Transition State Asymmetry in C-H Bond Cleavage by Proton-Coupled Electron Transfer

Article abstract of DOI:10.1021/jacs.9b04303

The selective transformation of C-H bonds is a longstanding challenge in modern chemistry. A recent report details C-H oxidation via multiple-site concerted proton-electron transfer (MS-CPET), where the proton and electron in the C-H bond are transferred to separate sites. Reactivity at a specific C-H bond was achieved by appropriate positioning of an internal benzoate base. Here, we extend that report to reactions of a series of molecules with differently substituted fluorenyl-benzoates and varying outer-sphere oxidants. These results probe the fundamental rate versus driving force relationships in this MS-CPET reaction at carbon by separately modulating the driving force for the proton and electron transfer components. The rate constants depend strongly on the pK_a of the internal base, but depend much less on the nature of the outer-sphere oxidant. These observations suggest that the transition states for these reactions are imbalanced. Density functional theory (DFT) was used to generate an internal reaction coordinate, which qualitatively reproduced the experimental observation of a transition state imbalance. Thus, in this system, homolytic C-H bond cleavage involves concerted but asynchronous transfer of the H⁺ and e^-. The nature of this transfer has implications for synthetic methodology and biological systems.

Full text of DOI:10.1021/jacs.9b04303

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Article
Transition State Asymmetry in C–H Bond
Cleavage by Proton-Coupled Electron Transfer
Julia W. Darcy, Scott S. Kolmar, and James M. Mayer
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b04303 • Publication Date (Web): 14 Jun 2019
Downloaded from http://pubs.acs.org on June 14, 2019
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Transition State Asymmetry in C–H Bond Cleavage by
Proton-Coupled Electron Transfer
Julia W. Darcy,† Scott S. Kolmar,† and James M. Mayer*
† equal contribution
Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA
Abstract. The selective transformation of C–H bonds is a longstanding challenge in modern chemistry. A recent report details
C–H oxidationvia multiple-site concerted proton-electrontransfer (MS-CPET), where the protonandelectron inthe C–H bond
are transferred to separate sites. Reactivity at a specific C–H bond was achieved by appropriate positioning of an internal
benzoate base. Here, we extend that report to reactions of a series of molecules with differently substituted fluorenyl-
benzoates and varying outer sphere oxidants. These results probe the fundamental rate vs. driving force relationships in this
MS-CPET reaction at carbon by separately modulating the driving force for the proton and electron transfer components. The
rate constants depend strongly onthe pKa of the internal base, but depend much less onthe nature of the outer sphere oxidant.
These observations suggest that the transition states for these reactions are imbalanced. Density functional theory (DFT) was
used to generate an internal reaction coordinate, which qualitatively reproduced the experimental observation of a transition
state imbalance. Thus, in this system, homolytic C–H bond cleavage involves concerted but asynchronous transfer of the H+
and e–. The nature of this transfer has implications for synthetic methodology and biological systems.
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cofactors.3 In cytochrome P450 oxidations, for example,
C–H bonds are cleaved by proton transfer tothe oxo group
Introduction.
The selective transformation of C–H bonds remains one
concerted with electrontransfer to a heme/thiolate-based
of the primary challenges facing modern chemistry. The
orbital.6 HAT and MS-CPET are widely utilized, from
practical and fundamental interest in manipulating these
biological to energy to synthetic processes, as the
inert bonds has stimulated decades of research from the
concerted transfer of protonsandelectronscanavoid high
organometallic, synthetic, biological, inorganic, and
energy, charged intermediates.7
physical organic chemistry communities.1 Many methods
Well-characterized examples of MS-CPET, in both
synthetic and biological contexts, have occurred nearly
exclusively at polar bonds, typically at O–H or N–H bonds.
In these systems, MS-CPET proceeds through the pre-
formation of a hydrogen bond, which serves to align the
proton transfer coordinate.8 The canonical biological
example of MS-CPET is the oxidation of TyrZ in
photosystem II, where the phenolic bond is cleaved by
have been developed to overcome the inertness of C–H
bonds, including the use of activating and directing
groups, selective catalysts, and supramolecular
recognition.
Hydrogen atom transfer (HAT) is the classical
mechanism for C–H bond activation, central to
combustion, free-radical halogenation and many other
processes.2 HAT is one kind of proton-coupled electron
transfer (PCET) process, in which a hydrogen atom – a
proton and electron (H+ + e– ≡ HŸ) – is transferred from
one group to another in a single kinetic step.3 HAT
mechanisms for C–H bond activation have a strong
intrinsic selectivity and can be harnessed in a number of
ways for processes from petrochemical scale to synthetic
organic transformations.2e,4
proton transfer to
accompanied by long-range electron transfer to P680
a
proximal histidine ligand
+ 9
.
Similarly, MS-CPET reactions in small molecule model
systems10 and synthesis reactions11 all occur at polar
bonds.
We recently demonstrated that MS-CPET can occur
directly at the C–H bond in the absence of classical
hydrogen bonding interactions.12 In the fluorenyl-
Most enzymatic oxidations of unactivated C–H bonds
are described as HAT processes, including heme and non-
heme iron and copper enzymes.5 Many of these and other
biological reactions, however, might be better described
as multiple-site concerted proton-electron transfer (MS-
CPET). MS-CPET reactions occur when electrons and
protons are transferred to or from disparate sites or
–
benzoate shown in Scheme 1, Flr(H)CO2 , the fluorenyl C–
H bond is oxidized by proton transfer to an internal
carboxylate concerted with electron transfer to an outer
sphere oxidant (Scheme 1). Use of MS-CPET as a strategy
for activating C–H bonds relies on the appropriate
positioning of a basic cofactor to provide the necessary
kinetic setting for proton transfer.12
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–
Scheme 1. MS-CPET at fluorenyl-benzoates Flr(R)CO2 , R = CF3, H, OMe, NH2. The driving forces for proton and electron
transfer can be modulated by changing the pKa of the internal base and the E1/2 of the external oxidant, respectively. Oxidation
leads to the formation of the carbon centered radical, which is subsequently converted to the corresponding lactone.
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Our previous report examined the variation in the rate
constant for oxidation of Flr(H)CO2 with various outer
suggest an imbalanced or asynchronous transition state,
where electronic reorganization and proton transfer have
occurred to different extents. Density functional theory
(DFT) methods were used to contextualize the
experimental results and were analyzed in the context of
Bernasconi’s PNS. Overall, the results inform how the rate
of C–H bond oxidation can be controlled by changes to the
electron or proton transfer reaction coordinates, and
suggest how selectivity could be achieved in synthetic and
biological contexts.
–
sphere oxidants. The rate vs. driving force relationship
upon changing the oxidant was found to be very shallow:
∂ln(k)/∂ln(Keq) = ∂(∆G‡)/∂(∆G°) = α = 0.2. Semiclassical
Marcus-theory type treatments predict an α of 0.5, and
this is what has typically been observed in both HAT and
MS-CPET reactions.2a,3,13 The small α shows that the
reaction rate constants are not greatly affected by the
nature of the outer sphere oxidant.
We hypothesized that the shallow dependence on the
potential of the oxidant could be due to an asynchronous
or imbalanced transition state. Transition state
imbalances have been extensively described for E2
Results
I. Synthesis/Characterization
elimination
reactions14
and
deprotonation
of
The compounds shown in Scheme 1 were synthesized
via a Pd-catalyzed coupling reactionbetween fluorene and
the corresponding para-substituted methyl 2-
bromobenzoate in DMF.22 The carboxylic acid derivatives
Flr(R)CO2H were obtained from the respective methyl
esters via base hydrolysis (see S.I. Section 2 for details).
nitroalkanes,15 and have been observed in many classes of
bond breaking and forming reactions.16 Jencks invoked
imbalanced transition states in describing structure-
reactivity coefficients in the 1970s; these ideas were
developed into the widely-used visualizations presented
in More O’Ferrall-Jencks plots.17 Building on this
framework, Bernasconi introduced his Principle of Non-
perfect Synchronization (PNS) to describe elementary
reactions that involve multiple concurrent processes, e.g.
The carboxylic acids were deprotonated in situ using a
slightly
substoichiometric
amount
of
tetrabutylammonium hydroxide (TBAOH, asa 1M solution
in MeOH). Oxidation reactions of the carboxylates were
performed with various para-substituted aminium
bond
formation/cleavage
and
electronic
localization/delocalization. Differences in the progression
of these processes at the transition state are called
Ÿ
(NArX +) and ferrocenium (Fc+) oxidants. The driving force
for reactions with this series of oxidants spans 1.2 V.
Oxidations of the carboxylates eachgave good yields of the
corresponding lactone with regeneration of protonated
starting material, as described previously for the R = H
derivative (see SI).12
imbalances.16,18
Complementary
multidimensional
analyses have been developed by Grunwald19 and
Guthrie.20 Asynchronicity has very recently been
discussed for metal-mediated HAT reactions of C–H
bonds, which can occur through multiple mechanisms.21
Asynchronicity is important from a practical perspective
because when different thermochemical parameters
affect transition state energetics differently, rates and
selectivities can be modulated by the choice of reagents.
II. Kinetics of oxidation reactions
The kinetics of oxidation were measured for all four
carboxylates with up to seven different aminium and
ferrocenium oxidants, in MeCN solvent (Figure 1A, Table
1). The carboxylate was generated in situ immediately
before the reaction by deprotonating with 0.9 equiv
tetrabutylammonium hydroxide (TBAOH, as a solution in
MeOH). Reactions were performed with an excess of
carboxylate relative to the oxidant (3-30 equiv). The
timecourses of the oxidations were monitored optically
using a stopped-flow instrument, following the
–
The fluorenyl-benzoate system (Flr(R)CO2 ) is an ideal
model to study fundamental aspects of MS-CPET at C–H
bonds. Herein, we demonstrate that independently
modulating the proton transfer and electron transfer
portions of the reaction result in very different rate vs.
driving force relationships (Scheme 1). The observed
discrepancies in the rate/driving force relationships
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(C)
(D)
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Figure 1. (A) General reaction scheme for the oxidation of Flr(R)CO2– substrates. Reactions were performed with an excess
of carboxylate, generated in situ with TBAOH (as a solution in MeOH). Absorbance spectra were monitored on a stopped-flow
following the disappearance of the colored aminium and ferrocenium oxidants. (B) Representative absorbance vs. time data
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set monitoring the reaction of N(ArOMe)
•+ with Flr(OMe)CO2–. The inset shows the absorbance at the λmax of the oxidant, 752
3
nm, vs. time, and the fit to an exponential function using SpecFit global fitting software. (C) Plot of the logarithm of the MS-
CPET rate constants (kMS-CPET = k2/2) vs. changes in driving force for all substrates over a range of oxidants. Δlog(Keq) = –
∆∆G°rxn/2.303RT and ∆∆G°rxn = ∆BDFECH(CO2H) – 1.37∆pKa(CO2H) – 23.06Eox (see text and Scheme 2). The ∆log(Keq) for the
reaction of the R = H compound with FeCp*2+ has been set equal to zero,12 and all other values are relative to that based on
changes in BDFECH and pKa,COOH (see SI for all values). Uncertainty in the last decimal is shown in parentheses. (D) Plot of MS-
+
CPET rate constants vs. changes in driving force for the four substrates with a single oxidant (FeCp2 ).
Table 1. Second-order rate constants for the reactions of carboxylates with oxidants of varying potential (Eox) in MeCN.a
–
–
–
–
Flr(NH2)CO2
k2 (M-1 s-1)d
Flr(OMe)CO2
k2 (M-1 s-1)d
Flr(H)CO2
Flr(CF3)CO2
k2 (M-1 s-1)d
Eox
(V)c
Entry
Oxidantb
k2 (M-1 s-1)d,e
7.2 ´ 105
5.4 ´ 104
1.9 ´ 104
9.5 ´ 103
1.9 ´ 103
3.8 ´ 102
2.3 ´ 101
•+
2.6 ´ 106
1.6 ´ 105
6.3 ´ 104
3.6 ´ 104
5.0 ´ 103
1.0 ´ 103
1.1 ´ 102
1
2
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7
N(ArBr)3
0.67
0.48
–
–
•+
N(ArOMe)(ArBr)2
N(ArOMe)2(ArBr)•+
–
–
4.4 ´ 103
1.1 ´ 103
1.9 ´ 102
3.0 ´ 101
–
0.32
–
•+
N(ArOMe
)
0.16
–
3
+
5.2 ´ 104
1.0 ´ 104
1.3 ´ 103
FeCp2
0.00
FeCp*Cp+
–0.27
–0.48
+
FeCp*2
a Carboxylates generated in situ from carboxylic acids using 0.9 equiv. of TBAOH (1 M in CH3OH); – = not determined. b ArX = p-C6H4-
X; Cp = η5-C5H5; Cp* = η5-C5Me5; all oxidants are PF6– salts. E1/2 vs. FeCp2+/0 in MeCN. d In MeCN with 0.2 vol% MeOH (NAr3•+) or
c
0.4 vol% MeOH (Fc+), uncertainties in k2 ca. ± 10%. e Data previously reported in ref 12
.
disappearance of the colored oxidants (Figure 1B). Each
full set of absorbance spectra over time were fit using
SpecFit global-fitting software.23 The rate constant for the
C–H bond oxidation step, kMS-CPET, is half of the measured
rate constants (k2 in Table 1) because two equivalents of
the oxidant are consumed in the total reaction, though the
MS-CPET step is rate-limiting.12 The data for the R = H
compound (orange points in Figure 1C) were reported in
our previous study.12
Reactions of the carboxylates with the oxidants fit well
to a second-order kinetic model, with a few exceptions.
Reactions of both the NH2- and CF3- derivatives with the
•+
stronger aminium oxidants (e.g., N (ArOMe)(ArBr)2
)
display deviations from the second-order model, likely
due to oxidant/base incompatibilities.24 The most
electron-rich and the most electron-poor of these series of
benzoates have undesirable side reactions that occur with
stronger oxidants (S.I. Section 3). These incompatibilities
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can be mitigated by using the weaker ferrocenium B3LYP/def2-TZVP with a polarized continuum model
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oxidants, as these are less susceptible to nucleophilic
attack by the carboxylate, for example.
(PCM) in acetonitrile solvent. Free energies were
calculated for isodesmic reactions between the carbon
radical of one carboxylate species and the C–H bond of a
second carboxylate compound (S.I. 4.2). The change in
BDFE with substituent are given in Table 3 relative to the
Bimolecular rate constants for the reactions of
–
–
–
Flr(OMe)CO2 , Flr(H)CO2 and Flr(CF3)CO2 with
N•+(ArOMe
)
3
were measured at different temperatures.
–
R = H compound. The BDFECH(CO2 ) changes by less than
Using data from –40 to 15 C for the first two compounds,
and from –20 to 15 C for the CF3 derivative, the Eyring
parameters in Table 2 were obtained (S.I. 3.4). The data
show that the free energies of activation are enthalpy
controlled.
1 kcal mol-1 with changes to R, presumably because the
substituents are meta to the radical center.28
9
Table 3. Changes in thermodynamic parameters with
substituent for substituted fluorenyl-benzoates, from
experiment and DFT calculations.a
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Table 2. Activation parameters for oxidations of
Flr(R)CO2– by N•+(ArOMe)3.a
–
pKa(CO2H)
∆pKa(CO2H)
ΔBDFECH(CO2 )b
R
expt
expt
(kcal mol-1)
‡
‡
Compound
D
D
S
H
NH2
OMe
H
22.0
21.5
21.2
20.3
+0.8
+0.3
0
–0.06
0.22
0
– b
Flr(OMe)CO2
14.4 ± 0.1
15.2 ± 0.3
16.3 ± 0.2
11.8 ± 0.5
11.6 ± 1.0
12.2 ± 0.8
– b
Flr(H)CO2
– c
Flr(CF3)CO2
CF3
–0.9
0.83
a See S.I. 3.4. DH‡ in kcal mol-1; DS‡ in cal K-1 mol-1. Uncer-
tainties are one standard deviation (1σ). b Based on kMS-
CPET from–40 to 15 C. c Based on kMS-CPET from –20 to 15 C.
a Relative values are vs. the R = H compound. b Differences
in the DFT-computed bond dissociation free energies
(BDFEs) for the carboxylate fluorenyl C–H bond
(B3LYP/def2-TZVP with PCM = MeCN).
III. Thermochemical analysis
Scheme 2. Thermochemical cycle to determine the
relative free energies of MS-CPET oxidation of the
fluorenyl C–H bonds.
The driving forces for the various C–H bond oxidation
reactions were determined using the thermochemical
cycle in Scheme 2. The relative pKa’s of Flr(R)CO2H in
MeCN (eq 2) were determined experimentally by equili-
bration ofeach carboxylate with4-trifluoromethylbenzoic
acid (TFBA) and monitoring by 1H and 19F NMR
spectroscopies in CD3CN, using a previously described
method.10d Absolute values were determined by
equilibrating TFBA with benzoic acid (pKa = 21.5).25 The
experimental pKa’s vary over a range of 1.7 units (Table 3).
While the MS-CPET processes should initially form the E-
isomers of the carboxylic acids, not the more stable Z-
forms, the relatively energetics of these isomers varies
little with substituents (based on computational
studies).26 Thus, the differences in the measured pKa
values should be sufficient for the relative MS-CPET free
energy calculation in Scheme 2.
The relative C–H bond dissociation free energies
–
(BDFEs, eq 1) for Flr(R)CO2 and Flr(R)CO2H were
determined computationally, as described below (see also
SI 4.1). The reaction being studied involves cleavage of the
C–H bond in the carboxylate form (Figure 1A), so those
values are used in the Discussion below and are in Table
3. However, the thermochemical cycle to determine the
overall driving force uses the BDFECH(CO2H) for the
carboxylic acid because that allows the use of the
experimental pKa values (Scheme 2) (S.I. Section 4.1). The
free energy to separate H• into e– and H+ (eq 3) is constant
over the series,7 and the reduction potentials of the
oxidants (eq 4) were taken from previous reports.10d,27
IV. Rate vs. driving force relationships
The values in Table 3 and the analysis in Scheme 2 give
the relative free energies (eq 6) and equilibrium
constants, ∆log(Keq) = –∆∆G°/2.303RT, for all of the C–H
bond cleavage reactions. The rate constants can be
compared to the ∆log(Keq) values to examine rate versus
driving force linear free energy relationships (LFERs). The
The relative bond dissociation free energies of the
fluorenyl C–H bond (∆BDFECH) for the carboxylate with
different R substituents were computed using Density
Functional Theory (DFT). The computations used
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full set ofrate vs. driving force data for the four derivatives understand what features of the reaction coordinate
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studied, with various oxidants, are shown in Figure 1C.
Most sets of single-step reactions such as those studied
here follow a single linear free energy relationship (LFER),
such as equation 7.17c The slope of this relationship α,
indicates how the logarithm of the rate constant changes
with a given change in ∆log(Keq).
might account for this distinction. To do this, we have
calculated the internal reaction coordinate (IRC). This is
defined as the minimum energy reaction pathway which
connects a transition state (TS) to the reactants and
products of a reaction. We take the IRC to be a reasonable
description of the potential energy surface (PES).
Our approach to analyzing these reactions follows the
computational studies of PT at carbon centers by
Bernasconi.29 While such adiabatic DFT calculations are
not the best approach to a reaction with an outer sphere
electron transfer component, we believe that this side-by-
side comparison of PT and MS-CPET provides valuable
insights. There are much more sophisticated theoretical
treatments of proton-coupled electron transfer
reactions,30 In particular, Sayfutyarova, Goldsmith, and
Hammes-Schiffer have very recently reported a study of
7
8
9
∆log(kMS-CPET) = a ∆log(Keq)
(7)
The dataset in Figure 1C is interesting because the
dependence of log(kMS-CPET) on Δlog(Keq) cannot be fit by a
single LFER. Even though the compounds and reactions
are very similar, a given value of ∆log(Keq) corresponds to
four different log(kMS-CPET) values, for the four different
substrates. The four MS-CPET rate constants at the same
∆log(Keq) differ by almost two orders of magnitude.
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Two different sets of LFERs are needed to describe the
results. The dependence of log(kMS-CPET) on Δlog(Keq) for a
single substrate over a series of oxidants will be termed the
electron transfer α, αET, because the Keq is changed only by
using outer sphere oxidants with different reduction
potentials. The αET value reports on how the rate constants
respond to changes in the electron transfer component of
MS-CPET. As shown inFigure 1C, all ofthe substrates have
αET @ 0.2, as found for Flr(H)CO2– in our previous report.12
The rate constants are much larger for the substrates with
the more basic carboxylates; for instance, the rate
constants for the -NH2 compound are on average an order
of magnitude larger than those for -OMe.
–
the oxidations of Flr(H)CO2 that treats the proton as a
quantum particle and emphasizes the importance of
vibrational excited states.31
Our goal with these DFT studies was to connect with the
prior physical-organic literature on proton transfers from
C–H bonds and its emphasis on imbalanced transition
states. To that end, we first describe computations of the
intramolecular proton transfer (PT) from fluorenyl C–H to
–
the carboxylate in Flr(H)CO2 . We then use the same
methodology to explore the more complicated MS-CPET
–
•+
reactions between Flr(H)CO2 and N(ArBr)3
and
•+
N(ArH)3
.
The IRCs for intramolecular PT and MS-CPET were
calculated using B3LYP/def2-SVP, because the MS-CPET
calculation with the def2-TZVP basis set was prohibitively
expensive. Both used a PCM solvent model with
acetonitrile solvent. First, the geometry of the substrate
and the product were optimized. Then, best guess
structures for the TS were used as a starting point for
transition state calculations. The true TS structures (at
this level of theory) were identified (i) by having a single
imaginary frequency along the appropriate reaction
coordinate (proton transfer between the fluorenyl carbon
and the carboxylate oxygen) and (ii) by IRC calculations of
the minimum energy pathway giving the optimized
reactant and products (S.I. 4.2, 4.3, and 4.5). The degree of
proton transfer and electronic reorganization (vide infra)
were then quantified along the IRC and at the TS.
The LFERs for reactions of a single oxidant with the four
differently substituted compounds have much steeper
slopes. This is shown in Figure 1C by the box surrounding
the four data points for reactions with Fc+. These four
points are plotted in Figure 1D, and show a slope of 0.58.
We term this the Brønsted αFc+, to indicate that it reflects
changes in the reactivity of the R-substituted fluorenes
with Fc+. For five of the seven different oxidants studied,
the Brønsted αox+ values are within the uncertainty of this
0.58 value (0.48 – 0.61); N(ArOMe)2(ArBr)•+ (0.36) and
FeCp*2 (0.99) are a bit different (S.I. 3.3, uncertainties
~±0.1). All of the αox+ values are substantially larger than
the αET for changes in the oxidant for with a given
substituted compound (two to five times larger).
+
The rate constants are much more sensitive to changes
in Keq that result from changing the benzoate substituent
versus changes in Keq from different outer sphere oxidants
(Figure 1C vs. Figure 1D). In the set of oxidations by
For both PT and MS-CPET, progress along the proton
transfer coordinate was defined as the distance between
the fluorenyl proton and carboxylate oxygen. For MS-
CPET, the extent of electrontransfer was determined from
the change inthe natural bondorbital (NBO) charge on the
nitrogen atom of the oxidant. Although the charge is
delocalized into the phenyl rings of the oxidant, the
nitrogen atom undergoes the largest change in charge and
thus provides a good measure of electron transfer.
FeCp2 , for instance, the rate constant for Flr(NH2)CO2– is
+
270 times faster than that of Flr(CF3)CO2– for a difference
in the equilibrium constants of 104 (Figure 1D). In
contrast, changing the oxidant from FeCp2+ to FeCp*Cp+, a
change in Keq of 3.5 ´ 104 results in a change in kMS-CPET of
only a factor of five. These data highlight the large
difference in slope between these two LFERs.
The calculations were also used to indicate the progress
of the Bernasconi-type “electronic reorganization” within
the fluorenyl group along this reaction coordinate.32 We
chose to use the pyramidalization of the fluorenyl carbon
as a measure of this reorganization, since it reflects the
extent of rehybridization from the starting saturated sp3
center to the sp2 carbanion or radical product of PT or
V. DFT calculated potential energy surfaces
A computational investigation was undertaken to
understand the origin of the very different dependencies
on changing the oxidant vs. changing the substituent in
these MS-CPET reactions. In particular, we aimed to
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C
D
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–
Figure 2. Comparison of the DFT-computed internal reaction coordinates and transition states for intramolecular PT in Flr(H)CO2
(A, C, and E) and for the MS-CPET reaction of Flr(H)CO2– and N(ArBr)3•+ (B, D, and F). (A and B) The transition state occurs at x = 0
along the reaction coordinate. Proceeding to negative values along the x-axis leads towards reactants, while proceeding to positive
values leads to products. Black circles show potential energy (∆E) along the reaction coordinate. (C and D) Red squares show the
distance between the fluorenyl proton and the carboxylate oxygen along the reaction coordinate, which is a measure of proton
transfer. For intramolecular PT, the fluorenyl proton has proceeded 76% towards the carboxylate oxygen. For MS-CPET, the
fluorenyl proton has proceeded 44% towards the carboxylate oxygen. (E and F) Blue triangles show the sum of the CCC bond angles
along the fluorenyl carbon along the reaction coordinate, which is a measure of electronic reorganization. For intramolecular PT, the
sum of the fluorenyl CCC bond angles has proceeded 45% towards the final geometry. For MS-CPET, the sum of the fluorenyl CCC
bond angles has proceeded 29% towards the final geometry.
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MS-CPET, respectively. This choice follows Bernasconi’s
study of the oxidation of the R = H compound, these
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calculations of the deprotonation of acetaldehyde
showing that pyramidalization of the α-carbon lags
significantly behind proton transfer to form the
enolate.18c,29a In our analysis, the sum of the CCC bond
angles around the fluorenyl carbon showed the progress
as it varied from 338° in the sp3 reactant to 358° in the sp2
products.
reactions proceed via concerted transfer of e– and H+
because the alternative initial PT or initial ET steps are
highly unfavorable.12 The data presented herein show that
the rates of this reaction are very sensitive to substituents
para to the benzoate base, but quite insensitive to the
reduction potential of the outer sphere oxidant.
The dependence of the rate constants on driving force
for this series of similar MS-CPET reactions cannot be
described by a single linear free energy relationship
(LFER). There is not a one-to-one correspondence of
log(kMS-CPET) with the changes in the free energies of the
reaction, described by ∆log(KMS-CPET). LFERs of very
different slopes are observed, depending on whether the
driving force is changed via changes in the outer-sphere
oxidant vs. the benzoate substituent (Figure 1C vs. 1D).
–
9
For intramolecular proton transfer in Flr(H)CO2 , PT is
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computed to be endoergic, with ∆E = +5.8 kcal mol-1 and
∆G° = +6.5 kcal mol-1 (Figure 2). The highest energy point
along the IRC, the TS, occurs when the proton transfer has
made 76% progress towards the product. At this point,
analysis of the TS structure shows that the sum of the
fluorenyl CCC bond angles is 349°, which is only 45%
progress towards the planar product (Figure 2C and E).
This indicates that for the PT reaction, PT is ahead of
fluorenyl rehybridization, or
Traditionally, experimental studies of MS-CPET (and
other types of PCET reactions) have used a Marcus-theory
approach.3 Most PCET reactions that have been studied at
this level of detail show similar sensitivities to ET and PT
driving forces and α’s close to 0.5.10a,d,33,34 We have argued
that such results imply synchronous transfer of the e– and
H+, with balanced transition states. A recent study by the
Knowles group of ketone reductions found a shallow α,
with the rate constants responding equally to changes in
the PT and ET portions.35 These reactions therefore
proceed via synchronous PCET. Goetz and Anderson
recently reported HAT reactions that are more dependent
on the pKa of the substrate than the C–H BDFE.21b There
are also PCET reactions that do not show simple
correlations of rate with driving force.36
electronic reorganization. This observation has been
made for many other deprotonation reactions at carbon,
as discussed below.
In comparison, the potential energy surface for MS-
–
•+
CPET between Flr(H)CO2 and N(ArBr)3 is highly
exoergic, with ∆E = –17 kcal mol-1 and ∆Go = –20.5 kcal
mol-1, and has a small barrier. The NBO charge on the
nitrogen atom of the oxidant stays constant until the TS,
then abruptly becomes more positive and stays constant
for the remainder of the reaction (S.I. 4.3). Thus, at this
level of theory, the ET component of the reaction occurs at
the TS. At the TS, the proton transfer has made 44%
progress towards the product while the sum of the
fluorenyl CCC bond angles is 344°, only 29% progress
towards the product (Figure 2D and F). As in the
computations of the PT reactions, the TS shows greater
progress in PT than in the electronic rearrangement of the
fluorenyl group. A similar result was found for the 2.1 kcal
The results reported here do not fit a simple Marcus-
type model. The observation that kMS-CPET does not simply
correlate with ∆G°MS-CPET – the presence of two LFERs for
the same range of driving forces – would require that the
intrinsic barriers vary substantially with substituent. This
seems very unlikely given the similarity of the compounds
and because the same αET is seen for each compound.
–
mol-1 less exoergic MS-CPET reaction of Flr(H)CO2 with
•+
N(ArH)3 (S.I. 4.5). (Calculations with ferrocenium
oxidants were found to be too computationally
expensive.) As expected from Hammond’s postulate, the
less exoergic reaction has proceeded farther along the
reaction coordinate, but the asymmetry is still observed.
In this case, PT has made 50% progress towards the
product, while the sum of the fluorenyl CCC bond angles
has made only 31% progress towards the product.
There are a number of other possible approaches that
could be used to interpret the apparent dual dependence
of log(kMS-CPET) on log(Keq-MS-CPET). A very recent study of
Sayfutyarova, Goldsmith, and Hammes-Schiffer analyzed
–
the oxidation ofFlr(H)CO2 with anapproach that includes
the quantum mechanical nature of the transferring
proton.31 They found significant contributions from
vibrational excited states in the reactant and product.
Both the MS-CPET and PT reactions proceed with
significantly more proton transfer from the C–H bond than
electronic reorganization within the fluorenyl group. In
both cases, electronic reorganization lags far behind the
proton transfer at the transition state. In the MS-CPET
cases, it is striking that despite the strongly exoergic
nature of the reaction, the proton has moved roughly half
way along its coordinate.
In this study, we have chosen to use an adiabatic DFT
model with a classical proton. While this cannot not
capture some effects, it allows a direct comparison with
classical physical-organic studies of proton transfer from
C-H bonds. In this model, the discrepancy between the
LFERs suggests that the H+ and e– transfer in a concerted
but asynchronous manner. DFT calculations indicate that
proton transfer is much more advanced at the transition
state than electronic reorganization, as observed in many
proton transfer reactions at carbon.16,32,37 In this
Discussion section, we identify the dominant effect of the
substituents and then contextualize the results in terms of
precedent in the physical organic chemistry literature.
Discussion
Presented here is a detailed kinetic study of the factors
that affect the cleavage of the C–H bond in four fluorenyl-
benzoate compounds by multiple-site concerted proton-
electron transfer (MS-CPET). As emphasized in our initial
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The strong analogies found between PT and MS-CPET at
C–H bonds are an important conclusion of this study.
radical (for MS-CPET) or carbanion (for simple PT). The
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calculations are consistent with the experimental
observation of two Brønsted α values. In many cases, the
Brønsted α is taken as a rough measure of the transition
state position.17c,40 The larger αox+ values for changes in
substituents should therefore imply a transition state that
is later – more product like – along the proton transfer
coordinate. We believe that these analyses provide a
qualitative rationale for the high sensitivity of our MS-
CPET reactions to the basicity of the carboxylate.
I. Disentangling substituent effects
Varying the outer sphere oxidant has the same effect for
each of the four compounds (Figure 1C): the rate
constants show a shallow dependence on the change in
the equilibrium constant. The αET, defined as ∆log(kMS-
CPET)/∆log(Keq) is 0.2 in all four cases. Analysis of the
effects of the different substituents is more complicated,
however, because the changes in substituent affect
multiple properties of the fluorenyl-benzoate molecules.
9
Reactions with imbalanced transition states have long
been discussed in the physical organic literature. In
particular, Bernasconi has argued that this is a very
common situation, as enunciated in his Principle of
Nonperfect Synchronization (PNS).18a,b,29b,18c,29a,41 Others
have developed similar ideas in different formalisms,
including Marcus,42 Kresge,15,40 More O’Ferrall, Jencks,
Grunwald,53 Guthrie19-20,43 and Bordwell.15 One classic
example is the deprotonation of nitroalkanes, where C–H
bond cleavage is more pronounced at the TS than the
electronic delocalization of the p system.15,37d
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Our analysis takes the following conceptual approach.
We consider that the fluorenyl radical is formed by
homolytic cleavage of the C–H bond, with the proton and
electron formed by this cleavage being transferred to the
carboxylate and the oxidant, respectively. This approach
is related to Savéant’s theory of electron transfer
concerted with bond cleavage, which emphasizes the
strength of the bond being cleaved, e.g., in electrochemical
carbon-halogen and peroxide O–O bond cleavages.38,39
The DFT analysis shows that pure proton transfer in
–
For the Flr(R)CO2 compounds, changing the R-group
–
Flr(H)CO2 behaves similarly to traditional C–H bond
affects both the basicity of the carboxylate and the C–H
BDFE. The larger effect is on the basicity, which
experimentally shifts by 1.7 pKa units, corresponding to a
change in ∆G° of 2.3 kcal mol-1. Shifts also occur in the
deprotonations, e.g., inaldehydes or nitroalkanes.16,18c The
Flr(H)CO2– PT transition state is imbalanced, with proton
transfer being farther along than the electronic
reorganization within the fluorene, as indicated by the
planarization of the incipient radical.
–
ΔBDFEC-Hs for the fluorenyl C–H bonds in Flr(R)CO2 ,
computed to vary by 0.9 kcal mol-1 (Table 2). The CF3
compound has the strongest C–H bond and is the slowest-
reacting substrate. However, the pattern of reactivity does
not otherwise follow the small changes in computed
∆BDFEs. Additionally, the -OMe compound reacts three
times faster than even the R=H compound, though the
R=OMe is computed to have a slightly stronger C–H bond.
While these comparisons may approach the limit of
relative computational accuracy, the changes in the C–H
BDFEs with benzoate substituent do not appear to be the
major contributor to the large variation of kMS-CPET with
substituent.
–
The imbalance of the proton transfer in Flr(H)CO2 is
illustrated in Figure 3A by a traditional More O’Ferrall-
Jencks plot.17a,44 The horizontal axis represents progress
along the PT coordinate and the vertical axis represents
progress along the internal electronic reorganization
coordinate. A synchronous reaction would be indicated by
progress along the diagonal of the square. The asynchrony
–
of PT in Flr(H)CO2 is indicated by the curved line that
connects the reactant to the product (bottom left to top
right corners). Because the transition state has more
progress along the proton transfer coordinate than the
electronic reorganization coordinate, the lines are curved
towards the bottom right corner.
The data indicate that the effects of the benzoate
substituents are primarily based on changes in the
basicity of the carboxylate acceptor. The spacing of the
LFER lines in Figure 1C, for instance, generally echo
differences in experimental pKa values for Flr(R)CO2H
(ΔpKa,COOH, Table 2), within the accuracy of the
measurements. The large Brønsted αox+ values thus
suggest a great sensitivity to the strength of the base, and
to the proton transfer portion of the MS-CPET reaction.
II. Imbalanced transition states
The computed proton potential energy surfaces for the
MS-CPET reactions described above suggest imbalanced
transition states for the MS-CPET reactions. In particular,
proton transfer appears to be more advanced than
expected from a simple Hammond postulate analysis.
Even though the reactions of Flr(H)CO2– and N(ArBr)3•+ or
•+
N(ArH)3 are strongly exoergic, at the TS the proton
transfer has progressed roughly half way to the product.
PT is more advanced than the electronic reorganization
within the fluorenyl unit to accommodate the incipient
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reaction is shown by a “jump” from one plane to another,
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because it occurs instantaneously on the timescale of
nuclear motions (the Frank-Condon principle).5a,30-31 This
takes the system to the upper plane where the nuclear
reorganization is completed to form the product. This
description is supported by the DFT calculations, which
show that the NBO charge on the nitrogen atom of the
oxidant sharply changes at the transition state, while the
nuclear motions proceed smoothly before and after the
transition state.
9
The late position of proton transfer along the reaction
coordinate provides a rationale for the larger Brønsted a
upon changing the substituent than the oxidant. It is,
however, more challenging to use this model to
understand the small dependence of the rate constants on
the reduction potential of oxidant (αET = 0.2). In a simple
Marcus theory formalism, a small α would normally
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indicate
a strongly exoergic reaction, with –∆G°
approaching l. This is not consistent with our estimates
that MS-CPET is close to isoergic for the oxidation of
–
Flr(H)CO2 with FeCp*2.12 In addition, this explanation
would require curvature of the log(kMS-CPET) vs. log(Keq-MS-
CPET) plots, which is not seen in Figure 1C. The TS for the
MS-CPET is early only in the “electronic reorganization”
coordinate, and this refers to p bond rearrangement in the
developing fluorenyl radical, not electron transfer to the
oxidant. Understanding the small α likely requires a more
complete treatment, asreportedrecently bySayfutyarova,
Goldsmith, and Hammes-Schiffer.31
Figure 3. (A) A More O’Ferrall-Jencks plot for intramolecular
proton transfer in Flr(H)CO2 . The progress of the proton
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transfer and electronic reorganization at the transition state
Conclusions
(‡) are noted with dashed lines. (B) A double More O’Ferrall-
–
Jencks plot for the MS-CPET reaction of Flr(H)CO2 with an
Reported here is a detailed study of the fundamental
properties of oxidative cleavage of C–H bonds, by
multiple-site concerted proton-electron transfer (MS-
CPET). This mechanism is a new addition to the arsenal of
C–H bond functionalization reactions. Kinetic studies of a
series of fluorene-benzoate substrates show that the
second-order rate constants are much more sensitive to
substituents on the benzoate than to changes in the
reduction potential of the oxidant. This shows,
surprisingly, that the kMS-CPET do not simply correlate with
the reaction driving force (Keq-MS-CPET). The kMS-CPET vary
much more dramatically when the Keq is changed via the
substituent (Brønsted αFc+ = 0.6) than when Keq is changed
with changes in the oxidant (αET = 0.2). Experimental and
computational analyses indicate that these differences
reflect a higher sensitivity to the pKa of the base rather
than the oxidizing power of the oxidant.
outer sphere oxidant. As in part (A), each of the two
horizontal planes illustrate the progress in the proton
transfer coordinate (horizontal) and in the electronic
reorganization coordinate. The jump from the bottom to the
top plane represents the electron transfer to the oxidant, an
essentially instantaneously step that takes the system from
one electronic state to another.
Extending Bernasconi’s PNS to MS-CPET requires
thinking not only about proton transfer and electronic
reorganization but also about the electron transfer
portion of the reaction. The adiabatic DFT calculations
used here are not the preferred treatment for electron
transfer processes, which can be non-adiabatic.30 Still, the
DFT analysis provides valuable insights into the structure
of the MS-CPET transition state. This transition state is
both the highest point along the proton reaction
coordinate and it is the point where the electron transfers
from Flr(R)CO2– to the oxidant (see above). The parallels
between the DFT description of MS-CPET with the PT case
are quite strong. Again, PT is farther along the reaction
coordinate than would be expected from the Hammond
postulate. Electronic reorganization within the fluorene
lags behind the proton transfer.
Computational experiments show that the MS-CPET
transition state (TS) is later on the proton transfer
reaction coordinate than would be expected from the
Hammond postulate. In addition, the TS shows
significantly more progress along the proton transfer
coordinate than along a coordinate that describes
electronic reorganization of the p bonding within the
fluorenyl group. Similar features were observed in DFT
analysis of intramolecular proton transfer (PT) within the
same substrate. These studies indicate strong analogies
between PT and MS-CPET, despite the latter reaction
involving an outersphere electron transfer component.
One way to visualize MS-CPET in the Bernasconi PNS
formalism is to represent the two electronic states as two
More O’Ferrall-Jencks planes, as shown in Figure 3B. The
bottom plane shows the nuclear reorganization to arrive
at the transition state. Electron transfer for the MS-CPET
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was extracted with Et2O (3 ´ 20 mL), then the organic
The description of these reactions is reminiscent of
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classical physical organic analyses of proton transfer from
C–H bonds, such as Bernasconi’s Principle of Nonperfect
Synchronization.
layer was washed with 1 M HCl (2 ´ 20 mL), H2O (2 ´ 20
mL) and brine (20 mL). The organic layer was dried over
MgSO4 and solvent evaporated. The crude reaction
mixture was purified on a silica gel column in 5%
EtOAc:hexanes eluent. The methyl ester products
generated via the above procedure were thentreated with
basic hydrolysis to yield the corresponding carboxylic
acid. The isolated methyl ester was added to a degassed
solution of ethanol and 3M aqueous KOH. This solution
was brought to reflux until a TLC revealed consumption of
the methyl ester starting material (usually in about 15-30
minutes). The reaction mixture was cooled to room
temperature and diluted with 1 M HClaq and washed with
Et2O to afford the carboxylic acids as white or off-white
solids.
The results reported here are, to our knowledge, the
first example of MS-CPET reactions that shows such a
clear differentiation between changes in the electron
transfer and the proton transfer reaction coordinates.
Since this is the only example that involves a C–H bond, we
tentatively suggest that this asymmetry could be
characteristic of MS-CPET of C–H bonds, just as it is for
simple deprotonation of C–H vs. N–H or O–H bonds. This
asynchrony of the concerted e–/H+ transfer should have
implications for broader development of MS-CPET as a
mechanism for C–H bond activation, for instance in
selectivity enforcement in synthetic reactions and
enzymatic processes.
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Experimental pKa measurements. Measurements of the
pKa’s were performed in analogy to a previous report.10d
In a typical experiment, a fluorenyl substrate was
deprotonated with 1.0 eq of 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU) in an N2-filled glovebox in CD3CN. Then, 4-
trifluoromethyl benzoic acid (TFBA) was added to the
solution, the mixture was allowed to equilibrate, and
1H/19F NMR spectra were measured to determine the
chemical shifts of chosen hydrogen and fluorine atoms at
equilibrium. The acid/base pair for each material are in
rapid equilibrium, so only an averaged signal was
observed for each. The chemical shifts of the averaged
signal give the ratio of acid to carboxylate for that species,
allowing determination of the quotient of the Ka’s of the
two acids in solution. These data were used to construct a
relative pKa scale. The relative pKa between TFBA and
benzoic acid was also measured, which gives the relative
scale an absolute anchor because the pKa of benzoic acid
in MeCN is known.
Experimental section
General considerations. Reagents were typically
purchased from Sigma Aldrich, Alfa Aesar, or Acros and
used as received. Solvents were obtained from Fisher,
deuterated
solvents
from
Cambridge
Isotope
Laboratories. Unless otherwise noted, experiments were
performed in an N2-filled glovebox using solvents that
were sparged with argon and plumbed directly into the
glovebox. Dimethylformamide was purified using a Glass
Contour Solvent Purification System (Pure Process
Technology, LLC, Nashua, NH). Acetonitrile was Burdick
Jackson low water grade and used without additional
–
drying. All oxidants used were hexafluorophosphate (PF6
) salts. Aminium27a and ferrocenium10d oxidants were
prepared as described previously. NMR samples following
MS-CPET reactions were prepared inan N2-filled glovebox
using degassed, deuterated solvents dried over activated
3 Å molecular sieves. NMR spectra were collected on
Agilent DD2-400 MHz, -500 MHz, or -600 MHz
spectrometers.
Kinetics. Kinetic measurements were recorded on an
OLIS-RSM
1000
single
mixing
stopped-flow
spectrophotometer in Burdick & Jackson low water
acetonitrile that was sparged with argon and plumbed
directly into an N2-filled glovebox. Measurements at
different temperatures were made on a TgK double
mixing stopped-flow instrument at temperatures ranging
from –40–15°C.
DFT calculations. All calculations were performed using
Gaussian16 software package. All optimized geometries
were confirmed to be local minima by vibrational analysis
(no imaginary frequencies). Geometry optimizations and
frequency calculations were performed at the
B3LYP/def2-SVP or B3LYP/def2-TZVP level of theory.
Cartesian coordinates of the optimized geometries of all
species are given in the Supporting Information.
Associated content
Supporting information
The Supporting Information is available free of charge on
the ACS publications website.
Synthesis. The carboxylic acids were generated by basic
hydrolysis from the corresponding methyl ester. The
methyl ester compounds were synthesized using a
modified procedure from a previous report.22 Fluorene
(1.2 eq), the appropriate methyl ester (1.0 eq), Pd(OAc)2
(2 mol%), PCy3•HBF4 (4 mol%), and Cs2CO3 (1.5 eq) were
added to a microwave vial that was equipped with a stir
bar. The vial was evacuated and backfilled with N2 on a
Schlenk line. DMF was taken directly from the solvent
system inside the glovebox and syringed into the reaction
vial. Then, the reaction was heated at 110 or 130°C
overnight (~16 h). The reaction was cooled to room
temperature and diluted with 1 M HCl. The aqueous layer
Synthesis and characterization, kinetic procedures and
tabulated data, DFT calculations, DFT calculated
coordinates (PDF)
Author information
Corresponding Author
* james.mayer@yale.edu
Notes
The authors declare no competing financial interest.
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(8) Gentry, E. C.; Knowles, R. R. Synthetic Applications of
Proton-Coupled Electron Transfer. Acc. Chem. Res. 2016, 49,
1546.
Acknowledgement
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5
We acknowledge the U.S. NIH (2R01GM50422 to J.M.M.)
for funding this work. We thank Zachary Goldsmith for
computational advice.
(9) Keough, J. M.; Jenson, D. L.; Zuniga, A. N.; Barry, B. A.
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transfer is misleading. If changes in the fluorene acidity were a
dominant effect in this reactivity, then we would predict a
substituent effect opposite of the one observed: the CF3
compound would be the most reactive as it would be the most
acidic.
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1
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TOC Graphic
k is less sensitive to
the potential of the oxidant
ox+
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O
O
H
O
HO
oxidative
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proton-electron
transfer
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R
R
= CF3, H, OMe, NH2
k is more sensitive to the
pKa of the internal carboxylate
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