C O M M U N I C A T I O N S
negative, eventually reaching an asymptote (Table 2, Figure S4).
Better H versus D differentiation occurs because the proton-transfer
step becomes slower with DMA radical-cation stabilization by the
electron-donating group. This translates into a larger KIEintra. In
the case of the intermolecular reaction, there is a negligible
difference in the isotope effect (KIEinter) as σ+ becomes more
negative (Table 2), indicating that the ET event is mostly irrevers-
ible. If there was a reversible preequilibrium ET followed by a
rate-limiting PT (peET/PT), one would expect to observe a KIEinter
profile that increases as σ+ becomes more positive.10g The flat
KIEinter profile indicates that the PT step has little influence on the
overall oxidation of R-DMA by 1H. In other words, the product
is determined by the (mostly irreversible) ET in the intermolecular
reaction, and not the PT step.
formed by Tolman and Itoh suggest that Cu2O2 complexes are cap-
able of performing HAT reactions from alkyl- and benzylamines.5,6
It therefore appears reasonable that as R-DMAs become harder
to oxidize, there is a shift in mechanism for oxidative N-dealkylation
by copper-dioxygen adduct 1Me2N from ET to HAT. By similar
criteria, a changeover in mechanism is also suggested for 1MeO (data
in Table 2) where the less easily oxidized CN-DMA reacts via a
rate-limiting HAT pathway and the other substrates (R ) H, Me,
MeO) are oxidized though an ET pathway.
In conclusion, we have shown that both HAT and ET mecha-
nisms occur for the oxidation of R-DMAs by dioxygen adducts
1R′. The reaction pathways are controlled by changes in the ease
of substrate one-electron oxidation and also the reduction potentials
of 1R′ (which are determined by ligand electronics).7,8 Coupled to
all of this will be changes in the pKa’s of the bis-µ-oxo-ligands in
1R′, with stronger donor ligands (R′ ) Me2N and MeO) expected
to produce better oxo bases (as H+ acceptors). Further investigations
are needed to sort out these details.
A rate-limiting ET is also supported by comparison of the
absolute values obtained for KIEintra versus KIEinter (see Scheme
3). This is a powerful mechanistic probe for distinguishing between
an ET or a HAT process.10e For a HAT mechanism, the KIEintra
should be nearly identical to the KIEinter.
10e This is because the rate
Acknowledgment. This work was supported by the NIH
(K.D.K., GM28962; J.S., GM 067447).
of HAT versus deuterium atom transfer will be proportional to the
C-H versus C-D bond dissociation enthalpies (BDEs). The
difference in BDEs should be approximately the same in the intra-
versus the intermolecular reaction. In the case of the ET process,
Supporting Information Available: Experimental details, KIE
profiles, and linear free-energy plots (PDF). This material is available
the expectation is that KIEinter < KIEintra.
10e This is because in the
intermolecular reaction the product will be determined by the ET
event, while in the intramolecular reaction the PT event can
potentially determine the product. For 1H, the values obtained for
KIEinter are all less than those obtained for KIEintra, which fully
supports a rate-limiting ET pathway for the oxidative N-dealkylation
of R-DMA (Table 2, Scheme 2a). Also, both KIEintra and KIEinter
values are relatively small in magnitude, in line with a rate-limiting
ET mechanism.17
References
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The situation is different in the case of 1Me2N. Competition
reactions do not show a strong R-group dependence, with krel
increasing only slightly as R is made more electron donating, Table
1. This is reflected in the linear free-energy correlation13 which
yielded a F value consistent with either ET or HAT (F ) -0.49, r2
) 0.98).15 The KIE profiles are largely inconclusive (Table 2),
showing no distinct pattern for either HAT or ET.13 In the case of
both KIEinter and KIEintra, what is observed is a general increase in
KIE as σ+ becomes more positive. Furthermore, the KIEs become
large in magnitude, consistent with a rate-limiting C-H bond
cleavage. This could occur through a switch in mechanism from
rate-limiting ET, to either a HAT or a peET/PT.10g
A comparison of the magnitudes of the KIEinter versus KIEintra
using the criterion mentioned above sheds further light on our
results. For R ) MeO and Me, the data suggest that 1Me2N oxidizes
R-DMA through a rate-limiting ET mechanism (KIEinter < KIEintra),
while for the less reducing R-DMAs (H and CN), oxidation
appears to occur through a rate-limiting HAT (KIEinter ≈ KIEintra).
This is strong evidence in favor of a HAT mechanism. In addition,
we favor the HAT over a peET/PT mechanism, as follows: In the
case of 1H, we established rate-limiting ET (vide supra). However,
1Me2N is a weaker one-electron oxidant,18 and the µ-oxo groups in
its Cu2O2 moiety should be more basic (as it possesses the stronger
donor ligand MePY2Me2N).7 Thus, one would expect slower electron
transfer and faster proton transfer in reactions of R-DMAs with
1Me2N relative to 1H; that is, ET would still be rate-limiting. Yet,
the KIE values and criteria indicate this is not the case. Thus, peET/
PT is unlikely, and we conclude that HAT is operative for H- and
CN-DMA in oxidations with 1Me2N. Other precedent comes from
(a) that P450 may operate in a similar manner (ET for easily
oxidized substrates and HAT for others),11 while (b) studies per-
(5) Itoh, S.; Taki, M.; Nakao, H.; Holland, P. L.; Tolman, W. B.; Que, L.,
Jr.; Fukuzumi, S. Angew. Chem., Int. Ed. 2000, 39, 398-400.
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Karlin, K. D. J. Am Chem. Soc. 2003, 125, 634.
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bis-µ-oxo isomer is present with more electron-donating R′)8 and rates of
THF and MeOH oxidation (>1500× increase in THF oxidation rate for
R′ ) Me2N vs R′ ) H).7
(10) (a) Karki, S. B.; Dinnocenzo, J. P.; Jones, J. P.; Korzekwa, K. R. J. Am.
Chem. Soc. 1995, 117, 3657-3664. (b) Goto, Y.; Watanabe, Y.; Fukuzumi,
S.; Jones, J. P.; Dinnocenzo, J. P. J. Am. Chem. Soc. 1998, 120, 10762-
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(12) Yields for R-MA are 1H, ∼60%; 1MeO, ∼80%; and 1Me2N, ∼90%.
(13) See Supporting Information.
(14) Yields are low, and 18-O incorporation in benzaldehyde varied from 36%
to 68%. We suspect the low yields are due to unfavorable steric interactions
between the dibenzyl groups and the Cu2(O2) core, and that the low isotope
incorporation is due to exchange of the carbonyl oxygen with residual
water in the solvent.13
(15) Johnson, C. D. The Hammett Equation; Cambridge University Press:
Cambridge, U.K., 1973.
(16) Going from a 10- to 100-fold excess of substrate did not change the relative
yields.
(17) All KIE values are within the semiclassical limit for ET and HAT reactions
at -80 °C (kH/kD could reach a maximum of 23.1).
(18) Shearer, J.; Karlin, K. D., unpublished results. For example, 1H will oxidize
certain ferrocene derivatives that 1Me2N will not.
JA0359409
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J. AM. CHEM. SOC. VOL. 125, NO. 42, 2003 12671