A two-state reactivity model explains unusual kinetic isotope effect patterns in C-H bond cleavage by nonheme oxoiron(IV) complexes

Article abstract of DOI:10.1002/anie.200804029

It's in the bond: The cleavage of C H bonds by two related oxoiron(IV) complexes shows a range of kinetic isotope effect (KIE) values that exhibit an unusual dependence on the C H bond strength. Large nonclassical KIEs are observed for bond strengths belo

Full text of DOI:10.1002/anie.200804029

Angewandte
Chemie
DOI: 10.1002/anie.200804029
Isotope Effects
ATwo-State Reactivity Model Explains Unusual Kinetic Isotope Effect
À
Patterns in C H Bond Cleavage by Nonheme Oxoiron(IV)
Complexes**
Eric J. Klinker, Sason Shaik,* Hajime Hirao, and Lawrence Que, Jr.*
À
The surging field of nonheme iron chemistry has led to the
identification of a variety of iron(IV) oxo intermediates,
which perform oxidative processes such as hydrogen-atom
abstraction (H-abstraction) and oxo-transfer reactions with a
variety of molecules.[1–3] The advent of both enzymatic and
synthetic examples has revealed in turn some puzzles of
fundamental importance in mechanistic bioinorganic chemis-
try. Thus, whereas the known enzymatic species, for example,
in taurine/a-ketoglutarate dioxygenase (TauD),[4] have been
shown by Mꢀssbauer analyses to possess a ground state with a
quintet spin (Q) quantum number (S = 2), all except one of
the synthetic iron oxo species have been shown by exper-
imental means to possess triplet (T) ground states (S = 1) and
low-lying quintet states.[2,3] Nevertheless, some of the reac-
tivity patterns of the enzymatic and synthetic reagents are still
similar. For example, use of deuterated taurine in reactions
with TauD has revealed a kinetic isotope effect (KIE) of
approximately 37 for the decay of the iron oxo species.[4,5] The
synthetic compounds [FeIV(O)(N4Py)]2+ (1, N4Py = N,N-
states of 1 and 2 must somehow be involved in C H
activation.[2,3] If this is indeed the case, the reactions of the
synthetic reagents should involve two-state reactivity
(TSR),[8] in which both the triplet and quintet states contrib-
ute to the overall bond activation. Subsequent calculations[9]
indeed showed the probable involvement of TSR, since the
excited quintet state lies close to the triplet ground state and
the triplet surface eventually crosses over to the quintet
surface as the reaction progressed.
The insight provided by the TSR model was utilized
recently to rationalize the counterintuitive results observed
when the series of [FeIV(O)TMC(X)]z+ reagents (TMC =
tetra(N-methyl)cyclam, X = MeCN, trifluoroacetate (TF),
N3, or thiolate (SR)) led to opposing reactivity trends in H-
atom abstraction versus oxo-transfer reactions.[10] A system-
atic study of the series demonstrated that the oxo-transfer
capability of [FeIV(O)TMC(X)]n+ towards PPh3 increased in
the order X = SR < N3 < TF < MeCN, but the reactivity in H-
abstraction from 9,10-dihydroanthracene (DHA) decreased
in the order L = SR > N3 > TF > MeCN, which is in the
opposite direction. Thus, the [FeIV(O)TMC(X)]n+ oxidant
exhibited a dichotomic reactivity pattern: in the oxo-transfer
series it behaved as an electrophile whereby electron-releas-
ing anionic ligands X diminished the oxidative reactivity,
bis(2-pyridylmethyl)-N-bis(2-pyridyl)methylamine)
and
[FeIV(O)(BnTPEN)]2+(2,
BnTPEN = N-benzyl-N,N’,N’-
tris(2-pyridylmethyl)-1,2-diaminoethane),[6,7] despite possess-
ing triplet ground states, also exhibit large KIE values
(greater than 30) for H-abstraction from ethylbenzene
versus [D10]ethylbenzene.[6] A primary isotope effect supports
À
whereas in the C H activation series the best H-abstractor
À
a rate-determining C H bond cleavage. Furthermore, the
was the poorest oxidant with X = SR. The TSR concepts
showed that the involvement of the quintet state in the
reaction is the origin of these unusual reactivity patterns.
Further validation of the TSR model was obtained from a
more recent study on the corresponding [RuIV(O)TMC(X)]n+
oxidants, in which the quintet state is too high to be able to
participate in the reaction;[11] this study revealed that the two
reaction series exhibit precisely the same trends, which is
indicative of the sole involvement of the triplet state.
We wished to investigate if it was possible to more directly
interrogate the TSR concept by experimental means. A set of
criteria has been suggested that could be used to probe the
feasibility of a TSR system.[9a,10b] It was hypothesized that the
crossover from triplet to quintet states provides a tunneling-
like pathway that may be probed by an investigation of KIEs.
Thus, the TSR model assumes that triplet processes will
exhibit nearly classical values for kH/kD. For the quintet
process, or in a process where spin crossover from triplet to
quintet occurs, values for kH/kD that are typical of a tunneling
mechanism were predicted. However, the critical prediction
observation of such large KIEs for both the enzymatic and
model system reactions suggests that the reactivity of 1 and 2
is analogous to the enzyme, namely, that the excited quintet
[*] Prof. Dr. S. Shaik, Dr. H. Hirao
Department of Organic Chemistry and
The Lise Meitner-Minerva Center for
Computational Quantum Chemistry
The Hebrew University, Jerusalem, 91904 (Israel)
Fax: (+972)2-658-4680
Dr. E. J. Klinker, Prof. Dr. L. Que, Jr.
Department of Chemistry and Center for Metals in Biocatalysis,
University of Minnesota
Minneapolis, MN 55455 (USA)
Fax: (+1)612-624-7029
[**] We thank the National Institutes of Health (GM-33162 to L.Q.), the
University of Minnesota Graduate School (dissertation fellowship to
E.J.K.), the Ministry of Education and Research within the Frame-
work of the German–Israeli Project Cooperation (DIP; to S.S.), and
the JSPS Postdoctoral Fellowship for Research Abroad (to H.H.) for
support of this research.
À
was that the KIE should vary with the strength of the C H
bond between the classical (less than ca. 7) and nonclassical
(much greater than 7) limits. Herein, we report the test of this
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804029.
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working hypothesis and present a study of hydrocarbon
mesitylporphinate dianion), which range from 28 at 238C to
360 at À308C (DEa = 7 kcalmolÀ1; AH/AD = 0.025 (lnAH = 8.6
and lnAD = 4.9)).[14]
oxidation by 1 and 2. Our results serve as a demonstration of
the complementary roles that experiment and theory can play
in a mechanistic investigation.
A determination of the KIEs for the oxidation of a series
À
Previous studies on the reactions of 1 and 2 with ethyl-
benzene (PhEt) and [D10]PhEt showed high, nonclassical
kH/kD values of 30 and 50, respectively, for reactions
performed at 258C.[6] KIEs of this magnitude are often
associated with a mechanism that involves hydrogen-atom
tunneling. However, there are more stringent criteria to
invoke a tunneling model, which may be established from an
evaluation of the temperature dependence of the reaction
rates by analysis of their Arrhenius plots. Features represen-
tative of a reaction that involves hydrogen-atom tunneling
include a difference in energies of activation (EaHÀEaD) for
the systems greater than the zero-point energy differences
of substrates with a range of C H bond dissociation energies
À
(D(C H)) by 1 and 2 revealed a rather surprising pattern
(Figure 2; these experiments were carried out at 408C to
À
À
(DZPE) of the reactant C H and C D bonds and a ratio of
the Arrhenius prefactors that yields AH/AD to be less than
0.7.[12,13] Figure 1 shows the temperature dependences of the
À
Figure 2. Plot of KIE values versus D(C H) for 1 (filled circles) and 2
(open squares). The filled square represents the KIE value for MeCN
as estimated from the t1/2 value of 2 in MeCN and [D3]MeCN. The
shaded area represents KIE values within the semiclassical limit, while
the dashed lines highlight the rising and falling trends of the KIEs as a
À
function of the C H bond dissociation energy.
À
shorten reaction times). For substrates with D(C H) less than
93 kcalmolÀ1 such as dihydroanthracene (DHA), Ph3CH
(TPM), toluene (PhMe), and THF, the KIEs are nonclassical,
as reported earlier for PhEt,[6] while the KIEs for substrates
À
with stronger C H bonds such as MeOH, CH2Cl2, and
Figure 1. Temperature dependence of the rate constants for the
reactions of 2 with PhEt (squares) and [D10]PhEt (triangles).
cyclohexane were smaller (4–8) and fell into the classical
range. A value of 4 was also found for the slow decay of 2 in
MeCN and [D3]MeCN. This unusual dependence of KIE on
À
rates of the reaction of 2 with PhEt from À40 to 408C and the
reaction of 2 with [D10]PhEt from 10 to 508C. From these
plots, it can be deduced that the KIE increases significantly
from a value of 40 at 408C to a value of 400 at À408C. Ea
values of 7.8 (3) and 12.0 (1) kcalmolÀ1 can be obtained from
the temperature-dependence plots for the oxidations of PhEt
and [D10]PhEt by 2, which correspond to a DEa of 4.2 kcal
molÀ1. The DZPE for the benzylic hydrogen and deuterium
atoms of PhEt can be obtained from vibrational data, which
shows a downshift of approximately 800 cmÀ1 upon deuterium
substitution; this shift corresponds to an energy difference of
2 kcalmolÀ1. Therefore, DEa is greater than DZPE. Addition-
ally, the Arrhenius plots give an AH/AD ratio of 0.03, a value
much lower than 0.7 and consistent with enzymatic systems
that are shown to involve hydrogen-atom tunneling.[13] Thus,
the reaction of 2 with PhEt exhibits all the necessary and
sufficient characteristics expected for a reaction involving H-
atom tunneling. The values obtained here for 2 are compa-
rable to those recently reported by Newcomb and co-workers
on the temperature dependence of the KIEs for the oxidation
of benzyl alcohol by [FeIV(O)(TMP+·)(ClO4)] (TMP = tetra-
D(C H) is unique.
A potentially similar relationship has been reported in
only one other system capable of H-atom abstraction.[15] The
reaction of the phthalimide N-oxyl radical (PINO) with a
similar set of substrates also showed a dependence of KIE on
À
À
D(C H) with values of 11–13 for the weaker C H bonds of
benzhydrol and fluorene and values of 24–27 for the stronger
À
C H bonds of PhEt, PhMe, and cyclohexane. Indeed the
maximum KIE was observed when the overall reaction free-
energy change was close to zero, as expected by the classical
Melander–Westheimer explanation for the variation of semi-
classical KIE with free energy changes during H-abstrac-
tion.[16] However, in the cases of the reactions of 1 and 2 with
substrates, the reactions are all exothermic, and this same
principle cannot be applied. Furthermore, the large KIE
values observed for the reactions of 1 and 2 are for the
À
substrates that have weaker C H bonds, and hence more
exothermic reactions. This behavior is clearly not that
expected from semiclassical trends in KIE; we therefore
turned to calculations to provide a way to rationalize the
À
D(C H) dependence of KIE for 1 and 2.
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Table 1: Semiclassical KIEs calculated by DFT (B3LYP/B1).
Since the reactions of PhEt figure prominently in the KIE
plots above, we calculated this reaction with 1, at the common
level used for the cases in previous studies, namely B3LYP/B1
Reaction[a]
KIE(T)[b]
KIE(Q)[b]
Observed KIE
for 1 (2)[c]
À
(B1 is LACVP) for characterizing the C H activation
KN4Py + C6H12
KN4Py + PhMe
KN4Py + MeCN
KN4Py + PhEt
6.8
5.9
6.7
6.4
6.8
1.9
1.4
5.4
1.4
2.7
– (–)
22 (30)
– (4)
45 (40)
– (6)
mechanism. The energy was corrected by using a larger
basis set, B2 (B2 is LACV3P + + **), and solvent corrections
(using the solvent parameters for CH3CN). Like in all
previous cases,[9,10] we also found a two-state-reactivity
(TSR) scenario (see Figure 3 and the Supporting Informa-
tion).
KBnÀTPEN + C6H12
[a] C6H12 =cyclohexane. Calculations at the B3LYP/LACVP level. KIEs
were calculated using the free energy difference between 3.5TSH and 3,5R
(
3,5KN4Py +substrate). The reacting H atom was replaced by D. [b] Semi-
classical values. [c] KIE values determined at 408C in [D3]MeCN, except
for MeCN, which was obtained from the t1/2 values of 2 in MeCN and
[D3]MeCN.
Small tunneling corrections based on Wignerꢁs formula do not
change these trends and do not affect the KIE(Q) values for
PhEt and PhMe at all (see the Supporting Information).
À
Similar results were obtained by de Visser for the C H
activation by the model iron oxo species of TauD.[17]
Importantly, the only semiclassical values that seem to
match the experimental ones are those for the substrates
À
with the stronger C H bonds, that is, C6H12 and MeCN.
Otherwise, the calculated KIEs show the expected trend[18]
from semiclassical values, namely generally larger KIEs for
À
higher barriers and stronger C H bonds (e.g., compare the
values for C6H12 and PhEt). Thus, the very small KIE(Q)
values are in line with the very small barriers on the quintet
surface, and the larger KIE(T) values are in line with the
larger triplet barriers.[18] Clearly, however, these semiclassical
values in Table 1 account for neither the trends nor the very
large KIE values in Figure 2 above. Furthermore, the very
small semiclassical KIE(Q) values are in clear disagreement
with the experimental KIE(Q) value (greater than 37) for
TauD, for which the oxoiron(IV) oxidant has a quintet ground
[17]
state[4] that is responsible for the C H bond activation.
À
We next investigated the exact kind of tunneling that the
experimental data in Figure 2 may correspond to. Traditional
tunneling through a single barrier is generally expected to be
more efficient as the barrier becomes narrower and to occur
through the thinner part of the barrier.[19,20] Assuming that the
area under the barrier is conserved in a series of substrates
that react with the same iron oxo reagent, then larger H-
abstraction barriers will have thinner cross-sections than
smaller ones. Thus, under this assumption, in tunneling
through a single barrier one can arguably expect the tunneling
to increase as the barrier increases. Since the H-abstraction
Figure 3. Energy profiles for the reactions of 1 (labeled as K) with
a) ethylbenzene and b) acetonitrile.[9b] The relative energies (in kcal
molÀ1) of each species correspond to the B2//B1+ZPE gas phase
value followed by a solvent-corrected value B2//B1+ZPE +solv. RC is
a cluster of the reactants, which is stable only in the gas phase. 2S+1I
corresponds to the FeIIIOH/RC intermediate with triplet or quintet spin.
À
barrier is known to increase as the C H bond strength
increases,[6,21] one might have expected that the KIE tunneling
À
value will increase as the C H bond becomes stronger. This is
manifested in the left-hand branch of Figure 2, but is not true
for the right-hand branch of the data set; here, the largest KIE
The semiclassical KIE values calculated for the H-
abstraction reactions of 1 and 2 with different hydrocarbon
substrates are listed in Table 1. It is seen that the semiclassical
values on the triplet surface are generally larger than those on
the quintet surface. For each spin manifold, the smallest
À
value is observed for PhEt, which has the weakest C H bond,
and normal semiclassical-type values are measured for the
substrates that have the strongest C H bonds.
To formulate a possible tunneling scenario that can serve
as a working hypothesis, the energy profiles for two extreme
cases, the reactions of [FeIV(O)(N4Py)]2+ with PhEt and
À
À
values are calculated for the substrates with the weakest C H
bond, namely PhEt and then PhMe. The quintet state KIE(Q)
values for PhEt and PhMe are only slightly larger than 1.
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À
MeCN, are shown in Figure 3. Inspection of the gas-phase
the D(C H) further increases. This seems to be the general
appearance of Figure 2.
energetics (the left-hand data in each pair) shows that, in each
case, the triplet surface starts as the ground state but is crossed
over by the quintet state. The triplet energy profiles in both
cases are steeper than the quintet profiles, but the barriers for
H-abstraction from MeCN are considerably higher than those
from PhEt, in agreement with experimental data.
Another factor that influences the tunneling behavior is
the solvent reorganization. As can be seen in Figure 3,
solvation raises the barriers by 4–7 kcalmolÀ1, which means
that the tunneling behavior should occur prior to solvent
reorganization. In turn, the solvent reorganization might
exhibit additional KIE because of barrier narrowing,[20a] or to
a frictionlike mechanism that will depend on the nature of the
solvent.[23]
Since the triplet barrier shown in Figure 3 is generally
higher than the quintet barrier, the crossing of the quintet
surface through the triplet barrier could afford a mechanism
that behaves like a tunneling process.[9a,10b] However, as
shown in Figure 3, this mechanism depends strongly on the
substrate. Thus, in the case of MeCN, the quintet energy
profile itself is quite steep even in the gas phase, while in the
case of PhEt the quintet energy profile is essentially flat. In
In conclusion, the mononuclear, nonheme oxoiron(IV)
complexes 1 and 2 are capable of oxidizing hydrocarbon
substrates over a wide range of D(C H) values. The rate
À
À
dependence of these reactions on D(C H) suggests a
mechanism of H-atom abstraction. This mechanistic proposal
is supported by the deuterium kinetic isotope effect that is
observed for each substrate studied, including the reaction
with the solvent, acetonitrile. For some of the substrates
5
fact, the TSH species in the case of PhEt is lower in energy
than the onset of the reactants on the quintet surface.
À
Therefore, the amplitude of the C H vibration explores the
À
entire region from the reactants to the transition state and
beyond to the intermediate 5I on the surface of PhEt.
Consequently, during the crossover of the reaction complex
examined, specifically those with a D(C H) value less than
about 93 kcalmolÀ1, large, nonclassical values of kH/kD are
observed. Such large KIEs suggest a mechanism of hydrogen
tunneling, which is also supported by other data. This
À
from the triplet to the quintet surface, the C H vibration
À
amplitude on the quintet surface will propagate the complex
directly to the intermediate 5I, and through the triplet barrier,
which results in tunneling behavior. On the other hand,
[D10]PhEt will have a quintet energy profile with a barrier, so
behavior is interpreted by using the TSR concept: the C H
vibration amplitude propagates the molecular complex from
the reactant-like geometry directly to the product whenever
the quintet energy surface is equal to or flatter than the zero-
À
À
the C D vibration will not suffice in this case to propagate the
point energy stored in the C H bond (Figure 3a) that
undergoes activation. Thus, the TSR concept provides a
rationale and a working hypothesis for a substrate-dependent
reaction complex directly to the intermediate. Thus, whenever
the quintet energy profile is very flat, a very large KIE value
would be expected. The observation of large KIE(Q) for
TauD, as well as the calculations of de Visser,[17] which reveal
a very flat quintet surface for the H-abstraction reaction of
the quintet state, provides further support for this hypoth-
esis.[22]
À
tunneling mechanism that varies nonintuitively with the C H
bond dissociation energy.
Received: August 14, 2008
Revised: December 12, 2008
Published online: January 7, 2009
In contrast to the flat quintet surface in the case of PhEt,
the quintet profile for the reaction with MeCN is rather steep,
with a net barrier of 10 kcalmolÀ1 in the gas phase. This
Keywords: bioinorganic chemistry · iron · isotope effects ·
isotopic labeling · two-state reactivity
.
À
barrier is well above the energy stored in the C H vibration,
and therefore the T–Q crossover and the reaction on the Q
surface will proceed in a normal barrier-climbing fashion, thus
leading to a normal (semiclassical) KIE value.
Our working hypothesis does not depend on the proba-
bility of spin crossover, but rather on the shape of the quintet
energy curve. Although we cannot make definitive specific
predictions for other substrates, we can outline trends. Thus, if
the barrier on the quintet surface is larger than the zero-point
´
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À
energy stored in the C H bond that undergoes activation, the
reaction on the quintet surface, after T–Q crossover, will
behave as a regular barrier-climbing reaction and lead to a
normal KIE in the semiclassical regime, whereas a quintet
surface flatter than or equal to the zero-point energy stored in
À
the C H bond will give rise to tunneling-like behavior, since
À
the C H vibration will explore a wide range of the quintet
potential surface and will propagate the system to the
product. Since the H-abstraction barriers are generally
À
À
proportional to the C H bond dissociation energies (D(C
H)), with a proportionality constant of around 0.3,[21] this
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À
narrow range of D(C H) values, with a rather abrupt drop as
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semiclassical KIE will remain approximately constant.
[19] L. Melander, W. H. Saunders, Jr., Reaction Rates of Isotopic
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À
[18] In the hydroxylation of C H bonds by P450, the computed KIEs
[23] R. J. Cannara, M. J. Brukman, K. Cimatu, A. V. Sumant, S.
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are small for weak bonds with small barriers and larger for
stronger bonds and larger barriers. See, for example, C. Li, W.
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