C O M M U N I C A T I O N S
of 28.3 kcal/mol. The generally accepted intramolecular [1,2] proton
shift in the Lu reaction is not possible owing to the very high
activation barrier of 39.6 kcal/mol required for this process.10
Calculations and experiments revealed that water assists this process
with an activation free energy of 7.7 kcal/mol. The discovery of
the catalytic role of a trace amount of water in the Lu reaction
suggests that a trace amount of water could also act as a catalyst
in some other “anhydrous” reactions involving [1,2] or [1,n] proton
shifts.12 The present study could have implications for other
organocatalytic reactions.8,13,14 Further mechanistic investigations
on allene chemistry and other organocatalytic reactions are in
progress.
Figure 1. The DFT computed energy surfaces of the Lu (3 + 2) reaction
(E1 ) E2 ) CO2Me, R ) CH3).9
Acknowledgment. We are indebted to generous financial
support from Peking University and the Natural Science Foundation
of China (Grants 9800445, 0240203, and 20672005).
Scheme 2. Isotopic Labeling Experiments (E ) CO2Me).11
Supporting Information Available: Computational and experi-
mental details. This material is available free of charge via the Internet
References
(1) Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 2906.
(2) For reviews on phosphine catalyzed reactions, see: (a) Lu, X.; Zhang,
C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. (b) Methot, J. L.; Roush, W.
R. AdV. Synth. Catal. 2004, 346, 1035.
(3) (a) Xu, Z.; Lu, X. Tetrahedron Lett. 1997, 38, 3461. (b) Xu, Z.; Lu, X.
J. Org. Chem. 1998, 63, 5031. (c) Xu, Z.; Lu, X. Tetrahedron Lett. 1999,
40, 549. (d) Zhu, X.-F.; Henry, C. E.; Kwon, O. Tetrahedron 2005, 61,
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(4) (a) Zhu, G.; Chen, Z.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. J. Am.
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with a ratio of 75:25. This indicates that the [1,2] proton transfer
from IN2 to IN3 is not a simple intramolecular process. We
speculated that the formation of 11 was due to the presence of a
trace amount of water in the reaction system. Therefore, we
computed a possible H2O assisted [1,2] proton shift process, which
is also given in Figure 1. Calculations showed that IN2 can form
a complex with water, and this complexation step is exothermic
by 7.6 kcal/mol and endergonic by 3.9 kcal/mol in benzene. Then
a proton transfer from water to the carbon atom connected with
the phosphorus atom requires only 0.4 kcal/mol activation free
energy in benzene. This step leads to the formation of another
complex 5, in which there is a strong attraction between the
hydroxyl anion and the PMe3 moiety. The subsequent step is the
abstraction of proton by hydroxyl anion with an activation free
energy of 7.7 kcal/mol in benzene, giving rise to another complex
6. Loss of water from complex 6 gives IN3, which can then easily
furnish final (3 + 2) cycloadduct 7 and PMe3 with an activation
free energy of 0.9 kcal/mol in benzene. The water assisted H-shift
process converting IN2 to the final product and PR3 requires only
7.7 kcal/mol activation free energy and is exergonic by 40.9 kcal/
mol.
We also ran the reaction between 8 and 9 in the presence of 1
equiv of H2O (II, Scheme 2). It was found that the ratio of 4-H
substituted product 11 was remarkably increased (from 25% to
88%). To rule out the possibility that the introduction of hydrogen
takes place between 1,3-dipole 3 and H2O, we conducted a control
experiment (Scheme 2). 1H NMR indicated that no deuterium and
hydrogen exchange between allenoate and water occurred, proving
that the hydrogen exchange happens after the formation of IN2
(Figure 1).11 These results further confirm that the intramolecular
[1,2] H-shift is impossible and a trace amount of water does play
a catalytic role in assisting the [1,2] proton transfer.
(5) (a) Du, Y.; Lu, X. J. Org. Chem. 2003, 68, 6463. (b) Wang, J.-C.; Krische,
M. J. Angew. Chem., Int. Ed. 2003, 42, 5855. (c) Pham, T. Q.; Pyne, S.
G.; Skelton, B. W.; White, A. H. J. Org. Chem. 2005, 70, 6369.
(6) (a) Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125, 4716. (b)
Tran, Y. S.; Kwon, O. Org. Lett. 2005, 7, 4289. (c) Wurz, R. P.; Fu, G.
C. J. Am. Chem. Soc. 2005, 127, 12234. (d) Evans, C. A.; Miller, S. J. J.
Am. Chem. Soc. 2003, 125, 12394. (e) Wang, L.-C.; Luis, A. L.; Agapiou,
K.; Jang, H.-Y.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 2402. (f)
Frank, S. A.; Mergott, A. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124,
2404.
(7) Only a few computational studies have been done to rationalize the
regiochemistry in the (3 + 2) cycloaddition step shown in Scheme 1,
see: (a) Pham, T. Q.; Pyne, S. G.; Skelton, B. W.; White, A. H.
Tetrahedron Lett. 2002, 43, 5953. (b) Ung, A. T.; Schafer, K.; Lindsay,
K. B.; Pyne, S. G.; Amornraksa, K.; Wouters, R.; Linden, I. V.; Biesmans,
I.; Lesage, J. A. S.; Skelton, B. W.; White, A. H. J. Org. Chem. 2002,
67, 227. (c) Dudding, T.; Kwon, O.; Mercier, E. Org. Lett. 2006, 8, 3643.
(8) For a recent thematic issue on organocatalysis, see: Houk, K. N.; List,
B. Acc. Chem. ReV. 2004, 137, 487 and references therein.
(9) Computational details and references are given in the Supporting Informa-
tion. The reported relative energies are free energies in benzene (∆Gsol),
and free energies (∆G298) and the zero-point energies corrected electronic
energies (∆E0), both in the gas phase, respectively. Even though for a bi-
or trimolecular process, the computed ∆Gsol values are somehow
overestimated (owing to the overestimation of the entropy contributions
in solution), the main purpose of such calculations is to appreciate how
solvent influences a reaction (such as on its reaction rate, regio- and
stereochemistry). A discussion of regiochemistry is given in the Supporting
Information.
(10) Calculations showed that tunneling effect for this step is negligible.9
(11) There is no deuterium and hydrogen exchange between the deuterated (3
+ 2) cycloadduct 10 and H2O in the presence of PPh3. For details of
these and other experiments, see the Supporting Information.
(12) [1,2] or [1,3] proton shift is proposed in many phosphine catalyzed
reactions: (a) Jung, C.-K.; Wang, J.-C.; Krische, M. J. J. Am. Chem. Soc.
2004, 126, 4118. (b) Kamijo, S.; Kanazawa, C.; Yamamoto, Y. J. Am.
Chem. Soc. 2005, 127, 9260. (c) Kuroda, H.; Tomita, I.; Endo, T. Org.
Lett. 2003, 5, 129. (d) Zhu, X.-F.; Schaffner, A.-P.; Li, R. C.; Kwon, O.
Org. Lett. 2005, 7, 2977. (e) Virieux, D.; Guillouzic, A.-F.; Cristau, H.-J.
Tetrahedron 2006, 62, 3710. (f) Fan, R.-H.; Hou, X.-L.; Dai, L.-X. J.
Org. Chem. 2004, 69, 689.
(13) Such water-assisted proton shifts have been found in many enzymatic
reactions, for a recent review, see: Blomberg, M. R. A.; Siegbahn, P. E.
M. Biochim. Biophys. Acta 2006, 1757, 969 and references therein.
(14) (a) Brogan, A. P.; Dickerson, T. J.; Janda, K. D. Angew. Chem., Int. Ed.
2006, 45, 8100. (b) Hayashi, Y. Angew. Chem., Int. Ed. 2006, 45, 8103
and references therein.
In conclusion, the Lu (3 + 2) cycloaddition has been investigated
with joint forces of computation and experiment. The formation of
a 1,3-dipole is slightly exothermic, and the subsequent (3 + 2)
cycloaddition is a stepwise process with an activation free energy
JA068215H
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