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Journal of the American Chemical Society
matters not whether there is a energy minimum prior to the TS undergoes a series of relevant bond vibrations, as would any inter-
1
2
3
4
because this in itself does not impact experimental observations or,
apparently, the qualitative behavior of trajectories.
mediate, and it can proceed from this structure in either forward or
backward directions, as true of any intermediate. The experimental
distinction fails, not because two mechanisms would give similar
observations, but because there is no experiment-impacting differ-
ence in the mechanisms.
A
H
B
A
H
B
central
TS
symmetric
real
antisymmetric
‡
5
6
7
8
9
A
H
B
A
H
B
late
TS
ASSOCIATED CONTENT
~symmetric
real
~antisymmetric
‡
Supporting Information
A
H–B
A
H–B
Complete descriptions of experimental procedures, calculations,
and structures. This material is available free of charge via the
TS
here
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
~symmetric
‡
H–B stretch
real
Figure 8. Changes in the normal modes as the transition state gets later
for general acid-base reaction.
AUTHOR INFORMATION
The involvement of an intermediate in acid-base catalysis would
still be recognizable if it is sufficiently long-lived to be diffusible.
When a reaction involves a long-lived intermediate after a proton
transfer, the concentration of that intermediate must reflect the
overall acidity of the medium. The reaction rate then does not
depend on the concentration of acid or base catalysts at a constant
buffered medium acidity. This is the classic test for general versus
specific acid-base catalysis. However, it should be recognized that
in a great many cases, such as intramolecular catalysis and enzymat-
ic catalysis, this test cannot be applied. The observation of a low or
inverse H/D KIE by itself cannot establish that there is an interme-
diate. The same would be true of the results of substituent effect
studies.
Corresponding Author
singleton@chem.tamu.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We thank the NIH (Grant GM-45617) for financial support.
REFERENCES
CONCLUSIONS
(1) (a) Kirby, A. J. in Hydrogen-Transfer Reactions; Hynes, J. T.; Klin-
man, J. P.; Limbach, H. –H.; Schowen, R. L., Eds.; Wiley-VCH: Weinheim,
2007; pp. 975-1012. (b) Jencks, W. P. Chem Rev. 1972, 72, 705-718.
(2) Jencks, W. P. J. Am. Chem. Soc. 1972, 94, 4731-4732.
(3) Reactions can be on the borderline between mechanisms in other
ways. For example, in stepwise mechanisms the proton transfer and the
heavy-atom motions may still be interdependent, so that the intermediate is
not well described as being purely in the “corner” of the More-O’Ferrall
Jencks diagram. Also, reactions may always proceed by mixtures of mecha-
nisms.
From the perspective that there is no stable intermediate along
the reaction coordinate, the decarboxylation of the β-ketoacid 1 is
certainly a concerted reaction. However, the proton-transfer and
heavy-atom bonding changes are separated in time, so separated
that a species along the reaction coordinate can undergo many
bond vibrations before the heavy-atom motion can complete the
reaction. This is unlike the ordinary asynchrony seen in most con-
certed multibond reactions, where one bonding change leads but
overlaps with another. The bonding-change overlap with ordinary
asynchrony is detectable experimentally, for example in asynchro-
(4) Hammes-Schiffer, S.; Soudackov, A. V. J. Phys. Chem. B 2008, 112,
14108-14123.
35
nous Diels-Alder reactions.
(5) (a) Pedersen, K. J. J. Am. Chem. Soc. 1929, 51, 2098-2107. (b) Ped-
erson, K. J. J. Phys. Chem. 1934, 38, 559-571. (c) Westheimer, F. H.; Jones,
W. A. J. Am. Chem. Soc. 1941, 63, 3283-3286. (d) Swain, C. G.; Bader, R. F.
W.; Estrve, R. M. Jr.; Griffin, R. N. J. Am. Chem. Soc. 1961, 83, 1951-1955.
(e) Brower, K. R.; Gay, B.; Konkol, T. L. J. Am. Chem. Soc. 1966, 88, 1681-
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(g) Bigley, D. B.; Thurman, J. C. J. Chem. Soc. B 1968, 436-440. (h) Hay, R.
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T.; Sharkawi, E. E. J. Org. Chem. 1972, 37, 85-87.
(6) (a) Wood, A. Trans. Faraday Soc. 1964, 60, 1263-1267. (b) Wood,
A. Trans. Faraday Soc. 1966, 62, 1231-1235. (c) It should be noted that the
13C isotope effects in (a) and the 14C isotope effects in (b) for the same
reaction are inconsistent with each other.
(7) Logue, M. W.; Pollack, R. M.; Vitullo, V. P. J. Am. Chem. Soc. 1975,
97, 6868-6869.
(8) Guthrie, J. P. Biorg. Chem. 2002, 30, 32-52.
(9) Bach, R. D.; Canepa, C. J. Org. Chem. 1996, 61, 6346-6353.
(10) Singleton, D. A.; Thomas, A. A. J. Am. Chem. Soc. 1995, 117, 9357-
9358.
(11) Zheng, J.; Zhang, S.; Corchado, J. C.; Chuang, Y.-Y.; Coitino, E.
L.; Ellingson, B. A.; Zheng, J.; Truhlar, D. G. GAUSSRATE, version 2009-A
University of Minnesota: Minneapolis, MN, 2010.
Here, it is not clear to us that any experimental observation can
even in principle distinguish the concerted decarboxylation from a
stepwise process. The reaction dynamics in fact emulate a stepwise
mechanism, despite their short duration. This is perhaps seen most
poignantly in the deep recrossing seen for trajectories passing the
transition state in the carboxylation direction. The carboxylation
“step” occurs but the structure obtained, a dynamic intermediate in
the area of 6, reverts to starting material when the second proton
transfer “step” fails. The proton transfer is barrierless, but it takes
time, and in the mean time the trajectory recrosses. A barrierless
stage of a concerted reaction is having the same effect here as would
a barriered step in a stepwise mechanism.
On the border between general and specific acid-base catalysis,
the delocalization of protons (or, quasiclassically, their fast motion)
enforces an overlap in their mechanisms. Experimental observa-
tions such as the H/D KIE then become unable to distinguish
whether there is an intermediate. However, this is not just a matter
of the isotope effect decreasing because a late TS has a nearly com-
plete proton transfer, as in the ideas of Westheimer. Rather, the
proton transfer is entirely complete and the dynamic intermediate
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