Selectivity in an Encapsulated Cycloaddition Reaction Jian Chen and Julius Rebek,Jr. Org. Lett. 2002, 4, 327-329 Tobe laboratory Shintaro 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 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. 2 Yoshizawa, M.; Tamura, M.; Fujita, M. Science 2006, 312, 251–254. 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. Guest molecule 1 2 Heinz, T.; Rudkevich, D. M.; Rebek, J., Jr. Nature 1998, 394, 764-766. Purpose of this work The 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-Dipole The neutral molecules which have a resonance forms as foll. • 1,3-Dipolar cycloaddition The reaction between a 1,3-dipole and alkenes or alkynes to form a five-membered ring. Guest molecules They 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. 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 measurement Accelerating a 1,3-dipolar cycloaddition t=0 t = 1540 min 2 50 mM 25 mM t = 4320 min 5 mM in Mesitylene-d12 t = 8500 min １H NMR measurement Regioselectivity ・Addition of DMF-d7 to A: in mesitylene-d12 B: in mesitylene-d12 C: in mesitylene-d12 (●): 1,4-isomer’s peaks (▼): 1,5-isomer’s peaks Only 1,4-isomer was produced. Selectivity of guest molecules Triazole compound or 2 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. １H NMR measurement Assignment 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 (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 measurement Assignment 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 NH resonance Equilibrium constant KD = 2/ 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 10 1 11 : 2 9 : 1 KD = 2/ = 22/1・1 = 4 Reaction rate v = kcat v: reaction rate kcat: reaction rate constant ・Volume of the cavity of 2 ~450 Å ・Observed initial reaction rate in 2 1.3 x 10-9 M s-1 ・Reactant concentration in 2 3.7 M ・Calculated reaction rate outside 2 5.4 x 10-12 M s-1 ・Estimated reaction rate in 2 ~6 x 10-8 M s-1 Reaction rate v = kcat v: reaction rate kcat: reaction rate constant ・Estimated rate is larger than initial rate ・Reaction rate in 2 is 240 times actually observed. faster than it outside 2. ・Reactants’ positions of 2 are not ideal for the transition state. 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.
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