Selectivity in an Encapsulated Cycloaddition

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 = [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
10
1
11
:
2
9
:
1
KD = [11]2/[9][10] = 22/1・1 = 4
Reaction rate
v = kcat[3][4]
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[3][4]
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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