Experimental Evidence for p Ka-Driven Asynchronicity in C-H Activation by a Terminal Co(III)-Oxo Complex

Article abstract of DOI:10.1021/jacs.8b13490

C-H activation by transition metal oxo complexes is a fundamental reaction in oxidative chemistry carried out by both biological and synthetic systems. This centrality has motivated efforts to understand the patterns and mechanisms of such reactivity. We have therefore thoroughly examined the C-H activation reactivity of the recently synthesized and characterized late transition metal oxo complex PhB (^tBuIm)₃Co^IIIO. Precise values for the pK_a and BDFE_O-H of the conjugates of this complex have been experimentally determined and provide insight into the observed reactivity. The activation parameters for the reaction between this complex and 9,10-dihydroanthracene have also been measured and compared to previous literature examples. Evaluation of the rates of reaction of PhB(^tBuIm)₃Co^IIIO with a variety of hydrogen atom donors demonstrates that the reactivity of this complex is dependent on the pK_a of the substrate of interest rather than the BDE_C-H. This observation runs counter to the commonly cited reactivity paradigm for many other transition metal oxo complexes. Experimental and computational analysis of C-H activation reactions by PhB(^tBuIm)₃Co^IIIO reveals that the transition state for these processes contains significant proton transfer character. Nevertheless, additional experiments strongly suggest that the reaction does not occur via a stepwise process, leading to the conclusion that C-H activation by this Co^III-oxo complex proceeds by a pK_a-driven "asynchronous" concerted mechanism. This result supports a new pattern of reactivity that may be applicable to other systems and could result in alternative selectivity for C-H activation reactions mediated by transition metal oxo complexes.

Full text of DOI:10.1021/jacs.8b13490

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Article
a
Experimental Evidence for pK-Driven Asynchronicity
in C-H Activation by a Terminal Co(III)-Oxo Complex
McKenna K. Goetz, and John S. Anderson
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b13490 • Publication Date (Web): 09 Feb 2019
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Experimental Evidence for pK -Driven Asynchronicity in C-H Activation
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a
by a Terminal Co(III)-Oxo Complex
McKenna K. Goetz and John S. Anderson*
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Department of Chemistry, University of Chicago, Chicago, IL 60637, USA
ABSTRACT: C-H activation by transition metal oxo complexes is a fundamental reaction in oxidative chemistry carried out by
both biological and synthetic systems. This centrality has motivated efforts to understand the patterns and mechanisms of
such reactivity. We have therefore thoroughly examined the C-H activation reactivity of the recently synthesized and charac-
t
III
terized late transition metal oxo complex PhB( BuIm)
3
Co O. Precise values for the pK and BDFEO-H of the conjugates of this
a
complex have been experimentally determined and provide insight into the observed reactivity. The activation parameters
for the reaction between this complex and 9,10-dihydroanthracene have also been measured and compared to previous lit-
t
III
erature examples. Evaluation of the rates of reaction of PhB( BuIm)
the reactivity of this complex is dependent on the pK of the substrate of interest rather than the BDEC-H. This observation
runs counter to the commonly cited reactivity paradigm for many other transition metal oxo complexes. Experimental and
3
Co O with a variety of H-atom donors demonstrates that
a
t
III
computational analysis of C-H activation reactions by PhB( BuIm) Co O reveals that the transition state for these processes
3
contains significant proton transfer character. Nevertheless, additional experiments strongly suggest that the reaction does
not occur via a stepwise process, leading to the conclusion that C-H activation by this Co -oxo complex proceeds by a pK
driven “asynchronous” concerted mechanism. This result supports a new pattern of reactivity that may be applicable to other
systems and could result in alternative selectivity for C-H activation reactions mediated by transition metal oxo complexes.
III
a
-
mechanisms (Scheme 1).9,21–23 This process involves the
INTRODUCTION
transfer of both a proton and an electron which can be
transferred simultaneously in a coupled fashion (coupled
proton electron transfer, CPET) or stepwise (proton trans-
fer-electron transfer, PTET, or electron transfer-proton
transfer, ETPT). It is generally accepted that coupling move-
ment of the proton and electron is energetically favorable;
thus, the details of how a proton and electron may couple in
these transfers has important implications in C-H activation
Transition metal oxo complexes are a remarkable class of
intermediates that mediate important C-H activation reac-
tivity in many fields including biology and organic synthe-
sis. As an archetypal example, cytochrome P450 enzymes
employ high valent iron oxo species to facilitate the oxida-
1
tive degradation of pharmaceuticals. Inspired by the suc-
cess of nature, a variety of synthetic transition metal oxo
complexes have been made and their C-H activation reactiv-
13,24
reactivity.
2–5
ity studied thoroughly. Transition metal catalyzed C-H ac-
In addition to the limiting extremes mentioned above, it
has been proposed that concerted proton and electron
Scheme 1. Mechanisms of net H-atom transfer.
tivation has also been increasingly investigated as a syn-
thetic strategy, with particular emphasis on controlling se-
6
–8
lectivity. C-H activation by a transition metal oxo complex
involves the net transfer of a hydrogen atom and discussion
of the intricacies of this transfer has also been a topic of in-
9
–13
tense interest.
Understanding this process in detail is
crucial for providing a framework for the factors that gov-
ern reactivity and selectivity in both natural and synthetic
systems.
A broad body of research dedicated to understanding C-H
activation by transition metal oxo complexes has estab-
lished that the reactivity is generally dictated by the ther-
modynamics of the bond dissociation (free) energies
(
BD(F)Es) of the C-H bond being broken and the O-H bond
being formed. This paradigm, which follows the Bell-Evans-
14,15
Polanyi principle,
suggests that in the simplest case,
electronic selectivity should be exclusive for the homolyti-
2
,9,16–20
cally weakest C-H bond in the substrate.
However, net
hydrogen atom transfer from an organic substrate to a tran-
sition metal oxo complex can occur via multiple possible
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Page 2 of 13
transfer can occur along a spectrum of “asynchronicity” in
which the transition state for the net hydrogen atom trans-
fer can contain either more proton transfer or electron
NMR spectroscopy that TBD (TBD = 1,5,7-triazabicy-
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
clo[4.4.0]dec-5-ene, pKaMeCN = 26.03 ) was not a competent
base for the deprotonation of 2. Using the C value (C
34
G
G
=
2
1,23
+
•
transfer character (Scheme 1).
Computational quantifi-
standard reduction potential of H /H in a particular sol-
vent) of 54.9 kcal/mol in MeCN, we calculated an initial
9
cation of this distinction has been newly developed and sug-
gests that more synchronous processes actually have higher
lower bound value of 85 kcal/mol for the BDFEO-H of 1.
2
2
activation barriers. This computational proposal has intri-
guing implications for the selectivity of transition metal oxo
mediated C-H activation, but there is a dearth of experi-
mental support for this theory as the vast majority of well-
studied oxo complexes display rates which depend on
BD(F)Es as discussed above.
0
BDFE = 1.37pK
a
+ 23.06E + C
G
(1)
However, a more accurate value for the BDFEO-H of 1 was
desired to help understand the reactivity of 3 with sub-
strates. To accomplish this, we sought to explicitly deter-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
There are some limited examples that demonstrate alter-
native basicity controlled mechanisms of C-H activa-
mine the pK
a
of 2. This was carried out by titration of 3 with
an acid, [HMTBD][BF
clo[4.4.0]dec-5-ene, pKaMeCN = 25.49 ), in MeCN-d
tration was monitored by H NMR spectroscopy at −35 °C
where all species in solution (3, HMTBD , 2, and MTBD)
4
] (MTBD = 7-methyl-1,5,7-triazabicy-
2
1,25–28
34
tion.
their [(H
bond of 9,10-dihydroanthracene by utilizing a PTET mech-
For instance, Borovik and coworkers report that
3
. The ti-
III
2−
1
3
buea)Mn O] complex activates the weak C-H
+
III
anism due the high basicity of the Mn -oxo complex
pKaDMSO = 28.3). The effects of oxo or hydroxo ligand ba-
were in rapid equilibrium. As a result, the concentration of
each species in solution was evaluated by examination of
the observed chemical shift (obs) of the methyl protons of
27
(
sicity have been invoked in other systems as well. For in-
stance, compensation for low oxidation potentials with in-
creased basicity to maintain a high BDFEO-H (Equation 1)
has been seen in both synthetic and natural systems such as
+
1
HMTBD /MTBD in the H NMR spectra (See Experimental,
Figure S2). From this data, an equilibrium constant for the
reaction between 3 and [HMTBD][BF
be 1.2(1) (Table S1). Using the known pK
[HMTBD][BF ] we calculated a pK value of 25.58(5) for 2 in
4
] was determined to
1
7,29–32
cytochrome P450 enzymes.
Nonetheless “basic asyn-
a
value of
chronous CPET” has not been studied in a systematic fash-
4
a
2
1,22
ion but may be vitally important to these systems.
We have recently reported an unusual late transition
MeCN. We believe the slight discrepancy between this value
and our previously determined “lower bound” value is due
to hydrogen-bonding effects which complicate interpreta-
tion of the acid/base equilibrium with TBD. Using the more
t
III
metal oxo complex PhB( BuIm) Co O (3, Scheme 2) and
3
33
preliminary studies of its C-H activation reactivity. In the
current work, we have more precisely determined the
Co OH (1, Scheme 2) by explicitly
determining the pK of [PhB( BuIm) Co OH] to be ~25.6 in
precise pK value, we calculated a BDFEO-H of 84.6 kcal/mol
a
t
II
(Equation 1, Scheme S1). This value gives a useful bench-
mark for the types of C-H bonds that might be expected to
be activated by 3.
BDFEO-H of PhB( BuIm)
3
t
III
+
a
3
acetonitrile (2, Scheme 2). This value makes the corre-
sponding oxo complex, 3, one of the more basic examples
reported in the literature. We have compared these param-
eters and the reactivity of 3 with 9,10-dihydroanthracene
Scheme 2. Co complexes discussed in this work.
(
DHA) to related examples reported in the literature. In ad-
dition to these experiments, we have thoroughly investi-
gated the reactivity of 3 with a variety of H-atom donors and
found that contrary to the generally established pattern, the
reactivity of 3 is dependent on the pK of the substrate in-
a
stead of its BDEC-H. Experimental and computational exami-
nation of the transition state provides insight into the mech-
anism of H-atom transfer in the current system and sup-
ports the agency of a basic asynchronous CPET mechanism
in the C-H activation reactivity of 3 (Scheme 1). This work
represents a clear example of experimental evidence for
asynchronicity in C-H activation and opens the door for em-
ploying this concept in designing new oxidative reactivity
with alternative electronic selectivity.
The BDFEO-H of 1 is comparable to a sample of other well-
studied transition metal oxo/hydroxo complexes (Table 1),
and it therefore might be expected that 3 would activate C-
H bonds analogously to these other species. However, it ap-
RESULTS AND DISCUSSION
Thermodynamics
In beginning to examine the C-H activation reactivity in
this system, we first sought to accurately determine the
pears that the balance between pK and oxidation potential
a
for the cobalt complex discussed here is weighted in favor
of the basicity of the oxo ligand instead of the oxidizing po-
tential of the complex. Additionally, when compared to
BDFE for the O-H bond in 1 using the relationship between
0
pK
a
, E , and BDFE outlined in Equation 1 and Scheme S1.
0
IV
Previously, cyclic voltammetry data were collected that
computed pK and E values for a series of non-heme Fe -
a
II
III
showed that the Co /Co oxidation potential is −0.23 V ver-
oxo complexes, complex 3 is much more basic and much
+
22
sus Fc/Fc in acetonitrile (MeCN, Fc = ferrocene, Figure
less oxidizing. This imbalance could affect the mechanism
3
3
S1). Additionally, a lower bound pK
a
value of 26 in MeCN
of C-H activation and has been proposed to be a determining
1
22
was initially estimated for 2 due to the observation by H
factor in asynchronicity.
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Table 1. Thermodynamic data for selected transition metal oxo/hydroxo complexes and their reactivity parameters
with DHA.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
E0
(V vs
Fc/Fc )

H‡
S‡
(e.u.)
k
2
KIE
(k /k
pK
(DMSO)
a
BDFEO-H
(kcal/mol)
Complex
Ref.
a
a
−1 −1
a
b
(
kcal/mol)
(M s )
H
D
)
+
c
t
III d
PhB( BuIm)
3
Co O
11(1)
n.r.
−27(4)
n.r.
0.0288(7)
n.r.
10(2)
n.r.
6.8
~15
11
−0.23
0.036
−0.11
−1.51
n.r.
84.6
87
this work
35
IV −e
[(H
3
buea)Fe O]
IV − e
[(H
3
buea)Mn O]
5(1)
14(2)
n.r.
−49(4)
−14(6)
n.r.
0.026(2)
0.48(4)
0.14
15
89
27
III 2− e
[(H
3
buea)Mn O]
[Fe O(TMC)(MeCN)]2+f
2.6
28.3
n.r.
77
27
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
IV
10
84(1)
~80
90(3)
84.8
n.r.
19
V
g
1.8(5)*10−5
(
Cz)Mn O
n.r.
n.r.
n.r.
29
~11
~18
<−2
n.r.
−0.33
17
III
h
LCu OH
5.4(2)
n.r.
−30(2)
n.r.
186
−0.076
>2.2
20
IV
py]2+
[
Ru O(bpy)
2
125
35(5)
20
36,37
38
IV
i
Fe O(TPFPP)
n.r.
n.r.
13(2)
n.r.
a
b
n+
n+
Values for reaction with DHA at room temperature. pK
a
value for M -O/M -OH adjusted using the correlation between pK
a
c
0
n+
(n-1)+
+
d
t
−
values in DMSO, MeCN, THF, and H
tris(1-tert-butylimidazol-2-ylidene)phenylborate. H
methyl-1,4,8,11-tetraazacyclotetradecane. Cz
propylphenyl)-2,6-pyridinedicarboxamide. TPFPP = meso-tetrakis(pentafluorophenyl)porphinato. Entries depicting n.r. indicate
values not reported to the best of our knowledge.
2
O as necessary. E for M -OH/M
-OH adjusted versus Fc/Fc as necessary. PhB( BuIm)
-tert-butylureayl)-N-ethylene]aminato. TMC = 1,4,8,11-tetra-
3
=
e
3−
f
3
buea = tris[(N
octakis(para-tert-butylphenyl)corrolazinato.
3
g
3−
h
2−
=
L
=
N,N’-bis(2,6-diiso-
i
2−
Additionally, we measured a kinetic isotope effect (KIE)
when 3 was reacted with DHA-d of 10±2 (Figure S5). A KIE
4
Reactivity of 3 with 9,10-dihydroanthracene (DHA)
of this magnitude is common for C-H activation reactions
carried out by transition metal oxo/hydroxo species (Table
1) and is slightly beyond the “classical limit” of ~7, implying
As was previously reported, 3 reacts cleanly with DHA to
produce 1 and anthracene (Figure 1) under pseudo-first or-
der conditions. Due to the common use of DHA as a model
substrate for the C-H activation reactivity of transition
metal oxo/hydroxo species (Table 1), we chose to investi-
gate the reactivity of 3 and DHA further. Collecting rate data
at variable concentrations of DHA showed a dependence of
the rate of reaction on the concentration of DHA, giving a
3
9
some degree of contribution from tunneling effects. This
is not surprising, given that this reaction involves the over-
all transfer of both a proton and an electron, but our meas-
ured value is far from the extremely high (~30) KIE values
2
0
determined for some metal oxo/hydroxo complexes. Gen-
erally, larger KIE values are consistent with concerted
mechanistic processes where the transfer of the electron is
intimately coupled to the transfer of the proton, potentially
through tunneling. However, KIEs can vary widely depend-
−
2
−1 −1
second order rate constant, k = 2.88(7)*10 M s (Figure
2
S3, Figure S4). This demonstrates that the reaction follows
a second order rate law overall, being first order in [Co] and
first order in [DHA]. This k value falls in the middle of the
2
1
3,40–42
ing on the exact nature of the transition state.
makes conclusive interpretation of KIEs difficult.
Finally, we sought to determine the activation parame-
This fact
range of other transition metal oxo/hydroxo complexes.
‡
‡
ters, ΔH and ΔS , for the reaction between 3 and DHA. This
information has been reported for some transition metal
oxo/hydroxo complexes that react with DHA, allowing for
comparison of our system to those previously reported. Col-
lection of rate data at various temperatures and fitting using
the Eyring equation (Figure S6, Figure S7) gave the values
‡
‡
ΔH = 11(1) kcal/mol and ΔS = −27(4) e.u. The negative en-
tropy of activation is consistent with a bimolecular transi-
tion state in which two species must come together for the
reaction to proceed. Such a transition state would be con-
sistent with any of the mechanistic reaction pathways laid
out in Scheme 1 and cannot be used to distinguish between
them. The activation parameters determined for 3 are typi-
cal in the series of transition metal oxo/hydroxo complexes
shown in Table 1, with activation enthalpies between 5 to
1
e.u.
5 kcal/mol and activation entropies between −15 to −50
Figure 1. UV-vis spectra of the reaction between 3 (dark red
trace) and 10 equivalents of DHA to produce 1 and anthracene
(purple trace). Gray traces indicate 1-minute time points. Inset:
pseudo-first order kinetic analysis of the reaction monitored at
H-atom transfer reactivity with substrates
4
70 nm.
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Table 2. Kinetic data for the reaction of 3 with various C-H substrates.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
k
obs
k
2
KIE
(k /k
pK
a
BDEC-H
(kcal/mol)
Substrate
−
4
−1
a
−2 −1 −1
b
c
(10 s )
(10 M s )
H
D
)
(DMSO)
30.1
30.0
25.8
32.3
35
9
,10-dihydroanthracened
xanthene
4.7(3)
2.88(7)
n.d.
10(2)
n.d.
76.3
75
7.2(2)
1
,1,3,3-tetraphenylpropene
diphenylmethane
1,3-cyclohexadiened
0.21(9)
0.16(3)
n.d.
n.d.
77
0.009(2)
0.032(6)
n.d.
84.5
74.3
0.22(13)
n.d.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
9
-X-9H-fluorene
X
=
H
tBu
43(2)
2.8(4)
24(3)
n.d.
3.2(3)
n.d.
22.6
24.4
17.9
82
79.9
74
Ph
950(90)
n.d.
n.d.
a
b
Determined using 10 equivalents of substrate per equivalent of Co complex either directly or from the k
2
value. Data taken from
4
3 c
44 d
the Bordwell pK
a
table. Data taken from the CRC’s Handbook of Bond Dissociation Energies. Rates corrected for stoichiometry.
Entries depicting n.d. indicate values that were not determined.
As was mentioned above, the general trend in reactivity
for transition metal oxo complexes with various H-atom do-
nors is that substrates with stronger C-H bonds react more
argue that this steric effect likely leads to aberrantly slow
observed rates for these substrates.
9
,17
slowly. In an effort to investigate whether or not the re-
activity of complex 3 follows this same trend, we examined
the reactivity of 3 with a series of H-atom donors with dif-
ferent BDEC-H values (Figures S8-S18) and the results of
these studies are presented in Table 2 as observed rate con-
stants (kobs). All of these reactions demonstrate isosbestic
conversion from 3 to 1 by UV-vis spectroscopy (Figure 1).
Additionally, the reactions of 3 with DHA and fluorene were
examined by GC-MS and the expected products of the reac-
tion (anthracene and 9,9’-bifluorenyl, respectively) were
observed with 75-100% conversion (Figure S19, Table S2),
supporting the clean transformations seen by UV-vis spec-
troscopy.
Surprisingly, when the kinetic data are plotted as the
log(kobs) versus BDEC-H of substrate (Figure 2A) no discern-
ible correlation between the BDEC-H of the substrate and the
rate of reactivity is observed. This is contrary to what might
be expected based on literature precedent. As a particularly
illustrative series, the reactivity of 3 with 1,3-cyclohexadi-
ene (CHD), DHA, and fluorene shows an inverse relationship
with BDEC-H. To explain this discrepancy, we considered ad-
ditional parameters that could correlate with reactivity.
0
Two likely thermodynamic parameters are the pK or E of
a
the C-H substrate. Such parameters might be expected to
dictate the reactivity if the mechanism were stepwise or
asynchronous (Scheme 1). Plotting the log of the kobs values
versus the gas phase ionization energies (Figure S20) shows
little correlation between these two quantities, as might be
expected due to the low oxidation potential of our system.
Alternatively, examination of a plot of the log of the kobs val-
ues versus the pK
linear correlation where substrates with higher pK
a
of each substrate (Figure 2B) reveals a
values
a
react with slower rates. It is prudent to note that while there
is a definitive correlation between the rate of C-H activation
and the pK of the substrate being studied, there are a few
a
substrates that deviate from the line. Most notable in this
regard are 9-(tert-butyl)-9H-fluorene and 1,1,3,3-tetra-
phenylpropene. Both of these substrates contain tertiary C-
H bonds, likely introducing steric clashing with the three
tert-butyl groups that surround the Co-O bond in 3. We
Figure 2. Plots of log(kobs) vs (A) BDEC-H of substrate and (B)
pK
a
of substrate. Each kobs value is that for the reaction of 3
with 10 equivalents of substrate either determined directly or
from the k
mation). Linear fit in (B): log(kobs) = −0.18pK
2
value (see Experimental and Supporting Infor-
2
a
+ 1.6, R = 0.56.
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Journal of the American Chemical Society
of the substrate suggests a ba-
This correlation with pK
a
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
sicity-controlled mechanism of H-atom transfer and could
be consistent with a stepwise transfer of the proton and
electron (PTET mechanism) or a concerted mechanism in
which the transition state contains a significant amount of
proton transfer character (i.e. basic asynchronous CPET).
Stepwise C-H activation has been observed previously in
2
7,28
the literature,
with one well-studied example being the
V
reactivity of a Mn -imide complex with substituted phenol
substrates reported by Abu-Omar and coworkers. In this
study, it was found that for acidic enough substituted phe-
nols, the data were consistent with a stepwise PTET mech-
anism, while for the more basic substituted phenols, the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
28
data were consistent with a CPET process. On the other
hand, asynchronous mechanisms of hydrogen atom transfer
21,22
have also been proposed in some systems.
We therefore
set out to distinguish between these two mechanisms.
Figure 3. Hammett substituent plot for the reaction of 3 with
Mechanism of C-H activation by 3
9
-(4-X-phenyl)-9H-fluorenes. The red line shows the linear fit
2
of the data: ρ = 0.67(7), R = 0.96.
In order to better understand the mechanism of C-H acti-
vation employed by 3, we turned to various experimental
techniques for studying the characteristics of the transition
state of this reaction. Hammett analysis is a powerful tech-
nique in this regard that informs on the type of charge build-
up on the atom of interest in the transition state. In this in-
stance, we are probing the character of the charge build-up
on the carbon of the C-H bond being broken. We therefore
carried out Hammett analysis for p-substituted 9-phenyl-
9H-fluorenes. It has been shown previously that for a syn-
chronous CPET process, a negative Hammett correlation is
(
pK ~ 30 in DMSO). However, due to synthetic challenges
a
in obtaining three or more 3-substituted xanthene sub-
strates, kinetic analysis was carried out only with 3-
methylxanthene (Figure S24) and xanthene and we were
unable to obtain a meaningful Hammett slope. Nonetheless,
if this class of substrates is reacting via the same mechanism
as the p-substituted 9-phenyl-9H-fluorene derivatives, it
would be expected that 3-methylxanthene would react at a
slower rate than xanthene. Indeed, this is what was ob-
served, with the rate of reaction for 3-methylxanthene be-
ing ~3x slower than that for xanthene (Table 3). Thus, we
can say with confidence that these two classes of substrates
appear to be reacting via the same basicity-controlled
mechanism despite the large (~12 log units) difference in
17
expected. However, for mechanisms such as PTET or basic
asynchronous CPET a positive Hammett correlation would
be expected due to the build-up of negative charge.
The results of the Hammett analysis (Figures S21-S23)
are summarized in the first half of Table 3 and graphically
represented in Figure 3. There is a positive Hammett corre-
lation with  = 0.67(7). This positive slope supports our hy-
pothesis that the reactivity of 3 with H-atom donors is pro-
ton-controlled, consistent with either a stepwise PTET or
basic asynchronous CPET mechanism. While this trend is
clear in this series, we also wanted to carry out this analysis
for another class of substrates with C-H bonds at the upper
pK between the two. This supports the assertion that the
a
same mechanism is operative for all substrates studied in
this work.
In addition to the KIE data discussed earlier for DHA, we
also determined the KIE for fluorene (Figure S18, Table 2).
39
As has been previously established, large KIE values be-
yond the classical limit of ~7 are indicative of contributions
from tunneling effects, a common observation with transi-
tion metal oxo complexes that activate C-H bonds via syn-
chronous CPET. We observed such a KIE with DHA (KIE =
end of the pK
tuted phenylfluorenes are relatively acidic (pK
a
range studied due to the fact that the substi-
~19 in
a
DMSO). Thus, we chose to look at 3-substituted xanthenes
1
0(2)) which indicated to us that there may be some contri-
bution from tunneling. However, in the case of the more
acidic fluorene, we observed a KIE of 3.2(3) which is well
within the classical limit. As noted above, it is difficult to in-
terpret KIE values without a detailed picture of the transi-
Table 3. Rates for substrates used in Hammett analyses.
3
−1
a
− b
p
Substrate
k
obs (10− s )

1
3,40–42
tion state.
Nevertheless, we can propose a speculative
9
-(4-X-phenyl)-9H-fluorene
interpretation of these comparative values. The observed
KIEs could suggest that a stepwise PTET mechanism is op-
X =
OMe
Me
H
54(1)
66(1)
−0.26
−0.17
0.00
erative for fluorene and there is a pK
a
-dependent mecha-
V
28
95(9)
nism switch as seen in the Mn -imide system. Alterna-
tively, this difference in KIE values may be explained by one
asynchronous CPET mechanism where a larger degree of
asynchronicity results in a smaller KIE (i.e. the proton is less
CF
3
200(30)
0.65
3
-X-xanthene
2
2
X =
Me
H
0.22(2)
0.72(2)
−0.17
coupled to the electron). The reaction between 3 and flu-
orene would be expected to be more asynchronous than
0.00
that between 3 and DHA due to the smaller pK
between 3 and fluorene.
a
difference
a
b
Values obtained using 10 equivalents of substrate. Hammett
45
parameters obtained from Hansch, Leo, and Taft.
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Page 6 of 13
can be correlated to ket given the assumption that G‡
Scheme 3. Possible mechanisms of C-H activation by
complex 3.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
changes negligibly from heterogeneous to homogeneous
47
conditions, as has been previously shown. We conducted
this measurement (Figures S25-S27, see Experimental for
mathematical details) and found that the upper bound ket
3
−1 −1
for 1/2 is on the order of 10 M s at room temperature.
Based on this analysis, it is clear that 2 cannot accept an
electron fast enough to match the measured kinetics for the
reaction of 3 and fluorene (Table 2). This provides evidence
against a stepwise PTET mechanism of C-H activation
(Scheme 3).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
We also attempted to intercept 2 to see if it were a bona-
fide intermediate in the C-H activation reactivity of 3. Given
the steady-state approximation discussed earlier, it might
be expected that in the presence of an appropriate deuter-
ated acid, such as [DMTBD][BF ], scrambling of deuterium
4
into the organic product and the excess substrate would oc-
cur due to the presence of 2 and the substrate carbanion in
solution. This hypothesis hinges on the equilibrium ex-
change being appropriately fast while the electron transfer
rate from 2 to the carbanion is suitably slow. We can esti-
mate a lower bound for the rate of equilibrium proton ex-
change from the pK
above, where the peaks in the H NMR spectrum were fully
a
determination experiment described
1
coalesced at −35 °C. This implies a minimum rate of ex-
2
−1
48
change on the order of 10 s at this temperature. From
the room temperature experimentally estimated ket pre-
sented above, we can expect that ket at −35 °C should be on
1
−1 −1
the order of 10 M s (See Experimental). Thus, we can
reasonably expect to observe deuterium incorporation if a
pre-equilibrium is involved in the mechanism of C-H activa-
tion.
All of the experimental data presented above support that
proton transfer plays an integral role in the C-H activation
reactivity of 3, but these experiments cannot discern be-
tween a stepwise or concerted mechanism. As discussed
above, we envision two likely mechanistic scenarios
We carried out the scrambling experiment by reacting 3
with fluorene in the presence of excess [DMTBD][BF ] and
4
MTBD at −35 °C and evaluating the organic products by GC-
MS to test for deuterium incorporation. Comparison of the
mass spectra of both fluorene and 9,9’-bifluorenyl in the re-
action mixtures with and without added deuterated acid re-
veals no deuterium incorporation in any of the fluorene-de-
rived species (Figure S28). This observation strongly im-
plies that there is no buildup of 2 or substrate carbanion in
the reaction mixture and thus supports a concerted net H-
atom transfer mechanism, in this case basic asynchronous
CPET.
(Scheme 3). Firstly, one plausible possibility is a PTET
mechanism where a pre-equilibrium PT to generate 2 and
substrate anion is followed by ET to result in net H-atom
transfer. Secondly, an alternative pathway where a basic
asynchronous CPET is operative may also be feasible. Ex-
perimentally distinguishing between these two mecha-
nisms is difficult, but we reasoned that if 2 were a genuine
intermediate in the reactivity of 3, we should be able to
show that this species is kinetically competent to carry out
the reaction and that we might be able to intercept it in
some way to verify its agency.
Computational analysis
It is reasonable to assume that the stepwise mechanism
shown in Scheme 3 would occur under steady-state condi-
tions. This imposes a ket (homogeneous electron transfer
rate constant) value for the electron transfer between 2 and
the substrate carbanion that can be determined from the
While these experimental results are consistent with a
concerted asynchronous process, we also wanted to obtain
computational support for this pathway. We have per-
formed two sets of DFT studies to probe these C-H activa-
tion reactions in detail. Firstly, we followed the procedure
laid out by Srnec and coworkers for calculating the asyn-
chronicity parameters, , for the reactions of 3 with CHD,
measured k
2
value for a given reaction and the pK differ-
a
ence between the substrate and 2 (See derivation in the SI).
6
Taking fluorene as an example substrate, a ket value of ~10
22
DHA, and fluorene (Table S3). The value  is a parameter
1
− −1
M s at room temperature is required to be in agreement
with the experimentally determined kinetics.
that quantitatively informs on the relative thermodynamic
contributions of pK
for a net H-atom transfer reaction. A negative  value im-
plies that the pK is the dominant driving force whereas a
a
and redox potential to the driving force
We can estimate the upper bound of ket by measuring the
intrinsic ability of 1/2 to give up/accept an electron using
a
cyclic voltammetry (CV) and analyzing the change in E
p
positive  value implies that the redox potential is domi-
nant. Additionally, a larger magnitude of  demonstrates a
4
6
with varying scan rate. This measurement gives a k
s
value
(
the heterogeneous electron transfer rate constant) which
greater imbalance of the contributions of pK and redox
a
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Journal of the American Chemical Society
mechanisms with proton transfer character in the transi-
tion state. Additionally,  becomes more negative as the pK
of the substrate decreases, indicating that the reaction is
more asynchronous for more acidic substrates. Finally, it is
1
2
3
4
5
6
7
8
9
a
worth noting that the k values reported in Table 2 trend
2
logarithmically with  (Figure S29), with faster rates of re-
activity seen for more asynchronous processes. These re-
sults are consistent with the theory of asynchronicity as laid
out by Srnec, supporting the idea that lower barriers result-
ing from higher degrees of asynchronicity lead to faster
rates of reactivity, which is observed experimentally in our
system.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Secondly, we analyzed the reaction coordinate for C-H ac-
tivation. As a starting point, we note that while both starting
materials are singlets, we have been unable to locate a max-
imum along a singlet spin manifold. Instead, a maximum is
observed along a triplet spin surface (Figure 4). The overall
reaction to form 1 and the organic radical mandates a net
spin change from S = 0 to S = 1 (or potentially S = 2 if the
radical couples ferromagnetically) so the relevance of mul-
tiple spin manifolds is not surprising. The relative im-
portance of different spin manifolds has been extensively
invoked in transition metal oxo C-H activation reactivity as
4
9–51
well as in the reactivity of related Fe carbene systems.
While we have largely focused this discussion on probing
the relative importance of an asynchronous C-H activation
mechanism, we acknowledge that the involvement of multi-
ple spin states is a convolution that we have not yet thor-
oughly addressed.
To obtain further detail on the flow of protons and elec-
trons along the reaction coordinate and in the transition
state, we employed an intrinsic bond orbital (IBO) analysis
as reported by Knizia and coworkers and recently applied
to C-H activation by Fe-oxo complexes (Figure 4, Figure
52–54
S30).
This computational technique enables analysis of
the movement and localization of orbitals along a reaction
coordinate. This allows us to visualize and quantify how the
orbitals associated with electron transfer (Figure 4, blue or-
bital) and proton transfer (Figure 4, red orbital) change as
the O–H bond forms. This analysis clearly indicates that
both protons and electrons move along the reaction coordi-
nate in a coupled manner. To further test the concept of
asynchronicity, we plotted the normalized orbital move-
ment as a function of the O-H distance along the reaction co-
ordinate (Figure 4). This analysis supports that the proton
and electron move in a concerted manner, but also shows
that the degree of proton movement is greater than the de-
gree of electron movement at intermediate steps along the
reaction coordinate. This observation is consistent with the
concept of asynchronicity and supports our overall picture
of the reaction and experimental results.
CONCLUSIONS
Figure 4. IBO analysis showing the normalized orbital move-
ments involved in the proton transfer (red) and the electron
transfer (blue). A, B, and C indicate the stationary points at O-H
distances of 1.3, 1.2, and 1.1 Å respectively with the blue orbital
involved in the electron transfer and the red orbital involved in
proton transfer.
potential to the driving force which results in a propensity
for asynchronicity in the H-atom transfer reaction. In the
current system, all three of the computed  values are neg-
ative, implying that the reactions proceed via asynchronous
We have presented a thorough study of the C-H activation
III
reactivity carried out by a Co -oxo complex and have deter-
mined that this reactivity occurs via basic asynchronous
CPET. DFT calculations and experimental evidence indicate
that the reaction does not employ a stepwise mechanism
and the dependence of the rate on the pK of the substrate
a
indicates that proton movement is paramount. This is in di-
rect contrast to the vast majority of previous systems where
the reactivity is controlled by the substrate BDEC-H. While
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Page 8 of 13
such proton-controlled reactivity has been observed previ- To a solution of lithium diisopropylamide (0.30 mmol
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
ously, these systems have invoked stepwise PTET mecha-
nisms to explain their observations. To the best of our
knowledge, this is the first example demonstrating experi-
mental evidence for asynchronicity in C-H activation. This
asynchronous pathway offers a compelling alternative to
mechanisms that have been traditionally invoked. For in-
stance, a basic asynchronous mechanism would imply se-
lectivity for the most acidic C–H bond in a substrate as op-
posed to the homolytically weakest bond. Furthermore,
asynchronous mechanisms may be relevant in a number of
processes, as potentially indicated by the important role of
made in situ from a 1:1 mixture of 2.5 M n-BuLi and diiso-
propylamine) in THF (3 mL) in the glovebox was added a
solution of fluorene (166 mg, 0.10 mmol) in THF (3 mL). The
bright orange solution was stirred for 30 minutes at room
temperature after which fluorobenzene (141 L, 0.15
mmol) was added. The resulting dark solution was stirred
for 3 hours at room temperature before removal from the
glovebox and addition of methanol (1 mL). Ethyl acetate
was added to the pale yellow solution which was then
washed twice with brine. The organic layer was dried over
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
MgSO , filtered, and pumped down to a pale yellow solid.
4
29
basicity noted in cytochrome P450 enzymes. This obser-
Recrystallization from ethanol (EtOH) gave pure 9-phenyl-
vation could open the door to new selectivity in reactions
carried out by transition metal oxo complexes and adds to
our growing understanding of C-H bond activation.
9H-fluorene (90 mg, 37% yield) as a white solid which
1
56 1
matched the reported H NMR spectrum. H NMR (CDCl
400 MHz):  7.80 (2H, d), 7.41-7.23 (9H, m), 7.10 (2H, d),
.05 (1H, s).
3
,
5
EXPERIMENTAL
Materials and Instrumentation
Synthesis of 9-(4-X-phenyl)-9H-fluorene (X = OMe, Me, or CF
To a solution of 9-fluorenone (0.50 g, 2.8 mmol) in tolu-
ene (30 mL) under air was added TsNHNH (0.775 g, 4.2
mmol) and the mixture heated at 80 °C for 2 hours. To the
bright yellow homogeneous solution was added K CO
0.575 g, 4.2 mmol) and 4-X-phenylboronic acid (4.2 mmol).
The heterogenous mixture was heated at reflux at 110 °C for
hours before cooling to room temperature. Dichloro-
methane (DCM) and saturated aqueous NaHCO were added
3
)
All manipulations were performed under a dry nitrogen
atmosphere using either standard Schlenk techniques or in
an mBraun Unilab Pro glovebox unless otherwise stated. All
chemicals were obtained from commercial sources and
used as received unless otherwise stated. Solvents were
dried on a solvent purification system from Pure Process
Technologies before storing over 4 Å molecular sieves un-
2
2
3
(
5
der N
and passed through a column of activated alumina prior to
storing over 4 Å sieves under N . 9,10-dihydroanthracene,
2
. Tetrahydrofuran (THF) was stirred over NaK alloy
3
and the layers separated. The aqueous layer was washed
twice with DCM followed by washing the combined organic
2
and xanthene were recrystallized from hexanes and fluo-
rene and diphenylmethane were recrystallized from meth-
anol prior to use. 1,3-cyclohexadiene was distilled and
layers once each with saturated aqueous NaHCO
3
and brine.
The organic layer was dried with MgSO , filtered, and
4
pumped down to a yellow solid. Recrystallization from
EtOH afforded the desired compounds in pure forms which
stored over 4 Å molecular sieves prior to use. DHA-d was
4
prepared according to a literature procedure and recrystal-
1
57
matched the reported H NMR spectra. Yields were 47%,
55
lized prior to use. All other substrates were synthesized
1
3
2%, and 30% for X = OMe, Me, and CF
3
, respectively. H
using slightly modified literature procedures (see below).
NMR (CDCl
3
, 400 MHz, X = OMe):  7.78 (2H, d), 7.37 (2H, t),
.30-7.23 (4H, m), 7.00 (2H, d), 6.82 (2H, d), 5.01 (1H, s),
t
III
PhB( BuIm)
3
Co O was synthesized according to the previ-
7
3
ously reported procedure using potassium hexamethyldisi-
1
.78 (3H, s). H NMR (CDCl , 400 MHz, X = Me):  7.78 (2H,
3
3
3
lazide as the base. UV-vis spectra were recorded on a
Thermo Scientific Evolution 300 spectrometer with the VI-
SIONpro software suite. The UV-vis spectra for the reaction
of 3 with 9-(4-(trifluoromethyl)phenyl)-9H-fluorene were
recorded using an Agilent HP 8453 spectrometer with the
UV-vis ChemStation software suite. A Hellma Analytics Ex-
calibur Immersion Probe with a 10 mm path length (Article
No. 661-202-10-S-46) was used for variable temperature
UV-vis spectroscopic measurements and a standard 1 cm
quartz cuvette with an air tight screw cap with a punctura-
ble Teflon seal was used for room temperature measure-
ments. Variable temperature UV-vis spectra were smoothed
using the 10 points adjacent averaging function in Origin
d), 7.37 (2H, t), 7.32-7.23 (4H, m), 7.07 (2H, d), 6.99 (2H, d),
1
5
.02 (1H, s), 2.31 (3H, s). H NMR (CDCl
3
, 400 MHz, X = CF ):
3

7.81 (2H, d), 7.53 (2H, t), 7.41 (2H, m), 7.27 (4H, m), 7.21
2H, d), 5.10 (1H, s).
(
Synthesis of 9-(tert-butyl)-9H-fluorene
To a suspension of 9-fluorenone (1.05 g, 5.8 mmol) in 20
t
mL of hexanes was added a solution of BuLi dropwise (1.5
M in pentanes, 6.0 mL). The dark solution was allowed to
stir at room temperature overnight after which H O (25 mL)
2
was added and the layers separated. The aqueous layer was
extracted twice with hexanes and the combined organic lay-
1
13
(
OriginLab, Northhampton, MA). H and C NMR spectra
ers washed once with H
MgSO , filtered, and the solvent evaporated. The residue
was dissolved in DCM (20 mL) after which Et SiH (2 mL)
and BF •Et O (1.6 mL) were added. The resulting homoge-
neous solution was stirred at room temperature for two
days after which H O (20 mL) was added. The aqueous layer
was extracted twice with DCM and the combined organic
layers dried over MgSO , filtered, and pumped down to an
2
O. The organic layer was dried over
were recorded on a Bruker DRX-400 spectrometer and ref-
erenced to residual proteo-solvent peaks. GC-MS data were
collected using an Agilent 7890B GC equipped with an Ag-
ilent HP-5MS column coupled to an Agilent 5977A EI/PCI-
MS. Isotope patterns were compared to the NIST library to
confirm assignments. Electrochemical measurements were
carried out using a BAS Epsilon potentiostat and using BAS
Epsilon software version 1.40.67NT.
4
3
3
2
2
4
orange residue. The residue was dissolved in hexanes and
run through a silica plug to remove orange impurities. The
hexanes were removed and the resulting residue
Synthesis of 9-phenyl-9H-fluorene
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Journal of the American Chemical Society
recrystallized from methanol to give the desired product
(220 mg, 17% yield) in pure form which matches the re-
the aqueous layer washed again with hexanes. The com-
bined organic layers were washed with H O, dried over
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
1
58 1
ported H NMR spectrum. H NMR (CDCl
3
, 400 MHz): 
MgSO
4
, filtered, and pumped down. The residue was recrys-
1
7.68 (2H, dt), 7.54 (2H, ddd), 7.33 (2H, tdd), 7.22 (2H, td),
3.63 (1H, s), 1.00 (9H, s).
tallized from methanol (90 mg, 36% yield). H NMR spec-
troscopy showed 95% deuterium incorporation.
6
2
Synthesis of 1,1,3,3-tetraphenylpropene
Synthesis of [HMTBD][BF
To a solution of MTBD in Et
amount of HBF •Et O. The resulting precipitate was col-
4
]
1
,1-diphenylethylene (353 L, 2.0 mmol) and benzhydrol
184 mg, 1.0 mmol) were dissolved in DCM (30 mL). p-tol-
uenesulfonic acid (190 mg, 1.1 mmol) and FeCl •6H O (27
2
O was added an equimolar
(
4
2
lected and dried under vacuum to yield pure [HMTBD][BF
4
]
3
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
mg, 0.01 mmol) were added and the solution heated at re-
flux for 4 hours. The resulting green solution was cooled to
room temperature and the solvent evaporated. The residue
(500 mg, 64% yield). H NMR (CD
3
CN, 400 MHz):  5.95 (1H,
), 2.88 (3H, s, Me), 1.95 (4H, m, CH ).
CN, 100 MHz):  151.2, 48.8, 48.3, 47.8, 39.6,
s, N-H), 3.28 (8H, m, CH
2
2
13
C NMR (CD
3
was extracted with Et
2
O and filtered through silica. Recrys-
37.5, 21.5, 21.3.
tallization from EtOH gave the desired product (289 mg,
1
83% yield) which matched the reported H NMR spec-
Synthesis of [DMTBD][BF ]
4
5
9 1
trum. H NMR (CDCl , 400 MHz):  7.37-7.15 (20H, m),
3
This was made analogously to [HMTBD][BF
above, but DBF was used instead of HBF •Et
•Et
4
] described
O. The DBF
O and D
6.53 (1H, d), 4.83 (1H, d).
4
4
2
4
was prepared in situ by mixing together HBF
4
2
2
O
Synthesis of 3-methylxanthene
63
in a 1:3 ratio by volume. The product was recrystallized by
This synthesis was carried out in two steps. First, the cor-
responding 3-methylxanthone was made following a modi-
layering a THF solution under Et O at −35 °C and showed
2
1
90% deuterium incorporation at the acidic position by
NMR (200 mg, 51% yield).
H
60
fied literature procedure. 2-nitrobenzaldehyde (2.00 g,
1
3.2 mmol), m-cresol (1.86 g, 19.8 mmol), CuCl
2
(89 mg,
0
.66 mmol), PPh (260 mg, 0.99 mmol), and K
3
3
PO •H
4
2
O
t
III
Titration of PhB( BuIm)
3
Co O with [HMTBD][BF
] was monitored by
H NMR spectroscopy. As the product of the reaction, 2, is
4
]
(6.70 g, 29.0 mmol) were mixed in ~100 mL of dry toluene.
The heterogeneous mixture was refluxed at 110 °C under an
The titration of 3 with [HMTBD][BF
4
1
active flow of N
room temperature, ~250 mL of DCM was added and the
combined organic layers washed twice with H O and once
with brine. The organic layers were dried over MgSO , fil-
2
, during which it darkened. After cooling to
unstable above −35 °C, the samples were prepared and
stored cold and the spectra were collected at −35 °C. Spectra
were collected on three separate samples for each amount
of acid added. To prepare a typical sample, 0.25 mL of a 20
2
4
tered, and pumped down to a dark residue. This residue was
dissolved in pure DCM, washed twice with 1 M NaOH, dried
mM solution of 3 in CD
NMR tube. Next, 0.10 mL of a 50 mM solution of hexame-
thyldisiloxane (TMS O) in CD CN was added as an internal
standard followed by addition of varying volumes of a 50
mM solution of [HMTBD][BF ] in CD CN to reach 0.25, 0.50,
0.75, 1.0, or 1.5 equivalents of added acid relative to 3. Fi-
nally, the samples were diluted with CD CN to reach a total
volume of 0.50 mL and initial concentrations of 10 mM 3, 10
mM TMS O, and 2.5-15 mM [HMTBD][BF ]. It was discov-
3
CN was transferred to a J. Young
over MgSO , filtered through silica to remove dark colored
4
impurities, and pumped down to a brown solid. This solid
was recrystallized from EtOH to give pure 3-methylxan-
2
3
thone (376 mg, 14% yield) which was carried on into the
4
3
1
next step. H NMR (CDCl
(
3
, 400 MHz):  8.35 (1H, dd), 8.22
1H, d), 7.72 (1H, td), 7.48 (1H, dd), 7.38 (1H, td), 7.30 (1H,
3
s), 7.22 (1H, d), 2.52 (3H, s). A previously reported reduc-
6
1
tion procedure was used to produce 3-methylxanthene. 3-
methylxanthone (300 mg, 1.4 mmol) was dissolved in dry
2
4
ered upon collecting the spectra that all species in solution
(2, 3, [HMTBD][BF ], and MTBD) were in rapid equilibrium.
THF. BH
added under N
3
SMe
2
(1.78 mL of a 2.0 M solution in THF) was
and the reaction stirred at room tempera-
4
The concentration of each species in solution at equilibrium
was determined using Equations 2-6 and the observed
2
ture overnight. The THF was removed under vacuum and
the residue dissolved in DCM. The organic layer was washed
twice with 2 M NaOH and filtered. The filtrate was acidified
with concentrated HCl and filtered again. The filtrate was
chemical
shift
for
the
methyl
protons
of
MTBD/[HMTBD][BF
4
]. From this data the equilibrium con-
stant for the reaction shown in Equation 7, Keq, was calcu-
lated and the values obtained from each initial concentra-
tion tested averaged. Finally, the relationship shown in
then washed with H
2
O, dried over MgSO , filtered, and
4
pumped down to an off-white powder that was pure 3-
1
Equation 8 was used to calculate the K of 2.
methylxanthene (185 mg, 66% yield). The H NMR spec-
a
1
trum matched that reported in the literature. H NMR
(
CDCl
3
, 400 MHz):  7.16 (2H, m), 7.03 (3H, m), 6.87 (2H, m),
훿표푏푠 =X푀푇퐵퐷훿푀푇퐵퐷+푋퐻푀푇퐵퐷훿퐻푀푇퐵퐷 (2)
4
.01 (2H, s), 2.32 (3H, s).
[
퐻푀푇퐵퐷](ꢅꢆꢇꢈ−ꢅꢉꢊꢋꢌ)
푖
[
ꢀꢁꢂꢃꢄ]푒푞
=
(3)
ꢅꢍꢉꢊꢋꢌ−ꢅꢉꢊꢋꢌ
Synthesis of fluorene-d
Fluorene (250 mg, 1.5 mmol) was dissolved in DMSO-d
~0.8 M) and three equivalents of solid NaH were added.
The suspension was stirred for 3-6 hours before addition of
excess D O. The mixture was extracted with hexanes and
2
6
[ꢂꢁꢃꢄ]푒푞 =[ꢀꢂꢁꢃꢄ] ꢏ[ꢀꢂꢁꢃꢄ] (4)
ꢎ
푒푞
(
[
ퟐ]푒푞 =[ꢂꢁꢃꢄ]푒푞 (5)
2
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 13
[
ퟑ]푒푞 =[ퟑ] ꢏ[ퟐ] (6)
T is the temperature in Kelvin). The activation parameters
ΔH and ΔS were determined from the linear fit via the
Eyring equation (Figure S7, Table 1).
ꢎ
푒푞
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
‡
‡
퐾ꢐꢑ
ퟑ+[ꢀꢂꢁꢃꢄ][ꢃ퐹]→ ퟐ+ꢂꢁꢃꢄ (7)
4
퐾푎,ꢍꢉꢊꢋꢌ
ꢒ푒푞
=
(8)
Determination of the upper bound ket for 2 from CV measure-
ments
퐾푎,ퟐ
A 3 mM solution of 1 in MeCN was prepared with 0.1 M
Procedure for kinetic studies
TBAPF as the electrolyte. A glassy carbon working elec-
6
Data for rate determination were collected in triplicate at
ambient temperature unless otherwise noted. In a typical
experiment, 2.0 mL of a 1.25 mM solution of 3 in THF was
transferred to an air tight screw top cuvette. After an initial
scan (or single absorbance data point at 470 nm) was col-
lected, a solution of substrate in THF was injected through
the septum in the screw top. The reaction was monitored
for an appropriate amount of time to either reach comple-
tion or ~3 half-lives. To determine the observed rate kobs
values, the data were analyzed by plotting the natural log of
the absorbance at 470 nm at time t divided by the initial ab-
sorbance vs time in seconds to give kobs as the slope of the
linear fit of the data. For diphenylmethane, this plot was
generated using the absorbance at 556 nm due to a convo-
luting absorbance at 470 nm from the radical product gen-
trode with a 3 mm diameter was used along with a Pt wire
counter electrode and a Ag wire reference electrode that
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
was externally referenced to the Fc/Fc couple. CVs were
+
collected from −964 mV to +235 mV versus Fc/Fc at vary-
ing scan rates (10 mV/s, 25 mV/s, 50 mV/s, 75 mV/s, 100
mV/s, 150 mV/s, 200 mV/s, 250 mV/s, 300 mV/s, 400
mV/s, and 800 mV/s). The peak anodic and cathodic current
densities, j
p
, were plotted versus the square roots of the
1/2
scan rates ( ). The linear fits of these data were used with
Equation 9 (for quasi-reversible electron transfer) to deter-
mine the diffusion coefficients, D
R
and D , respectively, for
O
the reduced (1) and oxidized (2) species.  was assumed to
be 0.5, n = 1 for the single electron transferred, and c is the
concentration. The spread in the anodic and cathodic peak
potentials (E
p
) for each scan rate was converted to the di-
erated. To determine the second order rate constants k for
various substrates, the kobs values were collected at various
concentrations of substrate and plotted vs the substrate
concentration to give k
2
mensionless parameter  according to Reference 46.  was
−
1/2
plotted versus 
and the slope of the linear fit of this data
was used with Equation 10 to determine k
shows the relationship between G and k, where Z is the
collision frequency for the heterogeneous (Z
M = the mass of the complex, 533 g/mol) or homogeneous
, Equation 13,  = the reduced mass of the reactant pair,
26 g/mol, r = the distance between the reactant pair,
7*10 cm) process. Assuming that the difference between
G for these processes is negligible (see Reference 47), ket
can be estimated from k using Equation 14. Estimating ket
s
. Equation 11
2
as the slope of the linear fit of the
‡
data. These k values were used to estimate kobs at 10 equiv-
2
E
, Equation 12,
alents of substrate for diphenylmethane and 1,3-CHD due to
the kinetically competitive self-decay rate of 3 at low sub-
strate concentration. KIE values were obtained by evaluat-
(Z
H
1
ing k
H
/k for DHA and fluorene using the kobs values ob-
D
−
8
tained with 10 equivalents of substrate. Hammett analysis
was carried out by comparing the relative rates (kobs ob-
tained using 10 equivalents of substrate) of reaction of the
substituted substrates to the unsubstituted 9-phenyl-9H-
fluorene or xanthene.
‡
s
at different temperatures is done using Equation 15 which
‡
is derived from Equations 11 and 13 and assumes H ~ 10
kcal/mol.
Determination of activation parameters for the reaction be-
tween 3 and DHA
푗 =(3∗10)푛(푛훼)ꢓ/2ꢄꢓ/2푐휈ꢓ/2 (9)
5
푝
Data for rate determination were collected in triplicate at
each temperature used for the Eyring analysis. In a typical
experiment, 4.0 mL of a 1.25 mM solution of 3 in THF was
transferred to a custom made, air-tight apparatus equipped
with a 14/20 ground glass joint, #2 size ground glass plug,
and #25 size threaded Teflon plug for the immersion probe
to go through which was sealed with a Teflon coated O-ring.
The entire apparatus was sealed inside the glovebox and re-
moved before cooling to the appropriate temperature (10
°C, 0 °C, −10 °C, −20 °C, and −30 °C) under a positive pres-
ꢖ
−ꢓ/2
퐷푂
휋퐷푂ꢗꢘꢙ
ꢚ푇
훹=ꢔ퐷푅ꢕ 푘 ꢔ
ꢕ
(10)
푠
ꢜ
‡
∆퐺 =ꢏꢛꢁlnꢔꢕ (11)
푍
ꢓ/2
ꢚ푇
ꢝ퐸 =ꢔ
ꢕ
(12)
2휋푀
ꢓ/2
휋ꢚ푇
8
2ꢟ
푟2 (13)
ꢝ =(6.0ꢞꢞ∗10 )ꢔ
ꢕ
퐻
휇
sure of N through the ground glass plug. After collecting an
2
initial scan, 50 equivalents of DHA were added as a 1.25 M
solution in THF (200 L) injected through a rubber septum
in the ground glass joint. The reaction was monitored until
ꢜ
ꢜ
ꢐ푡
ꢈ
=
(14)
푍ꢠ
푍ꢍ
ꢢ
‡
ꢢ
ꢤ∆ꢍ
푅
ꢢ
~
3 half-lives had been completed. To determine the ob-
ꢜ
ꢜ
푇
ꢔ
−
ꢕ
ꢊꢡ
ꢊꢢ
ꢡ
ꢡ
ꢔ ꢕ ꢣ
ꢊꢡ ꢊꢢ
=
(15)
served rate kobs values, the data were analyzed by plotting
the natural log of the absorbance at 470 nm at time t divided
by the initial absorbance vs time in seconds to give kobs as
the slope of the linear fit of the data. Using the relationship
푇
ꢢ
Reaction of 3 and fluorene in the presence of [DMTBD][BF ]
4
and MTBD at −35 °C
k
obs = [DHA]*k
2
, the k
2
values were determined at each tem-
/T) vs 1/T was generated (where
Reactions were carried out in the glovebox on a 1.0 mL
scale at −35 °C with the same initial concentrations used for
perature and a plot of ln(k
2
ACS Paragon Plus Environment

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Journal of the American Chemical Society
kinetic measurements (see above). Before addition of sub-
strate, 2.0 equivalents of [DMTBD][BF ] and 3.2 equivalents
AUTHOR INFORMATION
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
4
of MTBD were added to the solution of 3. The reactions
were left in the freezer for ~24 hours after which they were
diluted by a factor of ~10, filtered through silica gel, and an-
alyzed by GC-MS to screen for any deuterium incorporation
into aromatic hydrocarbon products.
Corresponding Author
E-mail: jsanderson@uchicago.edu
*
Author Contributions
The manuscript was written through contributions of all au-
thors. All authors have given approval to the final version of
the manuscript.
Evaluation of representative reaction conversion percentages
by GC-MS
Notes
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Reactions were carried out in the glovebox on a 1.0 mL
scale with the same initial concentrations used for kinetic
measurements (see above). After the reaction was com-
plete, mesitylene was added as an internal standard (0.5
equivalents relative to the initial amount of 3 present). The
reaction solutions were then diluted by a factor of 10,
passed through silica to remove Co, and analyzed by GC-MS.
For analysis of the reaction with DHA, EI-MS was used. For
analysis of the reaction with fluorene, PCI-MS was used. In-
tegration of the peaks in the chromatograms and compari-
son to a calibration curve of pure mesitylene allowed for the
determination of the concentration of the products in solu-
tion from which the percent conversion was calculated.
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Work presented here was funded by the following sources: NSF
CAREER award Grant No. 1654144, and the University of Chi-
cago. We are grateful for the support of the University of Chi-
cago Research Computing Center for assistance with the calcu-
lations carried out in this work. We would also like to
acknowledge Dr. Ethan Hill for encouraging us to think about
basicity, Dr. Jonathan H. Skone for many helpful discussions
about DFT calculations, Professor Vlad M. Iluc for the insightful
suggestion of the deuterium crossover experiment, and Profes-
sor Gerald Knizia for his insight regarding IBO analysis.
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Geometry optimizations and numerical frequency calcu-
6
4
lations were performed using the ORCA program suite.
The O3LYP hybrid functional was used for these calcula-
tions. The basis sets for each atom were as follows: def2-
TZVPP for Co, N, O, the carbene carbons of the ligand, and
the carbon undergoing C-H activation in each substrate;
def2-SVP for all other atoms. The COSMO solvation model
for THF solvation was included in all geometry calculations.
A full frequency calculation was performed on each struc-
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and ensure true minima in the energies. The initial geome-
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(2)
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Que, L. “The Road to Non-Heme Oxoferryls and Beyond.” Acc.
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(
Nam, W.; Lee, Y.-M.; Fukuzumi, S. “Hydrogen Atom Transfer
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(5)
“
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6
5
ometry optimization in the Hyperchem program suite.
(6)
The computed energy for each species was corrected for
0
thermal energy contributions. Calculation of pK values, E
a
(
7)
Sun, C.-L.; Li, B.-J.; Shi, Z.-J. “Direct C−H Transformation via
Iron Catalysis.” Chem. Rev. 2011, 111 (3), 1293–1314.
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values, and  values were performed analogously to meth-
ods reported in Reference 22.
The intrinsic bond orbital (IBO) analysis52–54 was carried
out by scanning the reaction coordinate as a function of O-
H distance from 1.8 Å to 0.95 Å. This scan was carried out in
the ORCA program suite. Each point’s energy was mini-
mized during this scan. For these calculations, the BP86
functional was used with the TZVPP basis set on Co, N, and
O and 6-31G on the remaining atoms. The results from this
scan were examined in the IboView software
(8)
(
9)
(10)
(
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Huynh, M. H. V.; Meyer, T. J. “Proton-Coupled Electron
Transfer.” Chem. Rev. 2007, 107 (11), 5004–5064.
(http://www.iboview.org/index.html). The orbitals in-
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(12)
Cukier, R. I.; Nocera, D. G. “Proton-Coupled Electron Transfer.”
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Evans, M. G.; Polanyi, M. “Inertia and Driving Force of
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in Hydrogen Atom Transfer by High-Valent Metal-Oxo
Porphyrinoid Compounds.” J. Am. Chem. Soc. 2018, 140 (12),
Detection of a High Spin Fe -Oxo Species Derived from Either
III
III
an Fe -Oxo or Fe -OH Complex.” J. Am. Chem. Soc. 2010, 132
(35), 12188–12190.
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1
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