Conformational Change with Steric Interactions Affects the Inner Sphere Component of Concerted Proton-Electron Transfer in a Pyridyl-Appended Radical Cation System

Article abstract of DOI:10.1021/acs.joc.5b01427

Proton-coupled electron transfer (PCET) model systems combine one-electron oxidants and bases to generate net hydrogen atom acceptors. We have generated two persistent pyridyl-appended radical cations: 10-(pyrid-2-yl)-10H-phenothiazinium (PPT^?+) and 3-(pyrid-2-yl)-10-methyl-10H-phenothiazinium (MPTP^?+). EPR spectra and corresponding calculations indicate phenothiazinium radical cations with minimal spin on the pyridine nitrogen. Addition of hindered phenols causes the radical cations to decay, and protonated products and the corresponding phenoxyl radicals to form. The ΔG° values for the formation of intermediates (determined through cyclic voltammetry and pK_a measurements) rule out a stepwise mechanism, and kinetic isotope effects support concerted proton-electron transfer (CPET) as the mechanism. Calculations indicate that the reaction of PPT^?+ + ^tBu₃PhOH undergoes a significant conformational change with steric interactions on the diabatic surface while maintaining the hydrogen bond; in contrast, MPTP^?+ + ^tBu₃PhOH maintains its conformation throughout the reaction. This difference is reflected in both experiment and calculations with (Formula presented.) < (Formula presented.) despite (Formula presented.) > (Formula presented.). Experimental results with 2,6-di-tert-butyl-4-methoxyphenol are similar. Hence, despite the structural similarity between the compounds, differences in the inner sphere component for CPET affect the kinetics.

Full text of DOI:10.1021/acs.joc.5b01427

Article
pubs.acs.org/joc
Conformational Change with Steric Interactions Affects the Inner
Sphere Component of Concerted Proton−Electron Transfer in a
Pyridyl-Appended Radical Cation System
Evan A. Welker,† Brittney L. Tiley,† Crina M. Sasaran,† Matthew A. Zuchero,† Wing-Sze Tong,†
Melissa J. Vettleson,† Robert A. Richards,† Jonathan J. Geruntho,† Stefan Stoll,‡ Jeffrey P. Wolbach,*,¶
and Ian J. Rhile*,†
†Department of Chemistry and Biochemistry, Albright College, Reading, Pennsylvania 19610-5234, United States
‡Department of Chemistry, University of Washington, Seattle, Washington 98195-1700, United States
¶Eurofins Lancaster Laboratories, Lancaster, Pennsylvania 17601, United States
S
* Supporting Information
ABSTRACT: Proton-coupled electron transfer (PCET)
model systems combine one-electron oxidants and bases to
generate net hydrogen atom acceptors. We have generated two
persistent pyridyl-appended radical cations: 10-(pyrid-2-yl)-
10H-phenothiazinium (PPT•+) and 3-(pyrid-2-yl)-10-methyl-
10H-phenothiazinium (MPTP•+). EPR spectra and corre-
sponding calculations indicate phenothiazinium radical cations
with minimal spin on the pyridine nitrogen. Addition of
hindered phenols causes the radical cations to decay, and
protonated products and the corresponding phenoxyl radicals
to form. The ΔG° values for the formation of intermediates
(determined through cyclic voltammetry and pKa measurements) rule out a stepwise mechanism, and kinetic isotope effects
support concerted proton−electron transfer (CPET) as the mechanism. Calculations indicate that the reaction of PPT•+
+
tBu3PhOH undergoes a significant conformational change with steric interactions on the diabatic surface while maintaining the
t
hydrogen bond; in contrast, MPTP•+ + Bu3PhOH maintains its conformation throughout the reaction. This difference is
reflected in both experiment and calculations with ΔG⧧MPTP•+ < ΔGP⧧PT•+ despite ΔGM° PTP•+ > ΔGP°PT•+. Experimental results with
2,6-di-tert-butyl-4-methoxyphenol are similar. Hence, despite the structural similarity between the compounds, differences in the
inner sphere component for CPET affect the kinetics.
namics for the reactions. For example, insertion of a spacer
between the oxidant and base10 or increasing the distance of H+
transfer11 slows the overall kinetics. Here we describe two
radical cations with appended bases (PPT•+ and MPTP•+,
Figure 1) and investigate their reactivity with hindered phenols.
(Hindered phenols were employed since the corresponding
phenoxyl radicals are persistent and do not appear to couple
with the radical cations or each other. They are common
reaction partners in studies of CPET, in part because they are
hydrogen bond donors and because they have high-energy
intermediates for the potential stepwise mechanisms.8b) As
described below, PPT•+ undergoes a significant conformational
shift during its reaction with hydrogen atom donors; this
conformational shift results in a larger barrier for reaction
compared with MPTP•+, which does not undergo as dramatic a
shift. This is interpreted as a difference in the inner sphere
reorganization, in parallel to electron transfer.
INTRODUCTION
■
Radical chemistry is a dominant paradigm in organic chemistry,
and hydrogen atom transfer (HAT) is an important mechanism
in this paradigm. In HAT, the H+ and e− transfer from the same
bond. HAT has been contrasted to concerted proton−electron
transfer (CPET) for which the H+ is transferred between lone
pairs in a hydrogen bond and the e− is transferred between
different orbital systems.1 Some examples include reactions
with phenols,2 oximes,3 flavins,4 tryptophan,5 guanosine,6 and
structurally related compounds. CPET also extends to cases not
usually considered as HAT, such as reactions for which the H+
and e− are transferred to or from multiple reagents, sites, or
orbitals, and is sometimes qualified with “bidirectional”.7
(However, the orbital distinction between CPET and HAT
can be ambiguous,8 and it has been suggested that the degree of
nonadiabaticity is a better criterion.9)
Tethering a one-electron oxidant and a base generates a
reagent that is capable of undergoing CPET. Several groups are
using these systems to investigate what structures allow for
CPET and how the structure affects the rate and thermody-
Received: June 23, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01427
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
vs the concentration of phenol in excess provided second-order
rate constants: 12 1 and 790 80 M−1 s−1 for PPT•+ and
t
MPTP•+, respectively. Similar kinetics with Bu3PhOD provide
kinetic isotope effects: kD,PPT = 4.7 0.5 M−1 s−1 ≡ kH/kD =
•+
2.6 0.4; kD,MPTP = 90 9 M−1 s−1 ≡ kH/kD = 8.7 1.2.
•+
Activation parameters were determined for PPT•+ + tBu3PhOH
over a range of 13.4−62.6 °C: ΔH⧧ = 7.5 0.3 kcal mol−1 and
ΔS⧧ = −28.4 0.9 cal K−1 mol−1. Similar kinetics using 2,6-di-
tert-butyl-4-methoxyphenol (tBu2(OMe)PhOH) as the hydro-
gen donor afford rate constants of (7.5 0.7) × 103 and (9.0
0.9) × 104 M−1 s−1 for PPT•+ and MPTP•+, respectively.
Additional experiments provide thermodynamic parameters.
An acid−base equilibration study with thymol blue (pKa =
13.4)22 and PPT provided pKa[PPT{H+/0}] = 10.9
0.2.
Figure 1. Reactions with 10-(2-pyridyl)-10H-phenothiazinium
(PPT•+) and 3-(pyrid-2-yl)-10-methyl-10H-phenothiazinium
(MPTP•+).
Addition of triflic acid to PPT in electrolyte solution caused a
shift in the CV attributed to PPTH2+/+ at 0.67 V. (CVs of
protonated 10-ammoniumalkyl-10H-phenothiazines are rever-
sible, even in water.23) An equilibration study with tris(4-
tolyl)aminium (E = 0.38 V)17 provides an equilibrium constant
of 0.63, consistent with E[PPT•+/0] = 0.39 V. These data
provide an effective bond dissociation free energy (BDFE) for
RESULTS
■
The radical cations were synthesized by palladium-catalyzed
couplings and one-electron oxidation. Radical cation precursor
10-(pyridin-2-yl)-10H-phenothiazine (PPT)12 was synthesized
by a Buchwald−Hartwig amination,13 and 3-(pyrid-2-yl)-10-
methyl-10H-phenothiazine (MPTP) was synthesized from the
known pinacol borane14 via a Suzuki coupling.15 Cyclic
voltammetry (CV) of the neutral compounds provided a
reversible wave at 0.39 0.03 and 0.32 0.03 V, for PPT•+/0
and MPTP•+/0, respectively, vs Cp2Fe+/0 in 0.1 M NBu4PF6 in
MeCN (Figures S6 and S7). Similar systems undergo reversible
CV.16 Forming the radical cations in solution requires an
oxidant with a reduction potential higher than that of the
radical cation−neutral pair. Lewis acidic oxidants such as metal
ions and other strong electrophiles (e.g., NO+) reacted with the
pyridine lone pair. Oxidations with limiting tris(4-
PPTH+ → PPT•+ + H• of 79
1 kcal/mol. The pKa of
MPTP{H+/0} was determined by titration with pyridinium
(pKa = 12.6)23 and monitoring the growth of MPTPH+ to
provide pKa = 11.9. Further parallel experiments provided
E[MPTPH2+/+] = 0.51 V and the effective BDFE for MPTPH+
→ MPTP•+ + H• of 79
1 kcal/mol. The kinetic and
thermodynamic data are summarized in Table 1.
Table 1. Experimental and Calculated Parameters for
Radical Cations
PPT•+
MPTP•+
pKa (XPTH+ → XPT + H+)
E (XPT•+/0, V)
10.9 0.1
0.39 0.03
78.8 0.8
0.67 0.03
11.9 0.1
0.32 0.01
78.6 0.8
0.51 0.03
790 80
bromophenyl)aminium hexafluorophosphate (E = 0.67 V vs
17
Cp2Fe+/0
;
E
= 0.28 V ≡ Keq = 5.2 × 104 for NArBr •+ + PPT
rxn
3
⇌ NArBr + PPT•+; and Erxn = 0.35 V ≡ Keq = 1.2× 108 for
BDFE (kcal/mol)
3
E (XPTH2+/+, V)
NArBr •+ + MPTP ⇌ NArBr + MPTP•+) provide colored
3
3
k2,4,6‑ Bu PhOH (M−1 s−1
)
12
1
t
solutions, red for PPT•+ and purple for MPTP•+. Absorptions
at 515 (ε = 1.0 × 104), 779 (1.5 × 103), and 890 nm (1.4 × 103
M−1 cm−1) for PPT•+ (Figure S2) and 580 (9.8 × 103), 779
(2.0 × 103), and 864 nm (1.9 × 103 M−1 cm−1) in MeCN for
MPTP•+ (Figure S5) in the UV−vis spectrum are indicative of
phenothiazinium radical cations.18 Solutions of PPT•+ at ≤10
mM maintain their absorbance in the UV−vis over several days
in air (loss of absorbance per day ∼2−3%). EPR spectra were
recorded in CH2Cl2 (Figure S9 and Tables S1 and S2), and 1H
NMR spectra in CD3CN are silent. The persistence of the
radical cation echoes that of substituted phenothiazinium19 and
related aminium radical cations20 in the presence of pyridine.
Hindered phenols were employed as hydrogen atom donors
(Figure 1). Addition of excess 2,4,6-tri-tert-butylphenol
(tBu3PhOH, 1−10 mM) to the radical cations (0.1−0.3 mM)
in CH3CN causes a decay in the absorptions and appearance of
3
k2,4,6‑ Bu PhOD (M−1 s−1
)
4.7 0.5
90
9
t
3
kH/kD
2.6 0.4
7.5 × 103
8.7 1.2
9 × 104
k2,6‑ Bu (MeO)PhOH (M−1 s−1
)
t
2
Since PPT•+, MPTP•+, and MPTPH+ have significant
absorptions in the visible region, several equilibration experi-
ments were performed between the sets of compounds to
determine proton, electron, and proton−electron equilibrium
constants (Table 2). For example, an equilibration experiment
provides an alternate method to find the BDFE for MPTPH+.
The equilibrium constant for tBu3PhOH + MPTP•+
⇌
tBu3PhO• + MPTPH+ of 9.8 0.9 provides ΔG° = −1.1
t
0.1 kcal/mol, and the literature BDFE for Bu3PhOH of 77.1
kcal/mol8b provides a consistent BDFE of 78.8 1.3 kcal/mol.
21
t
peaks for Bu3PhO• at 400 and 626 nm. For PPT•+, the
Table 2. Experimentally Determined Equilibrium Constants
and ΔG°
resulting solutions were colorless with no significant
t
absorptions for PPTH+; the concentration of Bu3PhO• was
small enough to not provide visible color. For MPTP•+,
resulting solutions are intensely yellow corresponding to
MPTPH+ (λmax = 415 nm, ε = 9.6 × 103 M−1 cm−1),
confirmed by the protonation of MPTP with dimethylforma-
mide−triflic acid complex. The decay was monitored by
stopped flow under pseudo-first-order conditions. Rate
constants were determined through global fitting. Plots of kobs
ΔG°
equilibrium
Keq
(kcal/mol)
PPT + MPTPH+ ⇌ PPTH+ + MPTP
PPT + MPTP•+ ⇌ PPT•+ + MPTP
PPTH+ + MPTP•+ ⇌ PPT•+ + MPTPH+
0.17
0.031
0.32
−1.1 0.1
−2.1 0.1
−0.7 0.1
1.4 0.1
t
t
MPTP•+ + Bu3PhOH ⇌ MPTPH+ + Bu3PhO• 9.8
B
DOI: 10.1021/acs.joc.5b01427
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 2. (a) PPT•+ with numbering, (b) PPTH+, and (c) calculated TS for PPT•+ + tBu3PhOH → PPTH+ + tBu3PhO•. One tert-butyl group has
been truncated to a single carbon to aid in visualizing the TS geometry.
(Reactions with PPT•+ were slow to come to equilibrium at the
appropriate concentrations to measure the corresponding
equilibrium constant.)
conformation parallels many neutral 10-aryl-10H-phenothia-
zines.29 The progression of the backbone conformational
change during the CPET reaction is illustrated in Figures S30
and S31.
Calculations were performed on the radical cations, the
t
protonated products, Bu3PhOH, and both pre- and post-
The TS geometry is intermediate between PPT and PPTH+.
The phenothiazine ring at the TS resembles the boat-like
phenothiazine geometry of PPTH+. However, the pyridine ring
remains orthogonal as in PPT•+, but pseudoequatorial instead
of pseudoaxial. This conformation is required to maintain the
hydrogen bond while minimizing steric clashing with
tBu3PhO•; the smallest tert-butyl hydrogen−sulfur distance is
3.42 Å, only slightly larger than what is expected from van der
Waals radii. Vibrational frequency evaluation of the TS
produced a single imaginary frequency (882.5 cm−1). No
stationary point was found for placing the pyridine in the
reaction hydrogen bonded complexes (i.e., tBu3PhOH···PPT•+,
t
tBu3PhO•···PPTH+, Bu3PhOH···MPTP•+, and tBu3PhO•···
MPTPH+). In addition, the classical transition states (TS)
were located. All calculations were performed in Gaussian 0924
using the B972 model chemistry25 and the 6-31+G(d,p) basis
set.26
The pyridine ring of PPT•+ is orthogonal to the planar
phenothiazine ring (Figure 2) as in other 10-aryl-10H-
phenothiazinium radical cations.27 The conformations of 9-
phenylanthracene and related compounds are similar.28 The
singly occupied molecular orbital (SOMO) contains significant
electron density on the phenothiazine ring but negligible
density on the pyridine ring. (A more complete analysis of the
molecular orbitals and spin densities appears in the Supporting
Information.) The EPR spectrum has a small hyperfine
coupling for the pyridyl N (2.75−3.00 MHz), indicating a
0.5−0.6% spin population on it; DFT calculations are
consistent with this value. Figure S28 displays the spin density
of PPT•+, contoured at an isovalue of 0.0025 au; the spin
density is completely confined to the phenothiazine ring at this
level. Qualitatively, the planar conformation allows the charge
and spin density to be delocalized over the phenothiazine ring
with minimal steric interaction with the hydrogens at positions
1 and 8. In PPTH+, the phenothiazine N has pyramidalized.
The phenothiazine is boat-like with the pyridine pseudoaxial,
and the pyridine no longer bisects the phenothiazine ring. This
t
pseudoaxial position. Starting from isolated Bu3PhOH and
PPT•+, the calculated in vacuo ΔG⧧ is 14.7 kcal/mol, including
a basis set superposition error of 1.8 kcal/mol. Static solvation
of the in vacuo isolated reactant and TS geometries with the
SMD30 implicit solvation model resulted in a calculated ΔG⧧ of
21.8 kcal/mol. Calculations also were performed on the stable
intermediates for both electron transfer (ET) and proton
transfer (PT). Solvating the in vacuo optimized geometries of
each reactant and stable intermediate with the SMD implicit
solvation model provides ΔGPT = 34.8 kcal/mol (190.7 kcal/
mol in vacuo) and ΔGET = 10.5 kcal/mol (14.5 kcal/mol in
vacuo). The value for in vacuo PT is extremely high due to
charge-separation in the gas phase in contrast to ET or CPET.
The analogous reaction with MPTP•+ proceeds with a much
less significant conformational change (Figure 3). The
phenothiazine ring of MPTP•+ is nearly planar, and the
C
DOI: 10.1021/acs.joc.5b01427
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
frequency evaluation of the tBu3PhOH···MPTP•+ TS produced
a single imaginary frequency (709.3 cm−1). Starting from
t
isolated Bu3PhOH and MPTP•+, the calculated in vacuo ΔG⧧
is 10.1 kcal/mol (basis set superposition error 1.5 kcal/mol)
and the solvated ΔG⧧ is 21.8 kcal/mol; calculations on the
stable intermediates, including solvation, for both ET and PT
provide ΔGPT = 27.0 kcal/mol (170.6 kcal/mol in vacuo) and
ΔGET = 12.9 kcal/mol (16.9 kcal/mol in vacuo).
DISCUSSION
■
In this work, two persistent and structurally similar base-
appended radical cations are reacted with hindered phenols as
hydrogen atom donors to explore the mechanism and compare
the two compounds. Each compound combines a phenothia-
zinium radical cation and a pyridine, and hence each has the
components to accept an e− and a H+. We will consider the
mechanism for the two sets of reactions and then compare the
two cases.
From experimental and literature data,8b,31 ΔG° for ET and
PT intermediates can be estimated and the ΔG⧧ can be
calculated (from the Eyring equation) to explore the
mechanism (see Table 3 and Experimental Section) . The
Table 3. Experimental and Computational Free Energies
(kcal/mol)
experimental
computational
ΔGP°T
a
reactant pair
ΔG⧧ ΔGE°T
(est.)
ΔG⧧ ΔGE°T ΔGP°T
t
PPT•+ + Bu3PhOH
15.9
12.1
18.2
14.3
29.9
32.6
14.7
14.5
34.8
t
PPT•+ + Bu2(OMe)
PhOH
t
MPTP•+ + Bu3PhOH 13.4
19.8
15.9
26.4
29.2
10.1
16.9
27.0
MPTP•+
+
10.7
tBu2(OMe)PhOH
a
Calculated including implicit solvation.
t
data indicate ΔGET for PPT•+ + Bu3PhOH → PPT +
tBu3PhOH•+ of 18.2 1.4 kcal/mol and an estimated ΔGPT for
PPT•+ + tBu3PhOH → PPTH2+ + Bu3PhO− of 29.9 kcal/mol.
These ΔG° values are larger than the measured ΔG⧧ of 15.9
Figure 3. (a) MPTP•+ with numbering, (b) MPTPH+, and (c)
t
t
calculated TS for MPTP•+ + Bu3PhOH → MPTPH+ + Bu3PhO•.
t
0.7 kcal/mol. The corresponding data for Bu2(OMe)PhOH +
pyridine and phenothiazine rings are nearly coplanar in the
radical cation, in contrast to the orthogonal positioning in
PPT•+. Optimizations started with the pyridine orthogonal to
the phenothiazine system resulted in the described pseudopla-
nar geometry. Experimentally, the hyperfine coupling to the
phenothiazine nitrogen and the attached methyl group
dominate the EPR spectrum, although a small amount of
spin density is present on the attached, coplanar pyridine in the
calculation (Figure S29). As for PPTH+, the phenothiazine ring
of MPTPH+ is boat-like, but the methyl group is in the
pseudoequatorial position. The pyridine ring in MPTPH+ is
tilted relative to the attached phenothiazine, occupying a
position neither coplanar nor orthogonal to the phenothiazine
ring.
PPT•+ are similar: ΔGET = 14.3 1.4 kcal/mol; ΔGPT ≈ 32.6
kcal/mol; ΔG⧧ = 12.1 0.7 kcal/mol. MPTP•+ has a similar
pattern for the corresponding values: For reaction with
tBu3PhOH, ΔG⧧ = 13.4 0.7 kcal/mol, ΔGET = 19.8 1.4
t
kcal/mol, and ΔGPT ≈ 26.4 kcal/mol, and with Bu2(OMe)-
PhOH, ΔG⧧ = 10.7 0.7 kcal/mol, ΔGET = 15.9 1.4 kcal/
mol, and ΔGPT ≈ 29.2 kcal/mol; these data are summarized in
Table 3. These data suggest that CPET is the mechanism.
(While ΔGET is close to being within error of the experiment,
ET is unlikely to be barrierless.) Experimentally, ΔG⧧ < ΔGE°T
≪ ΔG°PT; the computed in vacuo values for ΔGE°T and ΔG⧧, and
the computed solvated value of ΔG°PT are in reasonable
agreement. The computed in vacuo difference between the
barriers (ΔΔG⧧) of 4.6 kcal/mol echoes the experimental
results (2.5 kcal/mol), with MPTP•+ reacting with a smaller
barrier; including the effects of solvation in the calculations
results in the barriers for both reactions being equal.
In the TS, the geometry of the acceptor component remains
similar to MPTPH+. The phenothiazine ring is boat-like at the
TS, the phenothiazine methyl is pseudoequatorial, and the
pyridine is tilted out of the plane of the phenothiazine with a
N17−C16−C6−C5 torsion angle of 39.4°. The transferring
hydrogen remains closer to the O with O···H and N···H
distances of 1.10 and 1.41 Å, respectively. These distances are
t
The kinetic isotope effects for the reactions with Bu3PhOH
of 2.6 0.4 and 8.9 1.2 for PPT•+ and MPTP•+, respectively,
indicate that the proton is involved in the rate-determining
step. The latter value is likely out of the classical range32
t
similar to those at the TS for Bu3PhOH + PPT•+. Vibrational
D
DOI: 10.1021/acs.joc.5b01427
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
suggesting a tunneling event, although measured kinetic isotope
effects vary from small (∼2)33 to very large (>400)34 for CPET
reactions.35 The difference between the two systems could be
ascribed to a balance among several factors (e.g., hydrogen
vibrational wave function overlap, frequency, reorganization
energy, and ΔG°)1a,36 and cannot be separated with the
reported experimental and computational data.
between proton donating and accepting sites are not
significantly different. The electron transfer distance is difficult
to compare; however, the pyridine ring acts as a discrete spacer
between the phenothiazine and the phenols for both the PPT•+
and MPTP•+ radical cations. Furthermore, the frontier orbitals
are similar in terms of contributions between the two
components.
In conclusion, a persistent pyridyl-appended radical cation
abstracts a net hydrogen atom from a phenol by CPET, with
separate sites for accepting the H+ and e−. The systems have
different conformation changes: reaction with PPT•+ requires a
more constrained TS than for MPTP•+, and this difference in
inner-sphere reorganization increases the TS energy.
Despite reactions with the MPTP•+ occurring with lower
barriers than those with PPT•+, the MPTP•+ reactions are less
favored thermodynamically. The ΔG° for the reaction can be
determined in two ways from the thermodynamic data. (1)
Using the E[XPT•+/0] and pKa[XPT{H+/0}] values, one obtains
BDFEs of 79.1 0.8 and 78.6 0.8 kcal/mol, respectively, for
PPTH+ → PPT•+ + H• and MPTPH+ → MPTP•+ + H•,
implying that the reactions with the phenols are 0.5 1.6 kcal/
mol (ΔΔG°) further downhill for PPT•+ compared with
MPTP•+. (2) A direct and more precise comparison can be
EXPERIMENTAL SECTION
■
General Considerations. Acetonitrile for kinetics and equilibra-
tion studies was purchased dry and used under N2. Toluene was either
distilled from Na/benzophenone under N2 or taken from a solvent
drying column before use. Methylene chloride was taken from a
solvent drying system. Triethylamine was distilled from sodium
hydroxide under nitrogen, and 1,4-dioxane was also refluxed and dried
over benzophenone and Na under nitrogen. The cyclic voltammogram
for 1,3-di-tert-butyl-2,5-dimethoxybenzene was taken under nitrogen in
a glovebox.
determined from the equilibrium constant for PPTH+
MPTP•+ ⇌ PPT•+ + MPTPH+; Keq = 0.32 implies ΔΔG° =
0.7 0.1 kcal/mol. (This is also consistent with the value
determined from combining the ET and PT equilibria,
+
providing ΔΔG° = 1.0
0.3 kcal/mol.) The difference in
the activation energies for reaction ΔΔG⧧ follow the reverse
t
trend, − 2.5 1.4 kcal/mol for reaction with Bu3PhOH and
−1.4 1.4 kcal/mol for reaction with Bu2(OMe)PhOH. For
Room-temperature electron paramagnetic resonance (EPR) meas-
urements were taken using 140 μL of solution in a 4 mm o.d. quartz
tube. Samples were prepared and filled into quartz tubes in the
glovebox and capped with a rubber septum and parafilm, and the EPR
spectrum was measured immediately after. Complete analysis of the
EPR spectra is given in the Supporting Information.
t
most CPET reactions with reagents of similar structure, the
driving force and activation energy are correlated for similar
reactions, with a lower activation energy for a more exergonic
reaction such as in a Marcus relationship.37 Hence, although
both PPT•+ and MPTP•+ have a pyridine appended to a
phenothiazinium radical cation, the order of activation energies
is reversed.
Synthesis. 2,4,6-Tri-tert-butylphenol-O-d was synthesized by the
procedure of Stack and co-workers.39 1,3-Di-tert-butyl-2,5-dimethox-
ybenzene was synthesized by deprotonating the phenol with NaH in
DMF and alkylating with methyl iodide.40 Tri-(p-tolyl)aminium
hexafluorophosphate and tri-(p-bromophenyl)aminium hexafluoro-
phosphate were synthesized using the neutral amine and AgPF6 and
The contrast between the geometry changes for the two
systems explains the mismatch between the driving force of
reaction and kinetics. As in other 10-aryl-10H-phenothiazine
radical cations,27 the calculations suggest that the pyridine ring
of PPT•+ is orthogonal to the phenothiazine ring. This
conformation allows for maximum overlap in the phenothiazine
π system including the N p-type orbital.27 The molecule
resembles 10-phenylanthracene, which has a similar orthogonal
conformation and a large barrier (>20 kcal/mol) to rotation
with a distorted TS.28 The nitrogen pyramidalizes upon
accepting the e− as in neutral, closed-shell phenothiazines.29
This is reflected in the TS with a partially pyramidalized N. The
41
I2 or with NOPF6.42 10-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxa-
borolan-2-yl)-10H-phenothiazine was synthesized by the procedure of
Muller and co-workers.14
̈
Synthesis of 10-(Pyridin-2-yl)-10H-phenothiazine.43−46 To 25 mL
of dry toluene was added phenothiazine (1.794 g, 9.00 mmol), sodium
tert-butoxide (1.394 g), DPPF (1,1′-bis(diphenylphosphino)ferrocene,
32.2 mg), 2-bromopyridine (0.996 mL, 1.643 g, 10.4 mmol), and
Pd2(dba)3 (40.2 mg; dba = dibenzylideneacetone), in that order. The
reaction was refluxed overnight. Additional Pd2(dba)3 (38 mg) and
DPPF (30 mg) were added after 24 h, and the mixture was refluxed
overnight. The reaction was filtered through silica, which was washed
with ethyl acetate, and the solvent was removed under reduced
pressure. The compound was subjected to column chromatography
(20/1 to 12/1 v/v hexanes/ethyl acetate gradient) to afford a solid
(1.829 g, 73.5%). 1H NMR (300 MHz, CDCl3, Figure S1): δ 8.28 (dd,
J = 8.0, 2.0 Hz, 1H), 7.56 (d, J = 13.3 Hz, 2H), 7.52−7.44 (m, 1H),
7.38 (dd, J = 12.8, 2.0 Hz, 2H), 7.32−7.24 (m, 2H), 7.18−7.11 (m,
2H), 6.93 (d, J = 14.1 Hz, 1H), 6.87 (dd, J = 11.7, 8.5 Hz, 1H). Mp
109.6−110.4 °C.45 The compound was recrystallized twice to a
colorless solid from 1/1 v/v hexanes/ethyl acetate before use in
kinetics and equilibration studies.
t
hydrogen bond between Bu3PhOH and PPT•+ must be
maintained for the H+ to be transferred, and hence placing the
pyridine in the pseudoaxial position would produce severe
steric interactions for the phenothiazine ring and the tert-butyl
groups. The pyridine is thus forced into the crowded
pseudoequatorial position in the TS. In contrast, the geometry
of MPTP•+ closely resembles that of MPTPH+ with fewer
constraints at the TS. That the MPTP•+ reactions are
inherently faster than the PPT•+ reactions despite a lower
driving force suggests that the inner sphere reorganization
reflected in the conformational changes are the best explanation
for the differences in these compounds, paralleling similar
effects in electron transfer reactivity.38 (However, the
calculations reflect a diabatic surface, while the CPET reaction
is likely to be nonadiabatic.)
Synthesis of 10-Methyl-3-(pyridin-2-yl)-10H-phenothiazine.15
A
combination of 10-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)-10H-phenothiazine (5.6 g, 1.64 mmol), Pd2(dba)3 (0.0329 g,
0.0573 mmol), and DPPF (0.0295 g, 0.0532 mmol) was added to a 2.0
M aqueous solution of Na2CO3 (2.454 mL) and 2-propanol (12 mL),
which was degassed by bubbling with nitrogen. This reaction was
stirred and refluxed under nitrogen for 56 h at 70 °C, when the
reaction was deemed complete by TLC. Water was added to this
reaction mixture, and the organic layer was extracted with three
portions of Et2O. These organic layers were collected, combined, and
dried over MgSO4. Column chromatography was used to purify the
Recently, distances between electron donating and accepting
sites have been related to kinetics, with an increased distance
slowing the reaction.10 In the CPET reactions presented here,
the distances between electron donating and accepting sites and
E
DOI: 10.1021/acs.joc.5b01427
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
compound (hexanes/ethyl acetate, 20:1 to 8:1), which results in
isolated compound as a solid (0.376 g, 1.26 mmol, 46%). H NMR
determined by mass balance. The slope of a plot of [PPT•+][MPTP]/
[MPTP•+] vs [PPT] provided the equilibrium constant (Figure S17).
Proton Transfer Equilibrium. The equilibrium constant for PPT +
MPTPH+ ⇌ PPTH+ + MPTP was determined by adding 50 μL
aliquots of a 25.4 mM solution of PPT to 3.0 mL of an 83.3 μM
solution of MPTPH+. The absorbance at 415 nm, corresponding to an
absorption of the MPTPH+ (ε = 9.6 × 103 M−1 cm−1), was used to
determine [MPTPH+] at equilibrium after correcting for volume
(Figure S18). The other concentrations were determined by mass
balance. The slope of a plot of [PPTH+][MPTP]/[PPTH+] vs [PPT]
provided the equilibrium constant (Figure S19).
Proton−Electron Transfer Equilibrium. The equilibrium constant
for PPTH+ + MPTP•+ ⇌ PPT•+ + MPTPH+ was determined by
adding 50 μL aliquots of a 3.58 mM solution of PPTH+ to 3.0 mL of
an 81.3 μM solution of MPTP•+. Absorbances at 422, 515, and 580
nm were used to determine the concentrations of MPTPH+, PPT•+,
1
(300 MHz, CDCl3, Figure S3) δ 6.66 (m, 1H), 7.87 (m), 7.74 (m),
7.67(m), 7.19 (m), 6.96 (m), 6.89 (m), 3.44 (s, 3H) ppm. 13C NMR
(400 MHz, CDCl3, Figure S4) δ 35.4, 114.09, 114.14, 119.6, 121.7,
122.7, 123.1, 123.8, 125.4, 126.0, 127.2, 127.5, 133.7, 136.7, 145.4,
146.5, 149.6, 156.3 ppm. Anal. Calcd for C18H14N2S: C, 74.45; H,
4.86; N, 9.65. Found: C, 74.06; H, 4.84; N, 9.56.
In Situ Generation of Radical Cation. The radical cation was
synthesized by combining a solution of tris(p-bromophenyl)aminium
hexafluorophosphate and a solution of excess PPT in acetonitrile.
Concentrations for kinetics were typically ∼0.2 mM in PPT and ∼0.1
mM for tris(p-bromophenyl)aminium hexafluorophosphate, although
concentrations up to 1 mM were stable. The reaction was assumed to
reach completion. Higher concentrations of PPT did not affect the
kinetics. Solutions for EPR were made similarly in CH2Cl2.
•+
and MPTP•+ (by solving abs422
=
ε422,PPT [PPT
]
+
• +
Cyclic Voltammetry. Cyclic voltammetry was performed in 0.1 M
Bu4NPF6 in acetonitrile with a glassy carbon working electrode, Ag/
AgNO3 (0.01 M) reference electrode, and platinum wire auxiliary
electrode. Ferrocene was added as an internal standard. Cyclic
voltammograms are provided in the SI (Figures S6−S8).
•+
+
•+
•+
+
•+
ε422,PTP [MPTP ] + ε422,PTPH [MPTPH ]; abs515 = ε515,PPT [PPT ]
+ ε515,PTP [MPTP•+] + ε515,PTPH [MPTPH ]; and abs580
=
+
•+
+
•+
•+
+
•+
•+
+
ε580,PPT [PPT ] + ε580,PTP [MPTP ] + ε580,PTPH [MPTPH ]; Figure
S20). [PPT] was determined by mass balance. The slope of a plot of
[PPT•+][MPTPH+]/[MPTP•+] vs [PPTH+] provided the equili-
brium constant (Figure S21).
t
t
Thermodynamic Parameters for Bu3PhOH and Bu2(OMe)-
PhOH and Calculation of ΔGET and ΔGPT. Thermodynamic
parameters for tBu3PhOH are known: E[tBu3PhOH•+/0] = 1.18 V and
pKa[tBu3PhO{H/−}] = 28.8b,31 E[tBu2(OMe)PhOH•+/0] can be
estimated to be 1.01 V from a experimentally determined CV on
The equilibrium constant for MPTP•+ + tBu3PhOH ⇌ MPTPH+ +
tBu3PhO• was determined by adding 50 μL aliquots of a 1.75 mM
solution of Bu3PhOH to 3.0 mL of a 71.8 μM solution of MPTP•+
t
t
neutral Bu2(OMe)PhOMe referencing to Cp2Fe+/0 (Figure S8). The
under N2. The absorbances at 422 and 580 nm were used to determine
the concentrations of MPTPH+ and MPTP•+ (by solving abs422
=
=
pKa for 2,6-di-tert-butyl-4-methoxyphenol was estimated by the
method of Kutt el al.47 using a value of 18.2 in DMSO:8b,48 0.980 ×
•+
+
• +
+
̈
ε422,PTP [MPTP
]
+
ε422,PTPH [MPTPH ] and abs580
•+
+
18.2 + 12.31 = 30.1. The free energy difference for ET is determined
by, for example, ΔGET = −nF(E[PPT•+/0] − E[tBu3PhOH•+/0]). The
free energy difference for PT is determined by a thermodynamic cycle
as follows:
•+
+
ε580,PTP [MPTP ] + ε580,PTPH [MPTPH ]; Figure S22). Concen-
trations of tBu3PhOH and tBu3PhO were determined by mass balance.
The slope of a plot of [MPTPH+][tBu3PhO•]/[ MPTP•+] vs
[tBu3PhOH] provided the equilibrium constant (Figure S23).
Acid−Base Equilibrium for pKa Determination. The equilibrium
constant for PPT and thymol blue (pKa[TH2 ⇌ TH− + H+, MeCN] =
13.422) was determined by adding 50 μL aliquots of a 12.1 mM
solution of PPT to 3.0 mL of a 0.89 mM solution of thymol blue
solution. The absorbance at 395 nm (λ = 1.65 × 104 M−1 cm −1),
corresponding to an absorption of the deprotonated thymol blue
(TH−),22 was used to determine [TH−] after correcting for volume,
and the other concentrations were determined by mass balance
(Figure S12). The slope of a plot of [PPTH+][TH−]/[TH2] vs [PPT]
provided the equilibrium constant (Figure S13).
Similarly, the equilibrium constant for MPTP and pyridinium was
determined by adding 50 μL aliquots of 29.2 mM pyridinium
hexafluorophosphate (pKa = 12.6)49 to 3.00 mL of 98.7 μM MPTP.
The absorbance at 415 nm (ε = 9.6 × 103 M−1 cm−1) was used to
determine MPTPH+, and the other concentrations were determined
by mass balance (Figure S14). The slope of a plot of [MPTH+][pyr]/
[pyrH+] vs [MPTP] provided the equilibrium constant (Figure S15).
Kinetics Studies. Solutions of radical cation were generated as
above in concentrations of 0.1−0.2 mM in acetonitrile in a glovebox,
and hydrogen atom donors (2,4,6-tri-tert-butylphenol or 2,6-di-tert-
butyl-4-methoxyphenol) were prepared at 5−100× these concen-
trations. Solutions were combined in a stopped flow spectropho-
tometer, and the absorbance over a 200 nm range centered at 515 nm
was observed. The decay of the spectra was fit globally to a first-order
decay using Spec-Fit. The slope of kobs vs concentration of hydrogen
atom donor provided the second-order rate constants. Sample plots of
data are given in Figures S24−S26.
Eyring Analysis. Kinetics were performed at five temperatures
between 13.4 and 62.6 °C as above. The activation parameters (ΔH⧧
and ΔS⧧) were determined from a plot of ln(k/T) vs 1/T (Figure
S27).
Computational Procedures. All calculations were performed
using the keyword int=ultrafine in Gaussian09. This produces a pruned
grid of 99 radial shells with 590 points per shell for numerical
integration. Frequency evaluations also included the keyword
int=(Acc2e=11) to force tighter convergence (10−11) of the two-
electron integrals as part of solving the CPHF equations.
Values of ΔG⧧ were determined using the rate constants and
the Eyring equation (ΔG⧧ = −RT ln[(kh)/(kBT)]) and are
reported at 298 K.
Equilibration Studies. Graphs and UV−vis spectra are provided
in the Supporting Information for these experiments. Reaction
t
between PPT•+ and Bu3PhOH was too slow to provide an accurate
equilibrium constant. Errors are estimated at 10% for these
experiments. Linear fits were to y = mx + b, but the y-intercepts
were negligible in all cases.
Electron Transfer Equilibrium. The equilibrium constant for tris(4-
tolyl)aminium and PPT was determined by adding 50 μL aliquots of a
12.1 mM solution of PPT to 3.0 mL of a 0.079 mM solution of tris(4-
tolyl)aminium hexafluorophosphate solution. The absorbance at 668
nm, corresponding to an absorption of the aminium, was used to
determine [NArMe •+] (at equilibrium) after correcting for volume
3
(Figure S10). The other concentrations were determined by mass
balance. The slope of a plot of [PPT•+][NArMe3]/[NArMe •+] vs
3
[PPT] provided the equilibrium constant (Figure S11).
The equilibrium constant for PPT + MPTP•+ ⇌ PPT•+ + MPTP
was determined by adding 50 μL aliquots of a 20.7 mM solution of
PPT to 3.0 mL of a 83.7 μM solution of MPTP•+. The absorbances at
515 and 580 nm, corresponding to λmax of PPT•+ and MPTP•+, were
used to determine their concentrations (by solving abs515
=
•+
•+
•+
•+
•+
•+
ε515,PPT [PPT ] + ε515,MPTP [MPTP ] and abs580 = ε580,PPT [PPT ]
•+
•+
+ ε580,MPTP [MPTP ]; Figure S16). The other concentrations were
F
DOI: 10.1021/acs.joc.5b01427
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
The BSSE at the transition state was calculated as the average of two
counterpoise calculations using two fragments each. In the first
calculation, the transferring hydrogen atom was assigned to tBu3PhOH
(the two fragments were tBu3PhOH and the radical cation form of the
acceptor), and in the second the transferring hydrogen was assigned to
(8) (a) Foti, M. C.; Daquino, D.; Mackie, I. D.; DiLabio, G. A.;
Ingold, K. U. J. Org. Chem. 2008, 73, 9270−9282. (b) Warren, J. J.;
Tronic, T. A.; Mayer, J. M. Chem. Rev. 2010, 110, 6961−7001.
(9) Hammes-Schiffer, S. Energy Environ. Sci. 2012, 5, 7696−7703.
(10) (a) Manner, V. W.; Mayer, J. M. J. Am. Chem. Soc. 2009, 131,
9874−9875. (b) Kuss-Petermann, M.; Wolf, H.; Stalke, D.; Wenger,
O. S. J. Am. Chem. Soc. 2012, 134, 12844−12854. (c) Markle, T. F.;
Tronic, T. A.; DiPasquale, A. G.; Kaminsky, W.; Mayer, J. M. J. Phys.
Chem. A 2012, 116, 12249−59. (d) Chen, J.; Kuss-Petermann, M.;
Wenger, O. S. Chem. - Eur. J. 2014, 20, 4098−104. (e) Chen, J.; Kuss-
Petermann, M.; Wenger, O. S. J. Phys. Chem. B 2015, 119, 2263−73.
(11) Markle, T. F.; Rhile, I. J.; Mayer, J. M. J. Am. Chem. Soc. 2011,
133, 17341−17352. (b) Warren, J. J.; Menzeleev, A. R.; Kretchmer, J.
S.; Miller, T. F.; Gray, H. B.; Mayer, J. M. J. Phys. Chem. Lett. 2013, 4,
519−523.
t
the hydrogen acceptor (the two fragments were Bu3PhO• and the
cationic form of the acceptor).
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01427.
Experimental and computational details (PDF)
(12) Jovanovic, M. V.; Biehl, E. R. J. Heterocycl. Chem. 1983, 20,
1677−1680.
AUTHOR INFORMATION
■
(13) (a) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118,
Corresponding Authors
7217−7218. (b) Franz, A. W.; Popa, L. N.; Rominger, F.; Muller, T. J.
̈
*E-mail: JeffreyWolbach@eurofinsUS.com.
*E-mail: irhile@albright.edu.
Notes
J. Org. Biomol. Chem. 2009, 7, 469−475.
(14) Kramer, C. S.; Zimmermann, T. J.; Sailer, M.; Muller, T. J. J.
̈
̈
Synthesis 2002, 2002, 1163−1170.
(15) Robichaud, J.; Oballa, R.; Prasit, P.; Falgueyret, J.-P.; Percival,
M. D.; Wesolowski, G.; Rodan, S. B.; Kimmel, D.; Johnson, C.; Bryant,
C.; Venkatraman, S.; Setti, E.; Mendonca, R.; Palmer, J. T. J. Med.
Chem. 2003, 46, 3709−3727.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
I.J.R. gratefully acknowledges support from the American
Chemical Society-Petroleum Research Fund (49447-UR4) and
James M. Mayer (via NIH Award GM050422) for supplies and
services for a sabbatical during which a portion of this research
was performed. J.P.W. gratefully acknowledges XSEDE Grant
TG-CHE120047 for computing resources used in part for this
research. J.P.W. and I.J.R. gratefully acknowledge support from
the Albright Creative Research Experiences program and
Albright College. S.S. gratefully acknowledges support from
the University of Washington.
(16) (a) Kulkarni, A. P.; Wu, P.-T.; Kwon, T. W.; Jenekhe, S. A. J.
Phys. Chem. B 2005, 109, 19584−94. (b) Franz, A. W.; Popa, L. N.;
Rominger, F.; Muller, T. J. J. Org. Biomol. Chem. 2009, 7, 469−75.
̈
(17) (a) Connelly, N. G.; Geiger, W. E. Chem. Rev. 1996, 96, 877.
(b) Rhile, I. J.; Markle, T. F.; Nagao, H.; DiPasquale, A. G.; Lam, O.
P.; Lockwood, M. A.; Rotter, K.; Mayer, J. M. J. Am. Chem. Soc. 2006,
128, 6075−6088. (c) Bandlish, B. K.; Shine, H. J. Org. Chem. 1977, 42,
561−563.
(18) Rosokha, S. V.; Kochi, J. K. J. Am. Chem. Soc. 2007, 129, 3683−
3697.
(19) Evans, J. F.; Lenhard, J. R.; Blount, H. N. J. Org. Chem. 1977, 42,
983−988.
REFERENCES
(20) Waidmann, C. R.; Miller, A. J. M.; Ng, C.-W. A.; Scheuermann,
M. L.; Porter, T. R.; Tronic, T. A.; Mayer, J. M. Energy Environ. Sci.
2012, 5, 7771−7780.
■
(1) (a) Hammes-Schiffer, S. J. Am. Chem. Soc. 2015, 137, 8860−71.
(b) Warren, J. J.; Mayer, J. M. Biochemistry 2015, 54, 1863−78.
(c) Solis, B. H.; Hammes-Schiffer, S. Inorg. Chem. 2014, 53, 6427−43.
(d) Migliore, A.; Polizzi, N. F.; Therien, M. J.; Beratan, D. N. Chem.
Rev. 2014, 114, 3381−465. (e) Weinberg, D. R.; Gagliardi, C. J.; Hull,
J. F.; Murphy, C. F.; Kent, C. A.; Westlake, B. C.; Paul, A.; Ess, D. H.;
McCafferty, D. G.; Meyer, T. J. Chem. Rev. 2012, 112, 4016−93.
(f) Saveant, J.-M. Annu. Rev. Anal. Chem. 2014, 7, 537−60. (g) Reece,
S. Y.; Nocera, D. G. Annu. Rev. Biochem. 2009, 78, 673−99.
(2) (a) Mayer, J. M.; Hrovat, D. R.; Thomas, J. L.; Borden, W. T. J.
Am. Chem. Soc. 2002, 124, 11142−7. (b) DiLabio, G. A.; Johnson, E.
R. J. Am. Chem. Soc. 2007, 129, 6199−6203.
(21) Manner, V. M.; Markle, T. F.; Freudenthal, J. H.; Roth, J. P.;
Mayer, J. M. Chem. Commun. 2008, 256−258.
(22) Kolthoff, I. M.; Chantooni, M. K.; Bhowmik, S. Anal. Chem.
1967, 39, 315−320.
(23) (a) Sackett, P. H.; Mayausky, J. S.; Smith, T.; Kalus, S.;
McCreery, R. L. J. Med. Chem. 1981, 24, 1342−7. (b) Mayausky, J. S.;
́
McCreery, R. L. Anal. Chem. 1983, 55, 308−312. (c) Zimova, N.;
̆
Nemec, I.; Waisser, K. Collect. Czech. Chem. Commun. 1990, 55, 63−
71. (d) Jovanovic, M. V.; Biehl, E. R.; De Meester, P.; Chu, S. S. C. J.
Heterocyclic Chem. 1984, 21, 1425−1429.
(24) Frisch, M. J. et al. Gaussian 09, Revision A.1; Gaussian, Inc.:
Wallingford CT, 2009. See Supporting Information for complete
reference.
(3) DiLabio, G. A.; Ingold, K. U. J. J. Am. Chem. Soc. 2005, 127,
6693−6699.
(4) (a) Silverman, R. B.; Zelechonok, Y. J. Org. Chem. 1992, 57,
6373−4. (b) Sawyer, D. T.; Calderwood, T. S.; Johlman, C. L.;
Wilkins, C. L. J. Org. Chem. 1985, 50, 1409−1412. (c) Knappe, W. R.
Z. Naturforsch., B: Anorg. Chem., Org. Chem. 1977, 32, 434−437.
(d) Huvaere, K.; Cardoso, D. R.; Homem-de-Mello, P.; Westermann,
S.; Skibsted, L. H. J. Phys. Chem. B 2010, 114, 5583−5593.
(e) Williams, R. F.; Bruice, T. C. J. Am. Chem. Soc. 1976, 98, 7752−
7768.
(25) Wilson, P. J.; Bradley, T. J.; Tozer, D. J. J. Chem. Phys. 2001,
115, 9233−9242.
(26) (a) Francl, M. M.; Pietro, W. J.; Hehre, W. J.; Binkley, J. S.;
DeFrees, D. J.; Pople, J. A.; Gordon, M. S. J. Chem. Phys. 1982, 77,
3654−3665. (b) Clark, T.; Chandrasekhar, J.; Spitznagel, G. W.;
Schleyer, P. v. R. J. Comput. Chem. 1983, 4, 294−301.
(27) (a) Clarke, D.; Gilbert, B. C.; Hanson, P. J. Chem. Soc., Perkin
Trans. 2 1975, 1078−1082. (b) Clarke, D.; Gilbert, B. C.; Hanson, P. J.
Chem. Soc., Perkin Trans. 2 1976, 114−214.
(5) (a) Gagliardi, C. J.; Binstead, R. A.; Thorp, H. H.; Meyer, T. J. J.
Am. Chem. Soc. 2011, 133, 19594−19597. (b) Zhang, M.;
(28) Nikitin, K.; Muller-Bunz, H.; Ortin, Y.; Muldoon, J.;
̈
Hammarstrom, L. J. Am. Chem. Soc. 2011, 133, 8806−8809.
̈
McGlinchey, M. J. Org. Lett. 2011, 13, 256−259.
(6) Murakami, H.; Esaka, Y.; Nakayama, T.; Uno, B. Chem. Lett.
2011, 40, 268−269.
(29) (a) Fronza, G.; Mondelli, R.; Scapini, G.; Ronsisvalle, G.;
Vittorio, F. J. Magn. Reson. 1976, 23, 437−454. (b) Klein, C. L.;
Conrad, J. M., III; Morris, S. A. Acta Crystallogr., Sect. C: Cryst. Struct.
Commun. 1985, C41, 1202−4.
(7) (a) Biczok
119, 12601−12609. (b) Biczok
99, 1843−1845.
́
, L.; Gupta, N.; Linschitz, H. J. Am. Chem. Soc. 1997,
́
, L.; Linschitz, H. J. Phys. Chem. 1995,
G
DOI: 10.1021/acs.joc.5b01427
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(30) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B
2009, 113, 6378−6396.
(31) (a) Osako, T.; Ohkubo, K.; Taki, M.; Tachi, Y.; Fukuzumi, S.;
Itoh, S. J. Am. Chem. Soc. 2003, 125, 11027−1033. (b) Bordwell, F. G.;
Cheng, J.-P. J. Am. Chem. Soc. 1991, 113, 1736−1743.
(32) Caroll, F. A. Perspectives on Structure and Mechanism in Organic
Chemistry, 1st ed.; Brooks-Cole: Pacific Grove, 1998; p 357.
(33) Roth, J. P.; Lovell, S.; Mayer, J. M. J. Am. Chem. Soc. 2000, 122,
5486−98.
(34) Huynh, H. V.; Meyer, T. J. Proc. Natl. Acad. Sci. U. S. A. 2004,
101, 13138−41.
(35) Other examples are cited in Decornez, H.; Hammes-Schiffer, S.
J. Phys. Chem. A 2000, 104, 9370−9384.
(36) Edwards, S. J.; Soudackov, A. V.; Hammes-Schiffer, S. J. Phys.
Chem. A 2009, 113, 2117−26.
(37) Warren, J. J.; Mayer, J. M. Proc. Natl. Acad. Sci. U. S. A. 2010,
107, 5282−5287.
(38) (a) Marcus, R. A.; Sutin, N. Biochim. Biophys. Acta, Rev. Bioenerg.
1985, 811, 265−322. (b) Nelsen, S. F.; Blackstock, S. C.; Kim, Y. J. J.
Am. Chem. Soc. 1987, 109, 677−682. (c) Chen, P.; Curry, M.; Meyer,
T. J. Inorg. Chem. 1989, 28, 2271−80.
(39) Goldsmith, C. R.; Jonas, R. T.; Stack, T. D. P. J. Am. Chem. Soc.
2002, 124, 83−96.
(40) Zaytsev, A. V.; Anderson, R. J.; Bedernjak, A.; Groundwater, P.
W.; Huang, Y.; Perry, J. D.; Orenga, S.; Roger-Dalbert, C.; James, A.
Org. Biomol. Chem. 2008, 6, 682−692.
(41) Bell, F. A.; Ledwith, A.; Sherrington, D. C. J. Chem. Soc. C 1969,
2719−2720.
(42) (a) Bandlish, B. K.; Shine, H. J. Org. Chem. 1977, 42, 561.
(b) Eberson, L.; Larsson, B. Acta Chem. Scand. 1986, 40, 210.
(c) Eberson, L.; Larsson, B. Acta Chem. Scand. 1987, 41, 367.
(43) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1996, 118, 7217−
7218.
(44) Franz, A. W.; Popa, L. N.; Rominger, F.; Muller, T. J. J. Org.
̈
Biomol. Chem. 2009, 7, 469−475.
(45) Jovanovic, M. V.; Biehl, E. R. J. Heterocycl. Chem. 1983, 20,
1667−80.
(46) Gilman, H.; Ranck, R. O. J. Org. Chem. 1958, 23, 1903−1906.
(47) Kutt, A.; Leito, I.; Kaljurand, I.; Soovali, L.; Vlasov, V. M.;
̈
̈
Yagupolskii, L. M.; Koppel, I. A. J. Org. Chem. 2006, 71, 2829−38.
(48) Bordwell, F. G.; Zhang, X.-M. J. Phys. Org. Chem. 1995, 8, 529.
(49) Augustin-Nowacka, D.; Chmurzynski, L. Anal. Chim. Acta 1999,
̃
381, 215−220.
H
DOI: 10.1021/acs.joc.5b01427
J. Org. Chem. XXXX, XXX, XXX−XXX