Proton-Coupled Electron Transfer Reactions with Photometric Bases Reveal Free Energy Relationships for Proton Transfer

Article abstract of DOI:10.1021/acs.jpcb.6b04011

The proton-coupled electron transfer (PCET) oxidation of p-aminophenol in acetonitrile was initiated via stopped-flow rapid-mixing and spectroscopically monitored. For oxidation by ferrocenium in the presence of 7-(dimethylamino)quinoline proton acceptors, both the electron transfer and proton transfer components could be optically monitored in the visible region; the decay of the ferrocenium absorbance is readily monitored (λ_max = 620 nm), and the absorbance of the 2,4-substituted 7-(dimethylamino)quinoline derivatives (λ_max = 370-392 nm) red-shifts substantially (ca. 70 nm) upon protonation. Spectral analysis revealed the reaction proceeds via a stepwise electron transfer-proton transfer process, and modeling of the kinetics traces monitoring the ferrocenium and quinolinium signals provided rate constants for elementary proton and electron transfer steps. As the pK_a values of the conjugate acids of the 2,4-R-7-(dimethylamino)quinoline derivatives employed were readily tuned by varying the substituents at the 2- and 4-positions of the quinoline backbone, the driving force for proton transfer was systematically varied. Proton transfer rate constants (k_PT,2 = (1.5-7.5) × 10⁸ M^-1 s^-1, k_PT,4 = (0.55-3.0) × 10⁷ M^-1 s^-1) were found to correlate with the pK_a of the conjugate acid of the proton acceptor, in agreement with anticipated free energy relationships for proton transfer processes in PCET reactions.

Full text of DOI:10.1021/acs.jpcb.6b04011

Article
pubs.acs.org/JPCB
Proton-Coupled Electron Transfer Reactions with Photometric Bases
Reveal Free Energy Relationships for Proton Transfer
Thomas T. Eisenhart, William C. Howland, and Jillian L. Dempsey*
Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599-3290, United States
S
* Supporting Information
ABSTRACT: The proton-coupled electron transfer (PCET) oxidation of p-aminophenol in acetonitrile was initiated via
stopped-flow rapid-mixing and spectroscopically monitored. For oxidation by ferrocenium in the presence of 7-
(dimethylamino)quinoline proton acceptors, both the electron transfer and proton transfer components could be optically
monitored in the visible region; the decay of the ferrocenium absorbance is readily monitored (λmax = 620 nm), and the
absorbance of the 2,4-substituted 7-(dimethylamino)quinoline derivatives (λmax = 370−392 nm) red-shifts substantially (ca. 70
nm) upon protonation. Spectral analysis revealed the reaction proceeds via a stepwise electron transfer-proton transfer process,
and modeling of the kinetics traces monitoring the ferrocenium and quinolinium signals provided rate constants for elementary
proton and electron transfer steps. As the pKa values of the conjugate acids of the 2,4-R-7-(dimethylamino)quinoline derivatives
employed were readily tuned by varying the substituents at the 2- and 4-positions of the quinoline backbone, the driving force for
proton transfer was systematically varied. Proton transfer rate constants (kPT,2 = (1.5−7.5) × 108 M−1 s−1, kPT,4 = (0.55−3.0) ×
107 M−1 s−1) were found to correlate with the pKa of the conjugate acid of the proton acceptor, in agreement with anticipated
free energy relationships for proton transfer processes in PCET reactions.
reactions, more effective and versatile methods for monitoring
PCET processes must be developed.
INTRODUCTION
■
Proton-coupled electron transfer (PCET) reactions involve the
transfer of both a proton and electron and can proceed through
either stepwise or concerted mechanisms. In stepwise reactions,
initial electron transfer (ET) is followed by proton transfer
(PT) (ET-PT) or vice versa (PT-ET). By contrast, in a
concerted proton−electron transfer (CPET) reaction both the
electron and proton move in a single kinetic step, circum-
venting charged, high-energy intermediates. These types of
reactions are found throughout chemistry and biology and play
an important role in the activation of small, energy-poor
molecules, like H2O and CO2, into energy-rich fuels.1,2 As such,
PCET processes underpin emerging energy technologies based
on photon-to-fuel conversion strategies, and thus under-
standing and controlling PCET reactions is a high priority for
the scientific community. However, elucidating the operating
mechanism of a given PCET process can be quite difficult.3,4
Extracting relevant kinetic information about proton and
electron transfers and interpreting the reaction parameters
controlling a PCET reaction is an even greater challenge.
Therefore, in order to advance our understanding of PCET
Spectroscopic monitoring of ET processes is enabled by the
fact that transition metals often have unique optical signatures
for each of their oxidation states. As such, time-resolved
spectroscopic techniques like optical spectroscopy coupled to
stopped-flow rapid mixing5−9 and transient absorption10−17
spectroscopy have been widely employed to monitor the ET
component of PCET reactions. Electrochemistry has also been
used to probe ET processes in PCET events.18−21 However, it
is significantly more difficult to monitor the PT component of a
PCET reaction through conventional methods. There are few
methods available by which proton movement can be
monitored on appropriate time scales; time-resolved infrared
spectroscopy has been successfully employed to monitor
PT,22−28 but when there is an accompanying ET reaction,
electron transfer kinetics must generally be determined in a
separate experiment. Our lab has recently reported the
Received: April 20, 2016
Revised: June 13, 2016
© XXXX American Chemical Society
A
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a
Scheme 1. General Schematic of the PCET Reaction between NH2PhOH, Fc+, and R-7DMAQ
a
NH2PhOH is oxidized by Fc+, generating NH2PhOH radical cation (NH2PhOH•+), which is then deprotonated by R-7DMAQ. Products of this
initial PCET reaction are ferrocenium, p-aminophenol radical, and R-7DMAQH+.
comprehensive optical monitoring of an excited-state PCET
reaction and the subsequent thermal PCET recombination, but
this is a rare example of concurrent spectroscopic monitoring of
electron and proton transfer processes.17 As a result, PCET
reaction mechanisms are generally inferred from reaction
products, KIE studies of the ET component, and thermody-
namic analyses.3,6,11,18,29,30 This approach has inherent short-
comings; as a result, little information is typically gleaned about
the role PT plays in a PCET reaction, and this has further
ramifications in the broader context of PT reactions.
opportunity to systematically examine the relationship between
−ΔGPT and kPT within in a PCET process. With these tools in
hand, we have explored the PCET reaction between the p-
aminophenol (NH2PhOH), these photometric bases, and mild
oxidant ferrocenium (Fc+) using optical spectroscopy and
stopped-flow rapid-mixing (Scheme 1). Both PT and ET
processes were monitored independently of one another, and
free energy relationships between the proton transfer rate
constants and the pKa of the photometric base are revealed.
EXPERIMENTAL SECTION
Recognizing the integral role PT plays in PCET reactions,
control over PT may offer a clear pathway to orchestrate and
manipulate PCET reaction pathways and provide avenues for
the development of catalysts that can, for instance, activate
inert, energy poor molecules for fuel synthesis. However, in
order to control PT, the parameters that govern a PT event
need to be well understood. For instance, can we develop clear
correlations between the driving force (−ΔGPT) and rate
constant (kPT) for PT within in a PCET process? While there
have been some experimental investigations into the relation-
ships between thermochemical parameters and reaction kinetics
of PCET reaction, a unified understanding, especially one that
includes concerted reaction mechanisms and nonaqueous
solvents, is not yet available.3,4,7,9,31−39 This further underscores
that to advance our understanding of PCET reactions, a
technique to effectively monitor PT must be developed.
Borrowing concepts from pH indicators and acid/base
chemistry, we have identified, synthesized, and characterized a
series of “photometric bases” and have demonstrated that these
molecules can be used to optically monitor PT processes in
PCET reactions. In this work, we present a series of 7-
(dimethylamino)quinoline (R-7DMAQ) derivatives that have
optical signatures in the visible region that shift upon
protonation. This red-shift in absorbance provides an excellent
handle directly probe a PT event. While similar approaches
have been utilized to study pure PT reactions (thermal and
excited state, in both water and nonaqueous solvents), these
studies have relied on indicator dyes, many of which are
carbon-based acids/bases and have limited tunability for PT
driving force and thus were not readily extendable to the PCET
studies of interest here.40−44
■
General Considerations. All solutions for electrochemical
and stopped-flow analyses were prepared in a nitrogen-filled
glovebox. The acetonitrile used (Fisher Scientific, HPLC,
>99.9%) was degassed with argon and dried with a Pure
Process Technology Solvent System. Reagents were purchased
from Sigma-Aldrich with the exception of 3,4-dimethoxy-
phenylboronic acid (VWR), 3,5-bis(trifluoromethyl)-
phenylboronic acid (Matrix), and phenylboronic acid (Chem-
Impex). 2-Picoline, tetrafluoroboric acid diethyl ether, and
aniline were degassed via the freeze−pump−thaw method (3+
cycles) and stored under an inert atmosphere. UV−vis spectra
were collected on an Agilent Cary 60 spectrometer.
Spectrophotometric titrations were carried out in a nitrogen-
filled glovebox using fiber optics that feed through a glovebox
port and couple to the Cary 60 spectrometer. Molar extinction
coefficients were determined spectroscopically using the Cary
60 spectrometer and the Beer−Lambert relationship. Mass
spectrometry was carried out with a LTQ FT (ICR 7T)
(ThermoFisher, Bremen, Germany) mass spectrometer.
Measurements were made on complexes dissolved in methanol.
Samples were introduced via a microelectrospray source at a
flow rate of 3 μL/min. Xcalibur (ThermoFisher, Bremen,
Germany) was used to analyze the data.
Synthesis of 7-(Dimethylamino)quinoline Derivatives.
7-(Dimethylamino)quinoline (H-7DMAQ). H-7DMAQ was
obtained via Skraup reaction as described by Picken45 with a
modification from Ozerov.46 1.0 g (4.8 mmol) of 3-
(dimethylamino)aniline dihydrochloride was dissolved in 10
mL of H2O, and to it 20 mL of 1.0 M sodium hydroxide was
added. Dichloromethane (4 × 25 mL) was used to extract the
basic aniline, and the combined organic layers were
concentrated in vacuo to a violet oil in a round-bottom flask.
Glycerol (0.5 mL, 6.8 mmol) and sodium iodide (1.08 g, 7.2
mmol) were added. The reaction flask was put on ice, and
concentrated sulfuric acid (2.7 mL) was added dropwise. The
mixture was heated to reflux (140−150 °C) for 3 h. After
cooling, equal volumes (40 mL) of H2O and CH2Cl2 were used
In the series of 7-(dimethylamino)quinoline derivatives
studied here, variation of the R-group at the 2,4-positions of
the quinoline allows the optical properties and pKa (in
CH3CN) to be systematically tuned. This allows (1) direct
access to a range of optical windows across the visible region in
which PT reactions can be monitored and (2) an opportunity
to vary PT driving force. The latter presents a unique
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Scheme 2. (a) General Scheme for the Synthesis of the R-7DMAQs Containing Aryl Substituents (Ph, MeO, and TMP-
ab
,
b
7DMAQ); (b) H-7DMAQ Synthesized in One Step via a Skraup Reaction; (c) Substituents of the R-7DMAQs and the
Nomenclature Used Throughout This Article
a
The substituents at the 2,4-positions of the quinoline backbone are determined by the identity of the boronic acid employed in the third step.
Details of these reactions are included in the Experimental Section.
b
to transfer the mixture to a 250 mL Erlenmeyer flask. The
Erlenmeyer flask was placed in an ice bath, and the mixture was
basified with aqueous sodium hydroxide (1.0 M) until the
solution was alkaline. Sodium sulfite was added to quench any
remaining I2, and the reaction mixture was filtered. CH2Cl2 (4
× 25 mL) was used to extract the organic product. The organic
layer was dried (MgSO4), filtered, concentrated to an oil, and
purified on silica gel (eluent, chloroform/methanol 99.5/0.5 to
95/5) yielding H-7DMAQ as a yellow oil (0.39 g, 47% yield).
1H NMR (400 MHz, CDCl3) δ (ppm): 8.74 (d, 1H), 7.96 (d,
1H), 7.64 (d, 1H), 7.19 (dd, 1H,), 7.16 (d, 1H), 7.10 (dd, 1H),
3.10 (s, 6H, s).
acetonitrile (60 mL) and refluxed for 3 h at 80 °C. After the
mixture was cooled, water was slowly added to the reaction
vessel until the solution stopped bubbling. Aqueous sodium
hydroxide (2 M) was then added until the solution reached
neutral pH and a precipitate formed. CH2Cl2 (4 × 50 mL) was
then used to extract the organic product. A simple silica column
with CH2Cl2 mobile phase separated the product mixture
(typically the second yellow band to elute). 2,4-Br-7DMAQ
was obtained as a green-yellow crystalline powder (0.53 g,
1
33%). H NMR (400 MHz, CD2Cl2) δ (ppm): 7.89 (d, 1H,
Ar−H), 7.44 (s, 1H, Ar−H), 7.14 (dd, 1H, Ar−H), 6.99 (d,
1H, Ar−H), 3.09 (s, 6H, CH3).
2,4-R-7-(Dimethylamino)quinoline. The procedure for the
Suzuki coupling of 2,4-Br-7DMAQ with arylboronic acid to
yield aryl-substituted 2,4-R-7-(dimethylamino)quinoline (R-
7DMAQ) was adapted from Watanabe49 and Suzuki.50 In a
nitrogen-filled glovebox, 2,4-Br-7DMAQ (1 equiv), an
arylboronic acid (2.2 equiv), Pd(PPh3)4 (0.04 equiv), and a
Teflon-coated stir bar were added to a Schlenk flask. The flask
was removed from the glovebox in a sealed vessel and placed
under nitrogen flow on a Schlenk line. Ba(OH)2 (3 equiv) was
degassed and cannula transferred to the Schlenk flask along
with a mixture of degassed dimethoxyethane/H2O (4:1, also
added via cannula transfer). The mixture was refluxed at 85 °C
under a N2 atmosphere for 48 h. After cooling of the reaction
mixture, water was added to the flask to aid in transfer to a
separatory funnel. The mixture was then extracted with CH2Cl2
and purified further using column chromatography. These
details, along with further characterization for each R-7DMAQ,
are included in the Supporting Information.
General Procedures for Aryl-Substituted 2,4-R-7-
(Dimethylamino)quinoline Derivatives. The four aryl-
substituted 2,4-R-7-(dimethylamino)quinoline derivatives (R-
7DMAQ) were synthesized in three steps.
2,4-Dihydroxy-7-(dimethylamino)quinoline. The synthesis
of 2,4-dihydroxy-7-(dimethylamino)quinoline was adapted
from Knierzinger and Wolfbeis.47 3-(N,N-Dimethylamino)-
aniline dihydrochloride (2.0 g, 9.6 mmol) was dissolved in 10
mL of H2O, and to it 40 mL of 1.0 M sodium hydroxide was
added. The solution was poured into a separation funnel, and
CH2Cl2 (4 × 50 mL) was used to extract the basic aniline. The
combined organic layers were concentrated in vacuo. Diethyl
malonate (1.5 mL, 9.6 mmol) was added to the round-bottom
flask containing the aniline, a Dean−Stark apparatus was fitted
to the flask (to distill off ethanol produced in situ), and the
mixture was refluxed between 180 and 200 °C for 3 h. Upon
cooling, grayish solids were left behind in the reaction flask.
The solids were transferred to a Buchner funnel and washed
thoroughly with H2O. Solids retained by the funnel were placed
in a beaker and stirred with acetone. This mixture was then
filtered, and the resulting solids collected are 2,4-dihydroxy-7-
(dimethylamino)quinoline (2,4-OH-7DMAQ) (1.4 g, 75%
Stopped-Flow Experiments. Stopped-Flow experiments
were performed on a HI-TECH SF-61DX2 double-mixing
stopped-flow spectrophotometer in single mixing mode with
Kinetic Studio data acquisition software (v2.33). For single
wavelength kinetics measurements, a tungsten light source and
dual-beam photomultiplier tube (Hamamatsu R928) were used.
For spectral analysis, a xenon light source and a photodiode
array were used. Stopped-flow measurements were all
performed under a nitrogen atmosphere. Samples were
prepared inside of an inert-atmosphere glovebox in septum-
sealed bottles. PEEK tubing was used to transfer solutions
directly from sealed bottles to the stopped-flow syringes. To
ensure purity of samples analyzed, each syringe was purged
three times prior to each measurement. In a typical experiment,
1
yield). H NMR (400 MHz, CD2Cl2) δ (ppm): 10.83 (s, 1H,
−OH), 10.70 (s, 1H, −OH), 7.54 (d, 1H, Ar−H), 6.60 (dd,
1H, Ar−H), 6.40 (d, 1H, Ar−H), 5.42 (s, 1H, Ar−H), 2.95 (s,
6H, CH3).
2,4-Dibromo-7-(dimethylamino)quinoline. The synthesis
of 2,4-dibromo-7-(dimethylamino)quinoline (2,4-Br-7DMAQ)
was adapted from Janin et al.48 To a round-bottom flask
containing a Teflon-coated stir bar, 2,4-OH-7DMAQ (1.0 g, 4.9
mmol), POBr3 (7.0 g, 24.5 mmol), and K2CO3 (2.0 g, 14.7
mmol) were added. This mixture was dissolved in dry
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Table 1. Absorbance Features, Redox Properties, and pKa Values for Each of the R-7DMAQs Compounds
base
pKa (CH3CN)
λmax B (nm)
ε, B (M−1 cm−1
)
λmax BH+ (nm)
ε, BH+ (M−1 cm−1
)
Ep,a (V vs Fc+/0
)
Ph-7DMAQ
H-7DMAQ
14.2
15.0
15.0
15.2
392
370
389
374
4300
3300
464
9880
0.45
0.39
0.44
0.51
432
6230
MeO-7DMAQ
TMP-7DMAQ
10000
6600
375, 465
446
20200, 20800
13300
one syringe was loaded with ferrocenium hexafluorophosphate
(60 μM) while the other was loaded with R-7DMAQ (30 μM)
and varying concentrations of NH2PhOH (100−500 μM).
Upon injection, absorbance vs time was monitored at various
wavelengths for kinetics traces. Fitting of the data was carried
out in MATLAB (The MathWorks, Inc.) and is described
elsewhere in the text.
Electrochemistry. All electrochemical measurements were
performed in a nitrogen-filled glovebox, using electrode leads
that were fed through a custom port and connected to a Pine
Instruments WaveDriver potentiostat. A three-electrode cell
was used for all experiments, utilizing platinum working
electrodes, a glassy carbon counter electrode (CH Instruments,
3 mm diameter), and a silver wire pseudoreference immersed in
a glass tube fitted with a porous Vycor tip and filled with a 0.25
M [Bu4N][PF6] acetonitrile solution. The glassy carbon
electrodes were polished using a Milli-Q water slurry of 0.05
μm polishing powder (CH Instruments, containing no
agglomerating agents), rinsed and sonicated in Milli-Q water,
and rinsed with acetone. Working electrodes were electro-
chemically pretreated with two cyclic scans between 1.5 and
−2.5 V at 200 mV/s in 0.25 mM [Bu4N][PF6] solution.
Background voltammograms of electrolyte-only solutions were
collected for every electrode at the appropriate scan rate. All
voltammograms were recorded in 0.25 M [Bu4N][PF6]
acetonitrile solutions and internally referenced to ferrocene.
Figure 1. UV−vis absorbance spectrum of TMP-7DMAQ (blue) in
acetonitrile (78 μM) and its conjugate acid TMP-7DMAQH+ (red,
formed in situ upon the addition of 1 equiv of HBF4).
Electrochemical analysis by cyclic voltammetry revealed
irreversible waves in the anodic scans (Ep,a = 0.39−0.51 V vs
Fc+/0) (Table 1 and Figures S13−S16). Cathodic scans indicate
the compounds are quite difficult to reduce (<−2.0 V vs Fc+/0).
Time-Resolved Optical Monitoring of PCET Reactions.
The termolecular PCET reaction between NH2PhOH, R-
7DMAQ, and Fc+ was initiated by stopped-flow rapid mixing of
a solution of NH2PhOH (100−500 μM) and R-7DMAQ (30
μM) with a solution of ferrocenium hexafluorophosphate (60
μM) and monitored via optical spectroscopy. Upon mixing, Fc+
oxidizes NH2PhOH, generating the aminophenol radical cation
NH2PhOH•+. This radical cation is much more acidic and is
readily deprotonated by basic species in solution,3,52,53
including R-7DMAQ, to generate R-7DMAQH+ and
NH2PhO•.
This PCET reaction was first explored with Ph-7DMAQ.
Absorbance spectra recorded at various time delays have
prominent features corresponding to Fc+ (λmax = 620 nm), Ph-
7DMAQ (λmax = 392 nm), and Ph-7DMAQH+ (λmax = 464
nm) (Figure 2). The peaks corresponding to Fc+ and Ph-
7DMAQ decay over the 0−100 ms time scale, while a new
feature consistent with Ph-7DMAQH+ grows in on a similar
RESULTS
■
Synthesis and Characterization of 2,4-R-7-
(Dimethylamino)quinoline Derivatives. The aryl-substi-
tuted 2,4-R-7-(dimethylamino)quinoline derivatives (R-
7DMAQ, R = aryl) were synthesized via the procedure
outlined in Scheme 2a. N,N-Dimethyl-3-phenylenediamine
was refluxed with diethyl malonate to form 2,4-hydroxy-7-
(dimethylamino)quinoline. Bromination of the hydroxyl groups
was carried out by refluxing the isolated reaction product in dry
acetonitrile with phosphorus oxybromide and potassium
carbonate. The final R-7DMAQ was obtained via a Suzuki
coupling; a wide variety of commercially available boronic acids
permits access to a range of aryl-substituted 7DMAQs. 7-
(Dimethylamino)quinoline (H-7DMAQ) was synthesized in
one step via a Skraup reaction (Scheme 2b).
Absorbance spectra of all the 7DMAQ derivatives exhibit a
broad absorption feature centered 370−390 nm that tails into
the visible region (Table 1, Figure 1, and Figures S9−S12).
Protonation of the 7DMAQ species to form 7DMAQH+ results
in a bathochromic shift of this absorbance feature of ca. 71 nm
and an increase in the extinction coefficient (λmax = 432−465
nm, Table 1, Figure 1, and Figures S9−S12). Of note, MeO-
7DMAQH+ has two pronounced absorbance features (λmax
=
375 and 465 nm). Spectrophotometric titrations were carried
out to determine the pKa values for these compounds; values
ranged from 14.2 to 15.2, with more electron-donating aryl
substituents giving rise to higher pKa values (Table 1 and
Figures S17−S20).7,17,51
Figure 2. Absorbance spectra recorded at various time delays (0−100
ms, 6 ms intervals) upon rapid mixing of NH2PhOH (100 μM) and
Ph-7DMAQ (30 μM) with Fc+ (150 μM) in CH3CN.
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time scale as the reaction proceeds. Clean conversion of Ph-
7DMAQ to its conjugate acid is indicated by the well-defined
isosbestic point at 415 nm.
Single wavelength kinetics traces monitoring the appearance
of the 7DMAQH+ peak (λobs = 440−460 nm) and the decay of
the Fc+ peak (λobs = 620 nm) were recorded as a function of
NH2PhOH concentration for each of the four R-7DMAQ
photometric bases (representative spectra in Figures 3 and 4;
the concentrations of NH2PhOH and Fc+ were held constant,
kinetics traces reveal that the decay of the Fc+ signal is not
sensitive to base concentration. These observations indicate
that this reaction is not operating under a CPET mechanism.
The viabilities of stepwise PT-ET and ET-PT pathways were
both considered. PT-ET would require an initial deprotonation
event, yet the differences between pKa values of NH2PhOH
(∼30) and the R-7DMAQH+ species (14.2−15.2) suggest that
protonation of R-7DMAQ by NH2PhOH is highly endergonic.
By contrast, an ET-PT process (eqs 1 and 2) involves a slightly
endergonic ET process (ΔGET ≈ 60 mV) followed by PT from
the NH2PhOH radical cation (NH2PhOH•+) to R-7DMAQ
(rough estimation of the pKa of NH2PhOH•+ in CH3CN from
the pKa reported in DMSO gives a value of 15.8;3,54 however,
observations of deprotonation by R-7DMAQ in this work
suggests the value is in fact lower as PT to R-7DMAQ appears
facile).
k1
NH2PhOH + Fc+ → NH2PhOH•+ + Fc0
(1)
NH2PhOH•+ + R‐7DMAQ
→ NH2PhO• + R‐7DMAQH+
Figure 3. Stopped-flow kinetics traces monitoring the appearance of
TMP-7DMAQH+ at 450 nm. Present in each reaction are 60 μM Fc+,
30 μM TMP-7DMAQ, and 100−500 μM NH2PhOH.
k2
(2)
k3
NH2PhO• + Fc+ → NH2PhO+ + Fc0
(3)
k4
NH2PhO+ + R‐7DMAQ → NHPhO + R‐7DMAQH+
(4)
NH2PhOH + R‐7DMAQH+
k5
HooI NH3PhOH+ + R‐7DMAQ
k−5
(5)
k6
NH2PhOH•+ + NH2PhOH → NH2PhO• + NH3PhOH+
(6)
Figure 4. Stopped-flow kinetics traces monitoring the disappearance of
Fc+ at 620 nm. Present in each reaction are 60 μM Fc+, 30 μM TMP-
7DMAQ, and 100−500 μM NH2PhOH.
k7
NH2PhO+ + NH2PhOH → NHPhO + NH3PhOH+
(7)
k8
2NHPhO → further products
(8)
full data set in Figures S21−S23). At both wavelengths, the
rates of reaction accelerated as the concentration of NH2PhOH
was increased. In a separate experiment, the kinetics of Fc+
reduction were monitored (λobs = 620 nm) as a function of R-
7DMAQ concentration (with constant concentrations of
NH2PhOH and Fc+). Notably, changes in the concentration
of the photometric base did not affect the decay kinetics of the
Fc+ signal (Figure S24).
k9
Fc+ + R‐7DMAQ HooI [Fc+ ··· R‐7DMAQ]
k−9
(9)
Our data qualitatively support an initial ET-PT mechanism
for the reaction of NH2PhOH, Fc+, and R-7DMAQ to form
NH2PhO•, R-7DMAQH+, and Fc. However, extensive studies
exploring the electrochemical oxidation of aniline and its
derivatives (including NH2PhOH) show that upon oxidation
the products formed are highly favored to undergo a second
one-electron, one-proton oxidation,55−59 and their two-
electron, two-proton chemistry is well precedented.60−66 Our
own electrochemical and mass spectrometric investigations of
NH2PhOH support this hypothesis and suggest that in the
presence of base, the one-electron oxidized product can be
readily deprotonated before undergoing a second oxidation and
deprotonation (Figures S25−S27). This observation, combined
with previous reports of two-electron, two-proton reactions
involving NH2PhOH, provides compelling evidence that
stopped-flow kinetics data contain details of the secondary
PCET reactivity of NH2PhO• to form p-benzoquinone imine,
NHPhO (eqs 3 and 4).
KINETICS ANALYSIS AND DISCUSSION
■
Proton-Coupled Electron Transfer Reactivity. The
stopped-flow experiments described above provide kinetics
data about both PT and ET processes in the oxidation of
NH2PhOH by the oxidant/base combination of Fc+ and R-
7DMAQ (the formal bond dissociation free energies3,36 range
from 74.4 to 75.7 kcal mol−1 for these oxidant/base
combinations). The observation that higher concentrations of
NH2PhOH correlate with increases in both the observed rates
of PT and ET suggests that the PT and ET components are
coupled. Qualitatively, however, these two processes do not
appear to occur with the same reaction kinetics. Further, for
samples in which the concentration of R-7DMAQ was varied as
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Figure 5. Stopped-flow kinetics traces monitoring (left) the appearance of TMP-7DMAQH+ at 450 nm and (right) the disappearance of Fc+ at 620
nm for the reaction between 100 and 500 μM NH2PhOH, 60 μM Fc+, and 30 μM TMP-7DMAQ. Dotted lines represent the kinetics simulation
based on the kinetics model described by eqs 1−9. Rate constants used in the simulation: k1, 1.2 × 105 M−1 s−1; k2, 7.5 × 108 M−1 s−1; k3, 5.0 × 105
M−1 s−1; k4, 3.0 × 107 M−1 s−1; k5, 2.7 × 103 M−1 s−1; k−5, 3.0 × 106 M−1 s−1; k6, 3.0 × 106 M−1 s−1; k7, 1.0 × 105 M−1 s−1; k8, 1.0 × 105 M−1 s−1; k9,
1.4 × 106 M−1 s−1; k−9, 38.9 s−1.
Equations 1−4 together describe two sequential stepwise
PCET reactions. A complete picture of the reactivity, and a full
kinetics analysis, however, must also account for additional
reactivity. While NH2PhOH is a weaker base than R-7DMAQ,
the high concentration of NH2PhOH in these experiments
requires that we take into account an equilibrium between R-
7DMAQH+ and NH2PhOH (eq 5). Spectrophotometric
titrations (Figures S28−S31) indicate a weak equilibrium
between these two reagents (K5 = 1 × 10−2−5 × 10−4). These
titrations provide an estimation of the pKa of NH3PhOH+ in
acetonitrile (12.5, see Supporting Information).
The amine group of unreacted NH2PhOH can also serve as a
proton acceptor for either of the radical cations generated in
eqs 2 and 4 (eqs 6 and 7). On the basis of the relative basicities
of the proton acceptors in solution, we posit that PT to
NH2PhOH will be slower than PT to R-7DMAQ. However,
because the concentration of 7DMAQ is half that of the oxidant
Fc+, and NH2PhOH in excess, NH2PhOH must serve as a
proton acceptor from both a stoichiometric and kinetic
perspective.
elementary reaction steps. The rate law for the coupled series
of reactions was solved numerically using an ordinary
differential equation solver. Initial concentrations of reactants,
intermediates, and products as well as the time interval of the
reaction and rate constants were provided as inputs. Solving
these equations resulted in time-dependent concentration
profiles for each speciesknown molar extinction coefficients
were used to convert time-dependent concentration profiles
into simulated stopped-flow kinetics traces.
In order to minimize floating parameters, kinetics traces
monitoring the loss of the Fc+ absorbance at 620 nm upon
rapid mixing with NH2PhOH in the absence of R-7DMAQ
were simulated to quantify the rates of ET between Fc+ and
NH2PhOH (eq 1) and NH2PhO• (eq 3) (Figure S38). To
describe reactivity in the absence of R-7DMAQ, rate constants
k2, k4, k5, k−5, k9, and k−9 were set to zero in the kinetics model,
and the remaining rate constants were adjusted iteratively to
simulate the kinetics traces. Simulations were extremely
sensitive to both k1 and k3 and yielded values of 1.2 × 105
M−1 s−1 and 5.0 × 105 M−1 s−1, respectively, for these two rate
constants. These rate constants are consistent with those
predicted by the Marcus cross-relation based on the self-
exchange rate constants for ferrocene/ferrocenium and
phenoxyl/phenoxide (the PhOH•+/0 self-exchange rate con-
stant is not known; see Supporting Information).71,72
Simulations also provided rate constants for proton transfer
from the oxidation products to NH2PhOH (k6 = 3.0 × 106 M−1
s−1 and k7 = 1.0 × 105 M−1 s−1; see below for further
discussion). The rate constant depicting terminal oligomeriza-
tion reactivity of p-quinone imine (k8 = 1 × 105 M−1 s−1) falls
in the range estimated for oligomer formation.65 The value of
this parameter had minimal influence on the kinetic fits but was
necessary to model the consumption of the p-benzoquinone
imine.64,65
To model kinetics data for samples incorporating the
photometric bases (λobs = 440−460 and 620 nm), the five
rate constants determined above in the absence of R-7DMAQ
were held constant. Values for K5 and K9, which describe the
equilibria of R-7DMAQ with NH2PhOH and Fc+, respectively,
were used to determine the ratios of k5:k−5 and k9:k−9. The
forward rate constants k5 and k9 were determined through
iterative simulation while the reverse rate constants k−5 and k−9
were fixed by maintaining Keq = k5/k−5 (k9/k−9). As a result, the
only remaining variables in the complete kinetics model
described by eqs 1−9 were the rate constants for proton
transfer from the initial oxidation products NH2PhOH•+ and
The aforementioned product NHPhO reacts further to form
oligomeric structures; we simplistically represent this complex
terminal reactivity with eq 8.64,65 Lastly, when Fc+ is titrated
into a solution of R-7DMAQ, the absorbance of R-7DMAQ
decreases, and a new peak appears at 460 nm, suggesting an
adduct between R-7DMAQ and Fc+ (Figure S32). However,
upon addition of a stronger base (that does not absorb in the
visible region), 1,8-diazabicycloundec-7-ene (DBU, pKa
=
24),67 the original absorbance spectrum of basic R-7DMAQ
is recovered. Quinolines are Lewis bases68 and can thus form
adducts with Lewis acids, like Fc+.69 To further confirm that the
absorbance shifts arise from a Lewis acid−base interaction, and
ensure the reactivity was not resulting from an endergonic
electron transfer reaction, the interaction of Ph-7DMAQ with
decamethylferrocenium (Me10Fc+, a 507 mV weaker oxidant)69
was tested. Upon titration with Me10Fc+, a similar change in
absorbance of Ph-7DMAQ is observed (Figure S33). This
Lewis acid−base interaction between the R-7DMAQs and Fc+
(eq 9) was quantified using a modified Benesi−Hildebrand
analysis70 (see Figures S34−S37) and taken into account when
modeling the kinetics of the described PCET system (vide
infra).
Kinetics Model for PCET Reactivity. Kinetics simulations
were performed with a series of differential equations (see
Supporting Information) derived from the kinetics model
described in eqs 1−9 to determine rate constants for
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J. Phys. Chem. B XXXX, XXX, XXX−XXX

The Journal of Physical Chemistry B
Article
NH2PhO+ to R-7DMAQ (k2 and k4, respectively). Rate
constants k2 and k4 were iteratively adjusted, together with k5
and k9, to achieve satisfactory simulation of the single
wavelength kinetics traces at both λobs = 440−460 nm and
λobs = 620 nm. Simulations were repeated across a set of
samples that contained varying concentrations of NH2PhOH to
obtain a self-consistent set of rate constants for each R-
7DMAQ. k2 values from these simulations fall in the range
(1.5−7.5) × 108 M−1 s−1 while the corresponding k4 values are
smaller, in the range (5.5−3.0) × 107 M−1 s−1 (Table 2).
Table 2. Rate Constants Determined through Kinetics
Modeling
R-7DMAQ photometric base
Ph-
7DMAQ
MeO-
7DMAQ
TMP-
7DMAQ
rate constants
H-7DMAQ
k1 (M−1 s−1
k2 (M−1 s−1
k3 (M−1 s−1
k4 (M−1 s−1
k5 (M−1 s−1
)
)
)
)
)
1.2 × 105
1.5 × 108
5.0 × 105
5.5 × 106
2.0 × 104
1.0 × 106
3.0 × 106
1.0 × 105
1.0 × 105
3.0 × 105
6.7
1.2 × 105
6.0 × 108
5.0 × 105
2.0 × 107
3.0 × 103
1.0 × 106
3.0 × 106
1.0 × 105
1.0 × 105
1.2 × 106
5.7
1.2 × 105
6.0 × 108
5.0 × 105
2.0 × 107
5.7 × 103
3.0 × 106
3.0 × 106
1.0 × 105
1.0 × 105
1.0 × 106
16.1
1.2 × 105
7.5 × 108
5.0 × 105
3.0 × 107
2.7 × 103
3.0 × 106
3.0 × 106
1.0 × 105
1.0 × 105
1.4 × 106
38.9
Figure 6. For proton transfer reactions from aminophenol oxidation
products, free energy relationships are observed between the rate
constants and the pKa value for the conjugate acid of the proton
acceptor, which is proportional to the driving force for proton transfer
within each set of reactions. Included on this plot are the values for k2
●
and k4, the rates of PT to R-7DMAQ derivatives ( , pKa(R-
k−5 (M−1 s−1
)
7DMAQH+) = 14.2−15.2), as well as k6 and k7, the rates of PT to
k6 (M−1 s−1
k7 (M−1 s−1
k8 (M−1 s−1
k9 (M−1 s−1
)
)
)
)
+
▲
NH2PhOH ( , pKa(NH3PhOH ) = 12.5). Across the R-7DMAQ
derivatives, linear free energy relationships (gray dashed lines) are
observed for proton transfer from NH2PhOH•+ (slope = 1.66) and
from NH2PhO+ (slope = 1.65). Including proton transfer from these
radical cations to NH2PhOH, the data fit best to a quadratic
relationship (blue and red dashed lines).
k−9 (s−1
)
To more closely examine the influence of individual rate
constants on simulations of single-wavelength kinetics traces,
the concentration profiles of individual reactants and
intermediates underpinning the kinetics simulations were
examined. In the studies described in this work, the
concentration of Fc+ is held constant (60 μM) while the initial
concentrations of NH2PhOH range from 100 to 500 μM.
These near pseudo-first-order conditions might suggest that all
of the Fc+ would be consumed through the oxidation of
NH2PhOH to NH2PhOH•+, and thus the subsequent oxidation
of NH2PhO• would not occur as the Fc+ concentration would
rapidly decay to zero. However, concentration profiles of Fc+,
NH2PhOH, NH2PhO•, and NHPhO show that with the rate
constants determined from the kinetics simulations Fc+ is not
immediately and completely consumed by reaction with
NH2PhOH; NH2PhO• forms rapidly, and Fc+ oxidizes both
NH2PhOH and NH2PhO• on the milliseconds time scale
(Figure S42). Incorporating the oxidation of NH2PhO• by Fc+
is critical for accurately describing the reaction of interest and
obtaining good kinetics simulations.
Driving Force Dependent Rate Constants for Proton
Transfer. Rate constants for proton transfer from NH2PhOH•+
(k2) and NH2PhO+ (k4) to R-7DMAQ, linear correlations are
observed between ln(kPT) and the pKa values for the conjugate
acids of the R-7DMAQ proton acceptors (Figure 6). While the
two trend lines have identical slopes (slope = 1.65) their
vertical offset reflects the difference in the unknown pKa values
of NH2PhOH•+ and NH2PhO+. As such, the pKa values on the
x-axis only linearly correlate with −ΔGPT within each set of
data.3 The free energy relationships observed are consistent
with what is predicted by the Brønsted relation for acid−base
reactivity, as well as theory developed by Bell based on the
transition state model.41,73−75 Indeed, linear correlations
between rate constants and driving force have been observed
in many examples of proton transfer, and Brønsted slopes have
been traditionally used to characterize reaction mechanisms and
compare proton transfer processes.33,34,41−43,73,75−79
When the rate constants for proton transfer from
NH2PhOH•+ (k6) and NH2PhO+ (k7) to NH2PhOH are
added to the plot (pKa(NH3PhOH+) = 12.5), these data points
fall off the linear trend lines defined by the four R-7DMAQ
bases, lending distinct curvature to the ln(kPT)−pKa relation-
ship (Figure 6). While NH2PhOH is a structurally distinct base
from the R-7DMAQ class of compounds, examples of free
energy relationships in proton transfer reactions involving
nitrogen and oxygen acids and bases have been shown to hold
across a range of proton donors/acceptors.80 The data sets (k2
and k6, k4, and k7) fit well to parabolas, consistent with the
quadratic correlation between ΔG‡ (the free energy of
activation) and −ΔGPT predicted by Marcus for proton transfer
reactions.41,73,75,81,82 In this context, the linear relation
observed for proton transfer to the R-7DMAQ bases could
simply result from the small ΔpKa range that these data points
span, across which the higher order terms of the quadratic can
be neglected to give an apparent linear relationship for dΔG‡/
dΔGPT.31,75,83 While parabolic free energy relationships have
long been theorized for proton transfer,81,82,84,85 limited
experimental examples revealing these relationships are
available, especially in either nonaqueous solvents or as part
of a PCET process.75,80,82,86 Unfortunately, the system studied
in this work limits the range of driving forces that can be
examined, preventing a more definitive assessment of the free
energy relationship for proton transfer. Nevertheless, these data
enhance our understanding of free energy relationships for
proton transfer processes in PCET reactions and motivate
extended study in this area.
G
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CONCLUSION
■
Utilizing a series of 7-(dimethylamino)quinoline derivatives as
photometric bases, both the PT and ET components of the
PCET oxidation of NH2PhOH were optically monitored upon
rapid mixing via stopped flow. Analysis of this complex
multielectron, multiproton reaction was enabled by spectro-
scopic handles for both proton transfer and electron transfer. A
comprehensive kinetics model was constructed, from which
rate constants for elementary reaction steps were determined.
These data reveal free energy relationships between PT rate
constants and the pKa values of the conjugate acids of the
proton acceptors. Over the driving force range examined, these
data suggest a Marcus relationship for proton transfer. Notably,
free energy relationships for PT components of PCET
reactions have recently been reported by our group for
elementary proton transfer steps involved in hydrogen
evolution catalyzed by transition metal complexes.33,34 Taken
together, these experimentally determined relationships en-
hance our understanding of PT processes in PCET reactions
and provide a framework to further study these reactions in a
comprehensive fashion.
(8) Warren, J. J.; Mayer, J. M. Hydrogen Atom Transfer Reactions of
Iron-Porphyrin-Imidazole Complexes as Models for Histidine-Ligated
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L. Concerted Proton-Coupled Electron Transfer from a Metal-
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̈
Transfer from Tryptophan: A Concerted Mechanism with Water as
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́
yi, G.;
̈
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jpcb.6b04011.
Åkermark, B.; Hammarstrom, L. Kinetic Effects of Hydrogen Bonds
̈
■
S
on Proton-Coupled Electron Transfer from Phenols. J. Am. Chem. Soc.
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(12) Johannissen, L. O.; Irebo, T.; Sjodin, M.; Johansson, O.;
̈
Hammarstrom, L. The Kinetic Effect of Internal Hydrogen Bonds on
̈
Experimental details, compound purification and charac-
terization (NMR, UV−vis, mass spectrometry, cyclic
voltammetry), spectrophotometric titrations, additional
stopped-flow kinetics, a modified Benesi−Hildebrand
analysis, and additional details of kinetics modeling
(PDF)
Proton-Coupled Electron Transfer from Phenols: A Theoretical
Analysis with Modeling of Experimental Data. J. Phys. Chem. B
2009, 113, 16214−16225.
(13) Gagliardi, C. J.; Westlake, B. C.; Kent, C. A.; Paul, J. J.;
Papanikolas, J. M.; Meyer, T. J. Integrating Proton Coupled Electron
Transfer (PCET) and Excited States. Coord. Chem. Rev. 2010, 254,
2459−2471.
(14) Bronner, C.; Wenger, O. S. Proton-Coupled Electron Transfer
between 4-Cyanophenol and Photoexcited Rhenium(I) Complexes
with Different Protonatable Sites. Inorg. Chem. 2012, 51, 8275−8283.
(15) Kuss-Petermann, M.; Wolf, H.; Stalke, D.; Wenger, O. S.
Influence of Donor−Acceptor Distance Variation on Photoinduced
Electron and Proton Transfer in Rhenium(I)−Phenol Dyads. J. Am.
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Photoexcited Metal Complexes. Acc. Chem. Res. 2013, 46, 1517−1526.
(17) Eisenhart, T. T.; Dempsey, J. L. Photo-Induced Proton-Coupled
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AUTHOR INFORMATION
Corresponding Author
*E-mail: dempseyj@email.unc.edu (J.L.D.).
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge support from the National Science
Foundation through a CAREER Award (CHE-1452615) and
the donors of the American Chemical Society Petroleum
Research Fund (53764-DN13). J.L.D. acknowledges support
from a Packard Fellowship in Science and Engineering. We
thank Eric Rountree for assistance with stopped-flow experi-
ments, Guy Goodman for insightful discussions, and Chris
Lennox for aid in optimizing reaction conditions. The lab of
Prof. Thomas Meyer is gratefully acknowledged for the use of
their stopped-flow instrumentation.
́
(18) Costentin, C.; Drouet, S.; Passard, G.; Robert, M.; Saveant, J.-M.
Proton-Coupled Electron Transfer Cleavage of Heavy-Atom Bonds in
Electrocatalytic Processes. Cleavage of a CO Bond in the Catalyzed
Electrochemical Reduction. J. Am. Chem. Soc. 2013, 135, 9023−9031.
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Concerted Proton-Electron Transfers. Consistency between Electro-
chemical Kinetics and Their Homogeneous Counterparts. J. Am.
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