05 × 10–3
h–1
.
0 50 100 150 2000.0
0.2
0.4
0.6
0.8
1.0
Benzene 1 Furan 1 Empty 1
Frac
tion
of H
ost /
-
Time / Hr
Fig. S10 Release kinetics of furan from cage 1 at 5 °C. At t = 0 benzene was added to the
sample, leading to an almost instant release of furan from the cage and encapsulation of
benzene.
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0 50 100 150 2000.0
0.2
0.4
0.6
0.8
1.0
Benzene 1 Furan 1 Empty 1
Frac
tion
of H
ost /
-
Time / Hr
Addition of Benzene-d6
Fig. S11 Release kinetics of furan from cage 1 at 5 °C. At t = 70 h benzene was added to the
sample, followed by an almost instant release of furan from the cage and encapsulation of
benzene.
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2.7. Diels-Alder kinetics at 5 °C
0 50 100 150 200 250
0.0
0.2
0.4
0.6
0.8
1.0
Addition of Benzene-d6
Control Benzene Delayed Addition
Prog
ress
of D
-A R
eact
ion
/ -
Time / Hr
Model ExpDec1
Equationy = A1*exp(-x/t1) + y0
Reduced Chi-Sqr
6.60896E-4 7.01886E-4
Adj. R-Square 0.97855 0.99289Value Standard Error
Blancoy0 1 0A1 -1 0t1 317.969 10.95092
Benzeney0 1 0A1 -1 0t1 12.89043 0.6981
ModelExpDec_Offset (User)
Equationy = A1*exp(-(x-t0)/t1) + y0
Reduced Chi-Sqr
0.0012
Adj. R-Square 0.98511Value Standard Error
Delayed
A1 -1 0t1 20.1867 1.96491t0 65.5783 1.07181y0 1 0
Fig. S12 Progress of the Diels-Alder reaction between furan and maleimide at 5 °C. The
formation of the Diels-Alder product was fitted to a mono-exponential growth function,
resulting in a rate constant (the inverse of the life time t1) of 3.14 ± 0.11 × 10–3
h–1
for the
control reaction and 7.76 ± 0.42 × 10–2
h–1
for the benzene-initiated reaction. This means that
at 5 °C the benzene-initiated Diels-Alder reaction is 25 times faster compared to the control
reaction. For the experiment where the benzene was added at t = 70 h, the following data
points were fitted to a mono-exponential growth function, resulting in a rate constant (the
inverse of the life time t1) of 4.95 ± 0.48 × 10–2
h–1
.
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3. References
S1. I. A. Riddell, M. M. J. Smulders, J. K. Clegg and J. R. Nitschke, Chem. Commun.,
2011, 47, 457.
S2. H. Kwart and I. Burchuk, J. Am. Chem. Soc., 1952, 74, 3094.
S3. Y. R. Hristova, M. M. J. Smulders, J. K. Clegg, B. Breiner and J. R. Nitschke, Chem.
Sci., 2011, 2, 638.
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