Supramolecular Control over Diels-Alder Reactivity by ... · PDF fileSupramolecular Control over Diels-Alder Reactivity by Encapsulation and Competitive Displacement ... Synthesis

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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

Electronic Supplementary Material (ESI) for Chemical ScienceThis journal is © The Royal Society of Chemistry 2011

S2

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.


S4

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


S5

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


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


Reduced Chi-Sqr

4.71482E-5


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.


S12

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.


S13

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


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


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

.


S14

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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Supramolecular Control over Diels-Alder Reactivity by ... · PDF fileSupramolecular Control over Diels-Alder Reactivity by Encapsulation and Competitive Displacement ... Synthesis