Selectivity in an Encapsulated Cycloaddition Reaction

Jian Chen and Julius Rebek,Jr.

Org. Lett. 2002, 4, 327-329

Tobe laboratoryShintaro Itano

Contents

• Introduction

Self-assembly

Cage-shaped molecular complexes

Previous work

Purpose of this work

• Results and discussion

1,3-Dipolar cycloaddition

1H NMR Measurement

Equilibrium constant and reaction rate

• Conclusion

Self-assembly• Self-assembly

the spontaneous and reversible organization of molecular units into ordered structures by non-covalent interactions.

Non-covalent interactions• hydrogen-bonding• dipole–dipole interaction• van der Waals interaction • metal–ligand coordination

O

O

OO

H

H

Lackinger, M.; Griessl, S.; Markert, T.; Jamitzky, F.; Heckl, W. M.J. Phys. Chem. B 2004, 108, 13652–13655.

Cage-shaped molecular complexes• Cage-shaped molecular complexes

The supramolecules formed by self-assembly via weak intermolecular interaction and having a cavity encapsulating guest molecules reversibly.

Yoshizawa, M.; Tamura, M.; Fujita, M. Science 2006, 312, 251–254.

2

Kang, J.; Rebek, J., Jr. Nature 1997, 385, 50-52.

Previous work: Capsule complex

The authors reported that the compound 1 dimerizes hydrogen bondings between edges. This cylindrical capsule 2 have a large cavity where two aromatic guest molecules can be accommodated.

1 2

CH3

Guest molecule

Heinz, T.; Rudkevich, D. M.; Rebek, J., Jr. Nature 1998, 394, 764-766.

Purpose of this workThe interior of molecular cage complexes becomes a space to stabilize reactive intermediates and to create new forms of stereoisomerism.

The authors investigated the ability of their capsule complex to accelerate a 1,3-dipolar cycloaddition with regioselectivity.

2

Accelerate?Regioselective?

1,3-Dipolar cycloaddition• 1,3-DipoleThe neutral molecules which have a resonance forms as foll.

• 1,3-Dipolar cycloadditionThe reaction between a 1,3-dipole and alkenes or alkynes to form a five-membered ring.

X Y Z X Y ZY ZX

X Y Z R1 R2X Y Z

R1 R2

YX Z

R1 R2

Guest moleculesThey chose phenylacetylene 3 and phenylazide 4 as the guest molecules. These compounds react to give a mixture of regioisomeric triazoles 5 and 6 equally in organic solvent.

N N

NN

NNH

H

N NN

H

N

H

N NN N

N

H

1,4-isomer 5

1,5-isomer 6

3 4

But, at ambient temperature the reaction rate is very slow. Rate constant k = 4.3 x 10-9 M-1 s-1

half life: several years (at 1 M each component)

1H NMR measurementAccelerating a 1,3-dipolar cycloaddition

t = 0

t = 1540 min

t = 4320 min

t = 8500 min

50 mM 25 mM

5 mM

2

in

CD3

D

CD3

D

D3C

D

N N NH

3 4

Mesitylene-d12

１ H NMR measurementRegioselectivity

・ Addition of DMF-d7 to

A: in mesitylene-d12

B:

in mesitylene-d12

C: in mesitylene-d12

N N

N

H

N N NH

3 4

Only 1,4-isomer was produced.

(●): 1,4-isomer’s peaks (▼): 1,5-isomer’s peaks

Selectivity of guest molecules

H

3

or

2

Triazole compound

N N N

H

H

N N N

3 + 7 + 2 3 + 8 + 2

The various encapsulated species

There are four encapsulated species in the solution; homocapsules 9 and 10, heterocapsule 11 and encapsulated 1,4-isomer 12.

NH resonance

１H NMR measurementAssignment of NH resonance

A: At t = 0 incubating

in mesitylene-d12

B: At t = 8500 min for incubating

in mesitylene-d12

C: in mesitylene-d12

N N NH

3 4

N N NH

3 4

(c) NH resonance of 11(d) NH resonance of 9(e) NH resonance of 10(f) NH resonance of 12(g) ortho-protons of the phenyl rings of encapsulated 1,4-isomer 5 in complex 12

NH resonance

１H NMR measurementAssignment of NH resonance

(c) NH resonance of 11(d) NH resonance of 9(e) NH resonance of 10(f) NH resonance of 12(g) ortho-protons of the phenyl rings of encapsulated 1,4-isomer 5 in complex 12

Equilibrium constant

KD = [11]2/[9][10]

KD: Equilibrium constant[x]: concentrations of x

・ Prediction by the statistical distribution

KD = 4・ Experimentally determined value

KD = 9 3

Experimentally observed value is larger than predicted value.　　　　　　　　　　　The space of 11 is better occupied or there is a weak attractive force between the occupants.

Prediction by the statistical distribution

HN

N

N

H

N

N

N

N

N

N

H H

N

N

N

10 11 9

1 : 2 : 1

KD = [11]2/[9][10] = 22/1 ・ 1 = 4

Reaction rate

v = kcat[3][4]v: reaction ratekcat: reaction rate constant

・ Observed initial reaction rate in 2 1.3 x 10-9 M s-1

・ Calculated reaction rate outside 2 5.4 x 10-12 M s-1

・ Volume of the cavity of 2 ~450 Å

・ Reactant concentration in 2 3.7 M

・ Estimated reaction rate in 2 ~6 x 10-8 M s-1

Reaction rate

v = kcat[3][4]v: reaction ratekcat: reaction rate constant

・ Estimated rate is larger than initial rate actually observed.

・ Reactants’ positions of 2 are not ideal for the transition state.

・ Reaction rate in 2 is 240 times faster than it outside 2.

Conclusion

• 1,3-Dipole cycloaddition was accelerated by the capsule complex 2.

• In the capsule complex 2, only 1,4-isomer was formed.

• Equilibrium constant KD was bigger than the prediction. It suggest that the space in 11 is better occupied or there is a weak attractive force between the occupants.

• The actual observed reaction rate is slower than the estimated rate, but 240 times faster than the calculated rate outside 2.