Separating Proton and Electron Transfer Effects in Three-Component Concerted Proton-Coupled Electron Transfer Reactions

Article abstract of DOI:10.1021/jacs.7b03562

Multiple-site concerted proton-electron transfer (MS-CPET) reactions were studied in a three-component system. 1-Hydroxy-2,2,6,6-tetramethylpiperidine (TEMPOH) was oxidized to the stable radical TEMPO by electron transfer to ferrocenium oxidants coupled to proton transfer to various pyridine bases. These MS-CPET reactions contrast with the usual reactivity of TEMPOH by hydrogen atom transfer (HAT) to a single e^-/H⁺ acceptor. The three-component reactions proceed by pre-equilibrium formation of a hydrogen-bonded adduct between TEMPOH and the pyridine base, and the adduct is then oxidized by the ferrocenium in a bimolecular MS-CPET step. The second-order rate constants, measured using stopped-flow kinetic techniques, spanned 4 orders of magnitude. An advantage of this system is that the MS-CPET driving force could be independently varied by changing either the pK_a of the base or the reduction potential (E°) of the oxidant. Changes in ΔG°_MS-CPET from either source had the same effect on the MS-CPET rate constants, and a combined Br?nsted plot of ln(k_MS-CPET) vs ln(K_eq) was linear with a slope of 0.46. These results imply a synchronous concerted mechanism, in which the proton and electron transfer components of the CPET process make equal contributions to the rate constants. The only outliers to the Br?nsted correlation are the reactions with sterically hindered pyridines, which apparently hinder the close approach of proton donor and acceptor that facilitates MS-CPET. These three-component reactions are compared with a related HAT reaction of TEMPOH, with the 2,4,6-tri-tert-butylphenoxyl radical. The MS-CPET and HAT oxidations of TEMPOH at the same driving force occurred with similar rate constants. While this is an imperfect comparison, the data suggest that the separation of the proton and electron to different reagents does not significantly inhibit the proton-coupled electron transfer process.

Full text of DOI:10.1021/jacs.7b03562

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Article
Separating Proton and Electron Transfer Effects
in Three-Component Concerted PCET Reactions
Wesley Daniel Morris, and James M. Mayer
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b03562 • Publication Date (Web): 03 Jul 2017
Downloaded from http://pubs.acs.org on July 3, 2017
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Separating Proton and Electron Transfer Effects in
ThreeꢀComponent Concerted PCET Reactions
Wesley D. Morris and James M. Mayer*
Department of Chemistry, Yale University, New Haven, Connecticut 06511, United States
james.mayer@yale.edu
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Abstract
Multipleꢀsite concerted proton electron transfer (MSꢀCPET) reactions were studied in a threeꢀ
component system. 1ꢀhydroxyꢀ2,2,6,6ꢀtetramethylpiperidine (TEMPOH) was oxidized to the
stable radical TEMPO by electron transfer to ferrocenium oxidants coupled to proton transfer to
various pyridine bases. These MSꢀCPET reactions contrast with the usual reactivity of TEMPOH
−
+
by hydrogen atom transfer to a single e /H acceptor. The threeꢀcomponent reactions proceed by
preꢀequilibrium formation of a hydrogenꢀbonded adduct between TEMPOH and the pyridine
base, which is then oxidized by the ferrocenium in a bimolecular MSꢀCPET step. The second
order rate constants, measured using stoppedꢀflow kinetic techniques, spanned four orders of
magnitude. An advantage of this system is that the MSꢀCPET driving force could be
independently varied by changing either the pK of the base or the reduction potential (E°) of the
a
oxidant. Changes in ∆G°MSꢀCPET from either source had the same effect on the MSꢀCPET rate
constants, and a combined Brønsted plot of ln(kMSꢀCPET) vs. ln(K ) was linear with a slope of
eq
0
.46. These results imply a synchronous concerted mechanism, in which the proton and electron
transfer components of the CPET process make equal contributions to the rate constants. The
only outlier to the Brønsted correlation are the reactions with sterically hindered pyridines, which
apparently hinder the close approach of proton donor and acceptor that facilitates MSꢀCPET.
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These threeꢀcomponent reactions are compared with a related hydrogen atom transfer reaction of
TEMPOH, with the 2,4,6ꢀtriꢀtertꢀbutylphenoxyl radical. The MSꢀCPET and HAT oxidations of
TEMPOH at the same driving force occurred with similar rate constants. While this is an
imperfect comparison, the data suggest that the separation of the proton and electron to different
reagents does not significantly inhibit the PCET process.
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Introduction
Protonꢀcoupled electron transfer (PCET) reactions are key to a wide range of processes from
1ꢀ4
chemical energy conversions to biochemistry. The simplest and most common examples
involve the transfer of one electron and one proton. These reactions can proceed by stepwise
proton transfer (PT) and electron transfer (ET) steps, or in the same kinetic step by concerted
proton electron transfer (CPET or EPT). One large class of CPET reactions are hydrogen atom
–
+
5
transfers, in which the e and H move ‘together’. At the other extreme, the proton and electron
can move to or come from separated locations or completely different reagents, termed multiple
6ꢀ8
siteꢀCPET (MSꢀCPET, or sometimes bidirectional PCET or orthogonal EPT). MSꢀCPET
reactions are key to many biological processes where nature uses protons to balance charges
1
,9
during oxidation and reduction reactions. Recently a number of catalytic processes utilizing
1
0ꢀ14
MSꢀCPET have been developed for organic synthetic applications.
Small model systems have been key to developing understanding of MSꢀCPET reactions.
Many laboratories, including ours, have studied twoꢀcomponent systems in which intermolecular
electron transfer is coupled to an intramolecular proton transfer across a hydrogen bond to a
1
5ꢀ23
covalently tethered base.
The covalent tether promotes formation of the hydrogen bond and
18,19,23
can probe the effects of different hydrogen bond distances.
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Threeꢀcomponent MSꢀCPET systems allow independent modulation of the proton and
electron components. Pioneering work by Linschitz et al. showed that phenols could be oxidized
by electron transfer to photoꢀexcited triplet C coupled to proton transfer to various pyridine
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…
The mechanism was shown to involve electron removal from a phenol pyridine
bases.
hydrogenꢀbonded pair, and the rate constants were dependent on the pK of the base. Fecenko,
a
Thorp and Meyer studied electrocatalytic MSꢀCPET oxidations of tyrosine in basic buffers with
metal trisꢀdiimine complexes, and reported the free energy dependence of these reactions upon
2
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varying both the oxidant and the base.
More recently, Wenger and coꢀworkers have observed
similar rates for bimolecular and termolecular photochemical MSꢀCPET reactions in the
8
presence of added pyridine using paraꢀsubstituted phenols as donors. Bourrez, Hammarström, et
al. have reported MSꢀCPET from a tungsten hydride complex with a series of bases and
2
8
oxidants.
Scheme 1. MSꢀPCET from TEMPOH to pyridine bases and ferrocenium oxidants
The study reported here examines how threeꢀcomponent MSꢀCPET rate constants
respond to systematic and independent variations of the oxidant, the base, the hydrogen bond,
and the overall driving force (∆G°CPET) of the process (Scheme 1). TEMPOH (1ꢀhydroxyꢀ
2
,2,6,6ꢀtetramethylpiperidine) was selected as the hydrogen atom donor because its properties
−
+
favor the concerted release of e and H over the competing stepwise PTꢀET or ETꢀPT
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mechanisms. Various commercially available pyridine bases were used as proton acceptors
because the basicity (and driving force for proton transfer) and sterics around the nitrogen can be
systematically modulated. Substitution on the para position changes the pK of the base without
a
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affecting the hydrogen bond geometry, whereas substitution at the ortho position probes the
sensitivity of MSꢀCPET reaction to the hydrogen bond structure. The effect of electron transfer
driving force was probed with different ferrocenium oxidants. These systematic changes show
that the MSꢀCPET process involves equal contributions from the proton and electron transfer
components, implying a synchronous transfer of the two particles. This study also provides
additional evidence against the intuition that MSꢀCPET reactions are less facile than related
hydrogen atom transfer processes, following Wenger’s related study with excited state ruthenium
8
oxidants.
Results
The results reported here are all consistent with preꢀequilibrium formation of a hydrogenꢀ
bonded adduct followed by a bimolecular reaction with the oxidant (Scheme 2), consistent with
8
,24,25
prior studies.
The following sections present studies of the hydrogenꢀbond equilibria, then
kinetic measurements and thermochemical analyses.
I. Hydrogen bond equilibria. The rates of hydrogenꢀbond formation and dissociation between
TEMPOH and the pyridine base are fast relative to the MSꢀCPET reaction so this is a rapid preꢀ
equilibrium process. To determine the second order MSꢀCPET rate constant (k ) in Scheme 2,
2
the hydrogen bond KHB values are needed. Initial experiments to measure KHB in acetonitrile
(
MeCN) solvent showed very little hydrogen bond formation, likely because MeCN competes
with pyridine. Therefore, our studies were done predominantly with CH Cl as the solvent.
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…
The hydrogenꢀbond equilibrium constant (K ) for formation of the TEMPOH Rꢀpy
HB
hydrogen bond was determined using IR spectroscopy. Solutions of TEMPOH in CH Cl show a
2
2
Scheme 2. Equilibrium formation of hydrogenꢀbonded adduct (top), followed by oxidation with
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a
an outer sphere oxidant (bottom), and the rate law for this mechanism.
−ꢀꢁꢂꢃꢄꢅ
ꢇ ꢌ ꢁꢏꢐꢑꢒꢓꢔꢅ ꢁꢖꢗꢅꢁꢂꢃ ꢅ
ꢄ
ꢋ
ꢍꢎ
ꢕ
ꢄ
=
ꢇꢈꢉꢊꢁꢂꢃ ꢅ =
ꢘꢘꢘꢘꢘꢘꢘꢘꢘꢘꢘꢘꢘꢘꢘꢘꢘꢘꢘ(1)
ꢀ
ꢆ
1 + ꢌ ꢁꢖꢗꢅ
ꢍꢎ
–
–––––––––––––––––––––––––
Equation (1) applies when [py] ≫ [TEMPOH].
a
a) 0
.30
.25
.20
.15
b) 3.0
Pyridine
,6ꢀLutidine
2ꢀMeꢀpy
4ꢀMeꢀpy
TEMPOH Only
0.24 M py
2
0
0
0
2.5
2.0
1.5
0.60 M py
0.92 M py
1.13 M py
4ꢀMeOꢀpy
1.42 M py
.71 M py
2.07 M py
.86 M py
1
DMAP
2
0.10
.05
0.00
1
.0
0.5
.0
0
0
3
600
3500
3400
3300
3200
0.0
0.5
1.0
1.5
2.0
2.5
ꢀ1
Wavenumber (cm )
[Base] (M)
Figure 1. (a) IR spectra of TEMPOH in CH Cl with increasing concentrations of py, showing
2
2
ꢀ1
decreasing absorbance at 3582 cm due to free TEMPOH and increasing intensity in the broad
ꢀ1
…
band at 3237 cm due to the TEMPOH py hydrogen bonded adduct. The sharp feature at 3150
ꢀ1
cm is from the pyridine aromatic CꢀH stretches. (b) Plot of [Adduct]/[TEMPOH] vs. [Rꢀpy] for
various substituted pyridines. Linear fits to the data are shown; the slope corresponds to the
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hydrogen bond equilibrium constant (K ). 2,6ꢀLutidine = 2,6ꢀdimethylpyridine; DMAP = 4ꢀ
HB
dimethylaminopyridine.
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ꢀ1
characteristic sharp OꢀH stretch at 3582 cm (Figure 1a). Addition of pyridine to such solutions
causes a decrease in this absorption and the appearance of a broad absorption centered at 3240
ꢀ1
…
cm , corresponding to the OꢀH stretch of the TEMPOH py adduct. These absorbances were
converted to concentrations using a massꢀbalance equation, and KHB was derived as the slope of
the plot of [adduct]/[free TEMPOH] vs. [Rꢀpy] (Figure 1b; Supplementary Information [SI]
Section 3). The adduct formation equilibrium constants for TEMPOH with all pyridine bases
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1
studied are given in Table 1. Hydrogenꢀbond formation was also examined by H NMR
spectroscopy and appeared similar, but quantitative analysis was not possible due to significant
variations in chemical shifts at the high pyridine concentrations required (SI Section 4).
II. Kinetic measurements. Termolecular rate constants for MSꢀCPET were measured for
+
reactions of TEMPOH with ferrocenium oxidants (Fc ) and pyridine bases in either CH Cl or
2
2
MeCN. The kinetics were monitored primarily in CH Cl because of the more favorable
2
2
…
TEMPOH Rꢀpy hydrogen bond in this solvent. These were typically performed under
conditions of excess TEMPOH and excess base (Rꢀpy), using a stoppedꢀflow kinetics apparatus.
Figure 2a is a representative data set showing the loss of the ferrocenium absorbance (λmax = 618
nm) concurrent with the appearance of the characteristic ferrocene absorbance (λmax = 437 nm).
Pseudoꢀfirst order rate constants were extracted using a global fit over all measured wavelengths;
the absorbances for a singleꢀwavelength and a singleꢀexponential fit are shown in Figure 1b. The
exponential fit over more than three halfꢀlives shows the firstꢀorder dependence on the oxidant.
Most experiments were done under conditions where only a small amount of the
hydrogen bonded adduct was formed, where K [Rꢀpy] ≤ 0.1. Under these conditions the
HB
measured kobs varied linearly with the concentration of TEMPOH and pyridine, demonstrating
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the termolecular rate law: ꢀd[Fc ]/dt = k [TEMPOH][Rꢀpy][Fc ]. Hydrogenꢀbond equilibrium
3
constants (from IR studies) combined with the measured rate constants kobs using equation 1 give
the bimolecular MSꢀCPET rate constants k (Table 1).
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The mechanism in Scheme 2 predicts that the kobs should show saturation behavior at
high enough pyridine concentration (eq 1). Experiments at very high [Rꢀpy], > 1 M showed such
predicted saturation kinetics. However, fitting a curved kobs vs. [py] plot such as SI Fig. S6 gave
apparent KHB values that were typically significantly higher than those from the IR and NMR
measurements. We attribute this discrepancy to the rate and equilibrium constants changing at
high Rꢀpy concentrations (1 M py in CH Cl is 6.5 mol% and 8.1 volume% pyridine).
2
2
0
.4
0.4
0.3
0.2
0.1
0.3
0.2
Data (618 nm)
Fit
0.1
450
500
550
600
0.0
0.2
0.4
0.6
0.8
1.0
Wavelength (nm)
Time (s)
+
Figure 2. (a) Optical absorption spectra showing the loss of the Cp Fe absorbance (over 1
2
second) at 618 nm. (b) Single wavelength trace at 618 nm and fit to single exponential.
+
Values of k were determined for Cp Fe with six different pyridine bases, 2ꢀmethylꢀ
3
2
pyridine, 4ꢀmethylꢀpyridine, 2,6ꢀdimethylꢀpyridine, 4ꢀdimethylaminoꢀpyridine, and 4ꢀmethoxyꢀ
pyridine. In addition, reactions were studied with [(MeCp) Fe]PF , [Cp(Cp*)Fe]PF , and
2
6
6
5
5
5
[Cp Fe]BF [MeCp = η ꢀC H Me, Cp = η ꢀC H , Cp* = η ꢀC Me ]. The results are given in
2
4
5
4
5
5
5
5
Table 1, along with the hydrogen bond equilibrium constants. Kinetic isotope effects were
measured using an excess of TEMPOꢀD. The values of k /k varied from 2.0 to 4.5, for 2ꢀ
3
H
3D
methylpyridine and pyridine, respectively.
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III. Thermochemical Measurements.
One of the MSꢀCPET reactions was also studied in the reverse direction, the reduction of
TEMPO with Cp(Cp*)Fe and excess 4ꢀmethylꢀpyridinium hexafluorophosphate ([4ꢀMeꢀpy]PF6)
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ꢀ2 ꢀ1 29
eq 2): kꢀ = 22 M s . The ratio of k and k is the equilibrium constant K , a direct
3
4
–4
4
ꢀ1
measurement of the thermodynamics of the reaction: ∆G° = –1.0 kcal mol . This provides an
anchor point for the measurements of relative thermochemistry in the next paragraphs.
(
2)
Reduction potentials in CH Cl for the ferrocenes used here were determined by cyclic
2
2
voltammetry, yielding relative E1/2 values (∆E , SI p. S2). The relative pK values for the
1/2
a
pyridine/pyridinum compounds were determined by equilibration under conditions similar to the
3
0
MSꢀCPET reactions, since a pK scale is not well established in CH Cl solvent. The position
a
2
2
1
of the equilibrium in eq 3 was easily monitored by H NMR spectroscopy. Pyridine bases and
their conjugate acids are in rapid equilibrium on the NMR timescale, so the averaged chemical
1
shift of the H NMR resonances in CD Cl indicates the extent of protonation of each base. The
2
2
relative pK values in CH Cl were confirmed with overlapping measurements (SI Section 5).
a
2
2
Together, the reduction potentials and relative pK values directly translate to differences in free
a
3
1
energies of reaction with eq 4.
+
+
pyH + Rꢀpy
py + RꢀpyH
(3)
(4)
o
ꢀꢀG = 1.37∆pK + 23.06∆E
a
1/2
In CPET processes, the driving force is typically most easily described as the difference
in the two bond dissociation free energies (BDFEs). This is evident for a hydrogen atom transfer
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process X–H + Y ꢀ X + Y–H, for which ∆G°HAT = BDFE(Y–H) – BDFE(X–H). As we have
3
1
–
discussed elsewhere, this approach is also valuable for MSꢀCPET reactions, even though the e
+
and H do not transfer to make a single Y–H bond. In the reactions presented here, the product
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
+
combination Cp Fe + RꢀpyH can be considered to have an “effective BDFE” (BDFE ) which is
2
eff
its thermodynamic ability to form H• (eq 5). By analogy with a single reagent X–H, the BDFEeff
can be determined from the redox potential of the oxidant, the pK of the base used, and a
a
constant (C ) which is specific for the solvent being used (eq 6). Then the free energy of the
G
reactions is the difference between the TEMPOH BDFE and the BDFE of the oxidation/base
eff
pair (eq 7).
+
+
+
X + BH ꢀ X + B + H•
∆G° = BDFE (X + BH )
(5)
(6)
(7)
eff
+
+
+/0
BDFE (X + BH ) = 1.37pK (BH ) + 23.06E°’(X ) + C
eff
a
G(solv)
+
∆
G°MSꢀCPET = BDFE(TEMPO–H) – BDFE (Cp Fe + RꢀpyH )
eff
2
In the current study, the BDFE values were obtained via equilibration rather than via eq
eff
6
, because C is not available in CH Cl (due to the lack of an absolute pK scale). The use of
G
2
2
a
–
relative pK s for structurally similar acids and the same PF6 counterion should minimize
a
differential contributions from the tight ion pairing in CH Cl . The conclusion is that in CH Cl ,
2
2
2
2
ꢀ1
ꢀ1
the BDFEeff for Cp(Cp*)Fe + [4ꢀMeꢀpyH]PF is 66 kcal mol , 1.0 kcal mol larger than the
6
6
,32
BDFE of TEMPOH (estimated from values in C H and MeCN ). The BDFE for all of the
6
6
eff
ꢀ1
6
combinations in Table 1 are given by 65 kcal mol (the BDFE of TEMPO–H) minus the
∆G°reaction given in the last column of the Table.
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Table 1. Rate constants, equilibrium constants and free energies for TEMPOH(D) oxidations with ferrocenium oxidants and pyridine
a
bases.
b
b
c
d
k
k
KHB
k2
ꢀG°
3
3
(H)
3(D)
b
Entry Oxidant
Base
Solvent
k
3(H)/ k3(D)
ꢀ2 ꢀ1
3
ꢀ2 ꢀ1
ꢀ1
3
ꢀ1 ꢀ1
ꢀ1
(
×10 M s ) (×10 M s )
(M )
1.08
1.76
1.04
1.12
0.49
2.66
1.08
1.08
1.76
1.04
2.66
(×10 M s ) (kcal mol )
1
[Cp Fe]BF
py
CH Cl
7.2
19
26
7.1
3.9
570
13
0.035
1.6
4.3
7.2
3.5
1.8
4.5
4.4
3.6
2.0
2.2
4.4
7.4
12
29
7.5
8.3
280
ꢀ6.1
ꢀ7.1
ꢀ8.1
ꢀ6.8
ꢀ8.2
ꢀ11.6
ꢀ3.7
ꢀ0.1
ꢀ1.0
ꢀ2.0
ꢀ5.5
ꢀ5.6
ꢀ7.0
ꢀ7.9
2
4
4
4
4
4
4
2
2
2
2
2
2
2
2
2
2
2
2
10
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12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
2
[Cp Fe]BF
4ꢀMeꢀpy
4ꢀMeOꢀpy
2ꢀMeꢀpy
2,6ꢀlutidine
CH Cl
2
2
3
[Cp Fe]BF
CH Cl
2
2
4
[Cp Fe]BF
CH Cl
2
2
5
[Cp Fe]BF
CH Cl
2
2
6
[Cp Fe]BF
4ꢀMe Nꢀpy
CH Cl
130
2
2
2
7
[(MeCp) Fe]PF
py
CH Cl
1.3
2
6
2
8
[Cp(Cp*)Fe]PF6
[Cp(Cp*)Fe]PF6
[Cp(Cp*)Fe]PF6
[Cp(Cp*)Fe]PF6
py
CH Cl
0.036
0.077
0.26
7.4
2
9
4ꢀMeꢀpy
4ꢀMeOꢀpy
CH Cl
0.11
0.23
2
10
11
CH Cl
2
4ꢀMe Nꢀpy
CH Cl
16
2
2
1
2
3
4
[Cp Fe]BF
py
CH CN
0.093
0.276
2
4
4
4
3
1
[Cp Fe]BF
4ꢀMeꢀpy
4ꢀMeOꢀpy
CH CN
2
3
1
[Cp Fe]BF
CH CN
0.693
2
3
a
b
c
Values measured at 298 K in CH Cl or CH CN as noted. Estimated uncertainties on k = 10%. K from IR; uncertainties are
2
2
3
3
HB
d
estimated as ±15% based on reproducibility (see text). Estimated uncertainty ±18% based on uncertainties in k and K .
3
HB
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6
Discussion
I. Mechanism. The results obtained are all consistent with the mechanism in Scheme 2 of rapid
…
preꢀequilibrium formation of a TEMPOH Rꢀpy hydrogen bonded adduct which then undergoes
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
rate limiting MSꢀCPET. This is indicated by the termolecular kinetics under typical conditions
and by saturation behavior at very high [Rꢀpy] (≥ 1 M). The observation of primary H/D kinetic
isotope effects indicates the involvement of proton transfer in the rate determining step.
The hydrogenꢀbonding preꢀassociation of TEMPOH and Rꢀpy is quite weak, with
–
1
equilibrium constants, K , of only 0.5 to 2.66 M . In general, the hydrogen bonds are slightly
HB
stronger for the more basic pyridines, but the KHB vary less than a factor of 6 for the set of
7
pyridines whose basicity varies by 10 in CH Cl (See SI). 2,6ꢀLutidine is an exception to the
2
2
trend, being more basic than py but having a roughly twoꢀfold smaller K , presumably because
HB
of its steric bulk inhibiting hydrogen bond formation.
Within the hydrogenꢀbonded adduct, the PCET processes can occur by stepwise paths
–
+
(PTꢀET or ETꢀPT) or by concerted transfer of the e and H . TEMPOH has a strong bias for the
concerted path because it is a very poor acid (pK = 41 in MeCN) and a very poor reductant
a
•
+/0
6
[E(TEMPOH ) = +0.71 V vs. Cp Fe in MeCN]. Using these values and the pyridine pK
2
a
3
3
values in MeCN, initial PT and ET from TEMPOH to the oxidants or bases are very endoergic.
This is illustrated in the top and left sides of Scheme 3 for the most basic pyridine and most
+
oxidizing ferrocenium used (4ꢀMe Npy and Cp Fe ). Initial ET and PT mechanism are ruled out
2
2
‡
by the ground state ∆G°ET and ∆G°PT being much larger than the ∆G calculated from the
ꢀ
1
bimolecular k values via the Eyring equation, by ≥16 kcal mol . While these calculations are for
2
MeCN solutions, for which the thermochemical values are available, the argument for the
concerted mechanism is even stronger in the less polar CH Cl , where the ionic intermediates of
2
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Scheme 3 are even less favorable. The thermochemical analysis thus shows that the k step in the
2
–
+
reactions presented here must involve the transfer of the e to the oxidant and the H to the
pyridine in a single kinetic step, MSꢀCPET.
10
11
12
13
14
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17
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19
20
21
22
23
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43
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46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
This analysis should, strictly speaking, use the ∆G°′ values for reactions between the
hydrogenꢀbonded precursor and successor complexes. In this case, however, we were unable to
29
measure the KHB,succ for the successor complexes. Still, with the measured values of K being
HB
3
4
close to 1, and KHB,succ likely being close to 1, make ∆G°′ very close to the ∆G° for the
separated reagents, and we use those values here and below.
Scheme 3. Square scheme showing free energies of proton transfers (horizontal axis) and
+
electron transfers (vertical axis) for the termolecular MSꢀCPET TEMPOH oxidation with Cp Fe
2
6
,33
‡
and 4ꢀMe Npy in MeCN.
The diagonal gives the ∆G from the measured k and the Eyring
2
2
equation.
H
N
N
ꢀG°PT =
31 kcal mol
OH
N
O
N
ꢀ1
+
+
Cp Fe+
+
2
+
Cp Fe
+
+
2
NMe2
NMe2
‡
ꢀ1
ꢀG°ET = –45 kcal molꢀ1
ꢀ
G°ET = +16 kcal molꢀ1
ꢀG ≅ 10 kcal mol
H
N
N
O
N
OH
N
+
Cp Fe
+
+
Cp Fe
2
+
2
ꢀ
G°PT
=
NMe2
ꢀ1
–30 kcal mol
NMe2
II. MSꢀCPET rate constants: dependence on driving force. The rate constants for the MSꢀCPET
step (k ) are sensitive to both the base and the oxidant. Electron donating groups on the para
2
position of the pyridine resulted in larger rate constants, with 4ꢀdimethylaminopyridine reaction
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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
…
occurring almost 40 times faster than the pyridine one. The oxidation of TEMPOH py is 200
+
+
times faster with [Cp Fe] than with [Cp(Cp*)Fe] .
2
The MSꢀCPET rate constants correlate very closely with the free energy of the reactions,
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
the ∆G° values determined in Results Section III above. A Brønsted plot of ln(k ) vs. ln(KMSꢀ
2
‡
CPET), equivalent to δ∆G /δ∆G°, is shown in Figure 3. All the data points except the one for 2,6ꢀ
lutidine (point 5, see below) fit well on a straight line, with a slope of 0.46(2) (called the
Brønsted α).
6
[
Cp Fe]+
2
12
[(MeCp) Fe]+
2
3
[
Cp(Cp*) Fe]+
2
10
8
2
2
,6ꢀLutidine
HAT rxn
1
1
5
4
1
7
6
10
8
9
4
0
5
10
15
20
ln (Keq)
Figure 3. Plot of ln (k ) vs ln (K ) for TEMPOH oxidations by the combination of a pyridine
2
eq
base with [Cp Fe]BF (blue squares, ■), [(MeCp) Fe]PF (red circle, ●), and [Cp(Cp*)Fe]PF
6
2
4
2
6
(green triangles, ▲) in CH Cl , with the numbers corresponding to the entries in Table 1. The
2
2
purple diamond (♦) represents the oxidation with [Cp Fe]BF and 2,6ꢀlutidine. The orange
2
4
t
inverted triangle (▼) marks the HAT reaction between TEMPOH and Bu PhO· (in CCl ).
3
4
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The linear fit in Figure 3 shows that the k values respond equally to changes in
2
∆
G°MSꢀCPET regardless of whether the driving force is changed with the E° of the oxidant or pKa
of the pyridine base. The slope of 0.46 means that changes in either the proton or electron
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53
54
55
56
57
58
59
60
ꢀ1
components that make a reaction more favorable by1 kcal mol lower the Eyring barrier by 0.46
ꢀ1
kcal mol . Looking at subsets of the data, the slope for the low driving force half of the plot,
ln(K ) < 11, is a bit higher, 0.55. Essentially this same slope is seen for reactions using
eq
+
[
Cp(Cp*)Fe] and four different bases, 0.59(2), and reactions using pyridine and three different
oxidants, 0.53(4) (the single values in parentheses are the standard errors of the linear fits).
These very similar slopes in this region further show that the rate constants are insensitive to
varying the ∆G°MSꢀCPET through the proton component (the nature of the base) versus variation
in the electron component (varying the oxidant). In the higher driving force region, 11 > ln(Keq),
+
there is a shallower slope of 0.41(3) for the reactions using [Cp Fe] and five different bases
2
(
excluding lutidine).
A few prior studies of threeꢀcomponent MSꢀPCET reactions have shown a linear
dependence of ln(kMSꢀCPET) on ln(K ) [∆G°MSꢀCPET]. Linschitz’s pioneering study varied the base
eq
24,25
with the same oxidant, photoexcited C .
Thorp and Meyer showed that ln(k) varied with
60
∆
G°MSꢀCPET, both upon varying the base with a single oxidant and upon varying the oxidant with
2
7
a single base. While both individual correlations presented had a Brønsted slope of 0.6, the
combined plot with all the data was nonꢀlinear, perhaps due to a quantum beat or perhaps a result
of the diversity of acids and bases used. For the oxidations of phenols by an excited ruthenium
8
oxidant and pyridine bases, Nomrowski and Wenger reported a slope of 0.52 ± 0.05. For MSꢀ
CPET oxidation of a tungsten hydride complex, Bourrez, Hammarström et al. reported a slope
–1 28
for ∂ln(kPCET)/∂∆G°PCET of (68 meV) , which is equivalent to a Brønsted α of 0.66. With one
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1
1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
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3
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5
5
5
5
5
5
6
series of tethered phenolꢀCH ꢀpyridine compounds, MSꢀCPET oxidations showed a linear
2
2
1
Brønsted plot (α = 0.54) with variation of both the oxidant and internal base, while a related
series containing conjugated phenolꢀpyridines showed a poorer correlation, likely due to
0
1
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3
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9
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2
3
4
5
6
7
8
9
0
2
1
communication between the phenol and the base.
–
+
III. Synchronous e and H transfer. The result that the MSꢀCPET rate constants respond
–
+
equivalently to the energetics of the ET and PT components means that the transfers of e and H
in this MSꢀCPET process are synchronous. There are a couple of different ways to think about
–
+
–
+
synchronous e /H transfer. If the e and H are considered as classical particles, this would mean
that they have transferred the same amount at the transition state. In the more realistic treatments
–
–
of Marcus Theory and in HammesꢀSchiffer’s Multistate Continuum Theory, the e or the e and
+
H are treated as quantum particles, whose transfers are made possible by solvent and inner
3
5,36
sphere reorganization of heavier nuclei.
In these models, synchronous transfer means that the
–
+
reorganizations and the transition structure(s) that lead to e and H transfer are halfway along
the reaction coordinate. This is also the conclusion based on the traditional interpretation of the
Brønsted α being close to 0.5 and the reversibility of the reactions. If electron transfer were
occurring at a transition structure in which the reorganization for proton transfer had mostly
occurred, then the MSꢀCPET rates would have been much more sensitive to changes in the
proton transfer energetics. Similarly, if electron transfer were occurring at a transition structure
in which the proton was little perturbed from the hydrogenꢀbonded precursor complex, then the
rate constants would have been relatively insensitive to the proton transfer energetics.
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a)
b)
c)
OH
N
O
N
+
+
py + Cp Fe
pyH
+
+ Cp Fe
2
2
reaction progress
disparity axis
10
11
12
13
14
15
16
17
18
19
20
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23
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46
47
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52
53
54
55
56
57
58
59
60
OH
N
O
N
+
+
py + Cp
2
Fe+
pyH+ + Cp Fe+
2
37
Figure 4. Grunwald analysis of the disparity of a twoꢀcomponent concerted reaction. In (b), a
hyperbolic paraboloid E(x,y) represents the free energy surface. The mean reaction progress is
given by the parameter x (from 0 to 1), shown as the solid arrow in (a), the More O’Farrell
diagram for MSꢀCPET and as r → p in (c). The perpendicular ‘disparity’ axis, 0 < y < 1 in shown
in (a) as a doubleꢀheaded dotted arrow. The disparity is indicated by the displacement of the
transition state along y, as the curvature of the reaction progress arrow toward one of the corners.
3
7
Figures b) and c) reproduced from with permission.
Grunwald has presented a quantitative analysis of concerted reactions that can be
described by two progress variables, determining the “disparity of progress of the two reaction
3
7
events.” He applied a twoꢀdimensional Marcusꢀtheory analysis to a More O’Farrell plot (Figure
4
), defining a disparity axis from y = 0 to 1 connecting the two intermediates in the stepwise
mechanisms. The deviation of y from 0.5 is a measure of the disparity. A key parameter is the
difference in energy between the two intermediates (here called ∆G°disp), which in MSꢀCPET is
the difference between ∆G°ET and ∆G° . Grunwald analyzed experimental data for degenerate
PT
doubleꢀproton transfer reactions involving methanol and a benzoic acid (Figure 4c), finding that
the concerted transfer was significantly displaced toward more deprotonation of the benzoic acid
and protonation of the methanol. This displacement is due to the higher acidity of the benzoic
–
+
acids, making the ArCO /MeOH intermediate at the bottom right of Figure 4c more stable
2
2
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2
2
2
2
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3
4
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4
4
4
4
4
4
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5
5
5
5
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5
5
5
6
than the alternative intermediate. The reaction was found to be quite displaced from the
symmetrical y = 0.5, with y varying from 0.15 to 0.22, depending on the acidity of the benzoic
ꢀ1
acid. ∆G°disp was varied by 4 kcal mol by changes in the acid, causing a factor of 14 change in
the rate constants for the degenerate processes (a change in ln(k) of 2.3).
0
1
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3
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5
6
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9
0
1
2
3
4
5
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8
9
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3
4
5
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7
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1
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3
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5
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9
0
1
2
3
4
5
6
7
8
9
0
For the reactions presented here in the low driving force regime (lnK < 11), the ∆G°disp
eq
ꢀ1
ꢀ1
was varied by 6.2 kcal mol by changing the oxidant and 5.5 kcal mol by changing the base.
These changes in the separate coordinates are larger than the changes examined by Grunwald.
Still, these changes do not cause any significant deviation of the rate constants from the expected
ln(k) vs. ln(K ) line, as evidenced by very similar slopes for changes in the base [0.59(2)] or
eq
changes in the oxidant [0.53(4)]. While it is clear that the Grunwald y must be quite close to ½,
deriving a specific y value does not seem possible for the nonꢀdegenerate MSꢀCPET reactions
based on this dataset. Using this analysis, the observed equal dependence of kMSꢀCPET on changes
in the ∆G°ET and ∆G°PT components is a good definition of synchronous transfer of the two
particles.
IV. Steric inhibition of MSꢀCPET. The k values for the 2,6ꢀlutidine and 2ꢀMepy reactions are
2
lower than predicted, as they lie below the fit line in Figure 3. The lutidine reaction has a ∆G°MSꢀ
very similar to the 4ꢀMeOꢀpy reaction, yet its k is a factor of 3.5 slower. The slower rate
CPET
2
constants for lutidine and 2ꢀMepy are very likely due to the orthoꢀmethyl substituents sterically
inhibiting proton transfer. We emphasize that these k values are for reactions starting from the
2
…
hydrogenꢀbonded adducts TEMPOH 2ꢀMe py, and in fact this kinetic effect is larger than the
n
effect of the methyl groups on the KHB to form the adducts. The KHB is only a factor of 2.1
smaller for lutidine than for 4ꢀMeOꢀpy. The lower rate constants for the sterically encumbered
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bases is very likely due to the favored transition state structure involving a compression of the
proton donorꢀacceptor distance from the initial adduct, as indicated by theoretical descriptions of
20,36,38
CPET.
Thus, the deviations of the 2,6ꢀlutidine and 2ꢀMepy reactions from the Brønsted
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correlation show the modest sensitivity of the MSꢀCPET reactions to changes in the hydrogen
bond and protonꢀtransfer coordinate.
In principle, one marker of a change in hydrogenꢀbond distance could be the kinetic
isotope effects (KIEs) for TEMPOH versus TEMPOD. However, these do not show any clear
correlation with hydrogen bond strength (K ) or driving force (∆G°MSꢀCPET). Surprisingly, the
HB
2,6ꢀlutidine and 2ꢀMeꢀpy reactions have the lowest KIE values. While a simple tunneling model
…
would predict a higher KIE for a longer OH N hydrogen bond, Multistate Continuum Theory
39
suggests that this is not a good approximation. In tethered phenolꢀbase compounds,
1
9,23
Hammarström et al. have reported larger KIEs for longer distances,
while we have observed
1
8
the opposite in one case. The results reported in the current study are consistent with the
conclusion that the KIE is not a simple reflection of the protonꢀacceptor distance.
V. Marcus Theory analysis of the reactions. Marcus Theory (eq 8), which has been widely used
1
ꢀ4,7,17
to interpret PCET reactions,
predicts that the Brønsted
α
for a series of similar reactions is
‡
35
given by eq 9 (ꢀG* being similar to the Eyring ꢀG for adiabatic reactions). In the low driving
2
k = κν exp(–ꢀG*/RT)
ꢀG* = (
λ
+ ꢀGº) /4
λ
(8)
(9)
α
≅ δꢀG*/δꢀGº = ½ + ꢀGº/2
λ
force limit with |ꢀGº|/λ ≪ 1,
α is predicted to be 0.5, as observed for the reactions examined
here (α = 0.46). Over a wider range of ∆G°, Marcus theory predicts a quadratic dependence of
ln(k) on ∆G°, and the data in Figure 3 provide a hint of that predicted curvature. The points at
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1
1
2
2
2
2
2
2
2
2
2
2
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5
6
either end are below the bestꢀfit line and those in the middle are on or above the line, except for
the lutidine and 2ꢀMePy points that were discussed above. As noted above, the slope of the line
in the lowꢀdriving force regime is 0.55(2) while the value at higher driving forces (ln(K ) > 11)
eq
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
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7
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9
0
1
2
3
4
5
6
7
8
9
0
is 0.41(3), illustrating the slight curvature. Fitting all of the points except 4 and 5 to the Marcus
1
1
ꢀ1
equation (eq 8) gives a very rough estimate of the intrinsic barrier,
λ ≅ 2.2 eV, and κν ≅ 10 M
ꢀ1
s . This estimated
λ is larger than those found for MSꢀCPET where the base is covalently
1
7,8,40,41
tethered to a phenol, which typically have λ ≤1.3 eV.
A recent study of phenol oxidations
8
by a ruthenium photooxidant in a termolecular MSꢀCPET system showed λ > 0.8 eV. The
apparently larger intrinsic barrier in the threeꢀcomponent systems reported here is likely due to
42,43
TEMPOH having an inherently large intrinsic barrier for PCETreactions
and could perhaps
be due to the extra degrees of freedom associated with the intermolecular TEMPOHꢀpy
hydrogen bond, compared with tethered analogs. Still, these comparisons of intrinsic barriers
must be considered tentative, as they involve our very approximate λ value and others often
derived in different ways.
VI. Comparing MSꢀCPET and HAT. This study can also address how the rate of CPET is
affected by completely separating the proton and electron. We compare the rate constants for the
threeꢀcomponent TEMPOH oxidations to the rate of a simpler hydrogen atom transfer (HAT)
reaction where the proton and electron move together from a single donor to a single acceptor, at
6
the same overall driving force (∆G°CPET). The orange inverted triangle (▼) in Figure 3
represents the HAT reaction from TEMPOH to 2,4,6ꢀtriꢀtertꢀbutylphenoxyl radical
t
• 32,44
( Bu PhO ).
This TEMPOH HAT reaction is a bit slower than the bimolecular rate constants
3
…
for the TEMPOH (Rꢀpy) + oxidant reactions at similar driving forces. We emphasize that this
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comparison is by nature approximate, and in this case, it is difficult to account for the steric
t
•
crowding about the oxyl radical in Bu PhO . Still, the steric crowding in the 2,6ꢀlutidine reaction
3
t
•
is not so different and slows the reaction by only a factor of ~3.5. The TEMPOH + Bu PhO
3
10
11
12
13
14
15
16
17
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HAT reaction is below the correlation line by about the same amount as the 2,6ꢀlutidine reaction.
–
+
Thus, the Marcus intrinsic barrier λ appears to be similar for e and H removal by the
+
t
•
Cp Fe /2,6ꢀlutidine pair and by Bu PhO . Therefore, despite the attendant uncertainties, it seems
2
3
clear that complete separation of the donor and acceptor does not substantially slow the MSꢀ
CPET oxidation of TEMPOH reaction compared to a related HAT reaction. This supports the
conclusion of Wenger et al. based on phenol oxidations by photoexcited ruthenium complexes,
comparing reactions in which the proton transfer occurs either to an external pyridine or to a
8
ruthenium bipyrazine ligand.
+
4
The TEMPOH + pyridine + Ox threeꢀcomponent reactions are, however, ca. 10 slower
than related reactions of tethered phenolꢀpyridines, PhOH py + Ox+ . The rate constant for
ꢀ1 ꢀ1
the threeꢀcomponent TEMPOH reactions at zero driving force (the intrinsic k°) is about 50 M s
•+
3+
(
Figure 3), while those for the tethered phenolꢀpyridines plus NAr3 and [Fe(diimine)3]
4
6
ꢀ1 ꢀ1 21
oxidants are between 4 × 10 and 5 × 10 M s . The faster reactions of the phenol compounds
2
1
is likely due to the two effects: (i) the much stronger hydrogen bond in the tethered systems,
–
+
and (ii) the apparently much lower intrinsic barrier for e and H removal from phenol than from
TEMPOH. We estimate the relative intrinsic barriers from their HAT selfꢀexchange rate
6
ꢀ1 ꢀ1
ꢀ1 ꢀ1
t
constants (X + HX → HX + X): 5 × 10 M s for PhO• + PhOH; 20 M s for Bu PhO• +
3
t
ꢀ1 ꢀ1
32
Bu PhOH; and 5 M s for TEMPO + TEMPOH. Future studies in our laboratory will probe
3
whether such relative intrinsic barriers are similar for HAT and MSꢀCPET reactions.
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Conclusions
The studies of threeꢀcomponent multipleꢀsite concerted proton electron transfer (MSꢀCPET)
reactions reported here show how the PCET reactions depend on independent variation of the
proton transfer and electron transfer components. The change in the rate constant for removal of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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9
0
1
2
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0
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0
–
+
e and H from the hydroxylamine TEMPOH is the same whether the driving force (∆G°MSꢀCPET)
is changed with the identity of the ferrocenium oxidant or the pyridine base. The combined
Brønsted plot shows a linear correlation of ln(kMSꢀCPET) with ln(K ), with a slope α = 0.46. The
eq
transition state thus responds equivalently to energetic changes in the proton and electron
transfer portions of the PCET reactions. This behavior, with α close to ½, has been seen in a few
8
,26,27,28
other MSꢀCPET systems.
These reactions are therefore synchronous, with the
–
+
reorganizations that enable the e and H transfers proceeding equally along the reaction
coordinate. Synchronicity is a fundamental aspect of a PCET processes that is possible to address
experimentally because of the threeꢀcomponent nature of these reactions. The sterically
encumbered 2,6ꢀlutidene base (2,6ꢀMe py) forms a weaker hydrogen bond with TEMPOH and
2
the rate constant for MSꢀCPET from this weak hydrogenꢀbonded adduct is slower than for other
pyridines. This suggests that the proton donorꢀacceptor distance typically must be compressed in
the MSꢀCPET transition state, consistent with PCET theory. A rough comparison of these threeꢀ
–
+
component e /H transfer reactions with a related hydrogen atom transfer from TEMPOH
suggests that the rate constants and intrinsic barriers are similar, despite the complete separation
–
+
of the e and H to different acceptors in the threeꢀcomponent case.
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Experimental
All compounds were obtained from SigmaAldrich and used as received unless otherwise
indicated. TEMPO was purified by sublimation under vacuum prior to use. Solvents were
purchased from Fisher and deuterated solvents were purchased from Cambridge Isotope Labs.
Methylene chloride was dried by running through a column of activated alumina, degassed, and
stored over 4 Å molecular sieves before use. TEMPOH was synthesized following the literature
10
11
12
13
14
15
16
17
18
19
20
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56
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59
60
4
5
reported anhydrous synthesis. MethanolꢀD (CH OD) was dried over 4 Å molecular sieves and
3
stored under inert atmosphere. Anhydrous TEMPOD was synthesized by stirring TEMPOH with
CH OD for 1h then removing volatiles under vacuum. Pyridine bases were distilled and dried
3
4
6
over 4 Å molecular sieves. 1,2,3,4,5ꢀpentamethylferrocene
was synthesized from
4
7
iron(II)bis(acetylacetonate) according to literature procedures. Ferrocene and 1,2,3,4,5ꢀ
48 1
pentamethylferrocne were oxidized with AgPF according to literature procedures. H NMR
6
spectra were recorded at ambient temperature on either an A400 or A500 DD2 Agilent
spectrometer operating at 400 MHz or 500 MHz, respectively. Spectra were referenced to the
residual solvent signal (5.32 ppm) for CHDCl . UVꢀvis spectra were recorded on an Agilent
2
Cary 60 spectrophotometer. IR spectra were recorded inside a Nitrogen filled glovebox with a
Bruker Alpha FTꢀIR spectrometer using a CsF liquid cell with a 1 mm pathlength. Kinetic
measurements were recorded on an OLISꢀRSM 1000 single mixing stopped flow
spectrophotometer in anaerobic methylene chloride solvent. Full details of these and other
measurements are given in the Supplementary Information.
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Acknowledgment
We gratefully acknowledge the financial support from the US National Institutes of Health,
R01GM50422. The authors are also grateful to valuable comments on the manuscript by Brian
2
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Koronkiewicz and Dr. Giovanni Parada.
Supporting Information.
1
Experimental details, derivations and data analysis for cyclic voltammetry, kinetics, IR and H
NMR spectroscopy, and relative pK measurements.
a
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+
spectroscopy. This is likely due to strong ion pairing between the 4ꢀMepyH cation and the
–
+
–
PF anion in CH Cl and the limited solubility of 4ꢀMepyH PF .
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2
2
6
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4. The rate constant is for a reaction in carbon tetrachloride solvent but the conditions should
be quite similar to the reactions studied here in methylene chloride.
4
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Table of Contents Graphic
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