Activation of Electron-Deficient Quinones through Hydrogen-Bond-Donor-Coupled Electron Transfer

Article abstract of DOI:10.1002/anie.201508060

Quinones are important organic oxidants in a variety of synthetic and biological contexts, and they are susceptible to activation towards electron transfer through hydrogen bonding. Whereas this effect of hydrogen bond donors (HBDs) has been observed for Lewis basic, weakly oxidizing quinones, comparable activation is not readily achieved when more reactive and synthetically useful electron-deficient quinones are used. We have successfully employed HBD-coupled electron transfer as a strategy to activate electron-deficient quinones. A systematic investigation of HBDs has led to the discovery that certain dicationic HBDs have an exceptionally large effect on the rate and thermodynamics of electron transfer. We further demonstrate that these HBDs can be used as catalysts in a quinone-mediated model synthetic transformation.

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International Edition: DOI: 10.1002/anie.201508060
German Edition: DOI: 10.1002/ange.201508060
Hydrogen Bonding
Hot Paper
Activation of Electron-Deficient Quinones through Hydrogen-Bond-
Donor-Coupled Electron Transfer
Amanda K. Turek, David J. Hardee, Andrew M. Ullman, Daniel G. Nocera,* and
Eric N. Jacobsen*
Abstract: Quinones are important organic oxidants in a variety
of synthetic and biological contexts, and they are susceptible to
activation towards electron transfer through hydrogen bond-
ing. Whereas this effect of hydrogen bond donors (HBDs) has
been observed for Lewis basic, weakly oxidizing quinones,
comparable activation is not readily achieved when more
reactive and synthetically useful electron-deficient quinones
are used. We have successfully employed HBD-coupled
electron transfer as a strategy to activate electron-deficient
quinones. A systematic investigation of HBDs has led to the
discovery that certain dicationic HBDs have an exceptionally
large effect on the rate and thermodynamics of electron
transfer. We further demonstrate that these HBDs can be
used as catalysts in a quinone-mediated model synthetic
transformation.
Whereas these important studies revealed that HBDs can
indeed couple with ET to enhance the reactivity of quinone
oxidants, this effect was only observed with weakly oxidizing
quinones that are good Lewis bases. In contrast, the HBDs
used in these studies had little discernible effect on the ET to
quinones
bearing
electron-withdrawing
substituents
(Figure 1), which increase their oxidizing ability but diminish
their Lewis basicity and binding ability.
H
ydrogen bonding influences the rates and product distri-
butions of many organic reactions of interest through direct
stabilization of transition structures and reactive intermedi-
ates.[1,2] In a largely different context, H-bonding is also
known to have a significant effect on the thermodynamics and
kinetics of electron transfer,[3–13] especially in biological
systems. Quinones are especially important cofactors that
play critical roles in electron transfer (ET) pathways, includ-
ing those of photosystem II.[14,15] In this system, a quinone
serves as the terminal electron acceptor in a chain of ET
events. Hydrogen bonds formed within the quinone binding
site play a critical role in stabilizing the semiquinone radical
anion after ET,[16] governing a conformational shift[17] that is
proposed to constitute the rate-determining step for the first
ET to the quinone.[18]
Figure 1. Effect of quinone structure on oxidizing ability and Lewis
basicity.
From a thermodynamic standpoint, HBD-coupled ET
using quinone oxidants [Eq. (1)] can be parsed into two
elementary steps: ET between the quinone (Q) and an
electron donor [D, Eq. (2)], and binding of the reduced
quinone to an HBD [Eq. (3)]. Althoughthe actual trans-
formation does not necessarily proceed by this mechanism
(e.g., binding of the HBD to Q may precede ET), dissection of
the overall process in this manner is instructive in defining the
challenge that is presented to achieving favorable ET
reactions (DGnet < 0) using HBDs.
With the knowledge that the behavior of quinones is
strongly influenced by H-bonding interactions, we became
interested in employing small-molecule hydrogen-bond
donors (HBDs) to activate quinone oxidants in a synthetically
interesting context. The effect of H-bonding on the redox
chemistry of quinones has been investigated in synthetic
model systems using a variety of HBDs, including simple
alcohols,[3,4] ammonium salts,[5] amino acids,[6] amides,[7,8] and
neutral dual HBDs such as ureas[9,10] and thioureas.[11]
CÀ
Cþ
HBD þ Q þ D Ð HBD Á Q þ D ðDGnet
Þ
ð1Þ
ð2Þ
ð3Þ
CÀ Cþ
Q þ D Ð Q þ D ðDGET
Þ
CÀ
CÀ
HBD þ Q Ð HBD Á Q ðDGassoc
DGnet ¼ DGET þ DGassoc
Þ
The activating effect of an HBD on the overall reaction
can be understood in terms of Eq. (3), which describes the
binding of the HBD to the reduced quinone (QCÀ). That
interaction must offset the thermodynamic penalty of the ET
(given a DGET > 0), which depends on the substrate D and the
intrinsic oxidizing ability of the quinone. The oxidation of
organic functional groups of interest (e.g., alkenes, aromatic
rings) by electron-rich quinones is so unfavorable that an
unattainably high binding energy (DGassoc) would be neces-
sary to enable the overall reaction with HBDs. ET in
[*] A. K. Turek, Dr. D. J. Hardee, A. M. Ullman, Prof. D. G. Nocera,
Prof. E. N. Jacobsen
Department of Chemistry and Chemical Biology, Harvard University
Cambridge, MA 02138 (USA)
E-mail: dnocera@fas.harvard.edu
jacobsen@chemistry.harvard.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201508060.
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synthetically interesting contexts with electron-deficient qui-
nones is less unfavorable.[19] However, as noted above, these
quinones and their reduced counterparts are inherently weak
H-bond acceptors. As such, the success of the proposed HBD-
coupled ET strategy relies on finding the appropriate balance
between HBD strength and quinone reactivity.
Herein, we report a systematic evaluation of several
small-molecule hydrogen-bond donors, with the goal of
activating electron-deficient quinones (Figure 2). ortho-
Scheme 1. a) Square scheme describing pathways for HBD-coupled ET
to quinones and their associated equilibrium constants. b) Extended
square scheme accounting for two binding events.
concentration of the HBD results in a more positive DE1/2,
effectively creating a more potent oxidant by favoring the
reduced state through binding. As illustrated by the square
scheme in Scheme 1a, K’
specifically describes this stabi-
QCÀ
lizing interaction. The equilibrium constants that govern this
shift in the potential can be elucidated electrochemically
through cyclic voltammetry and provide a quantitative mea-
sure of the stabilization provided by the HBD to QCÀ.
Our investigations were carried out with a range of HBDs,
including the representative dual HBDs 1–3, with the aim of
understanding how H-bonding interactions affect DGassoc
[Eq. (3)] when electron-deficient quinones are used. Electro-
chemical titrations of Q were performed with each HBD,
using cyclic voltammetry to record the DE1/2 value as a func-
tion of HBD concentration (Figure 3a–c). Each of the HBDs
studied has a significant, measurable effect on the apparent
potential that corresponds to the first ET.[22] Furthermore, the
reversibility of the CVs recorded in all titration experiments
indicate that the effect on E1/2 is the result of H-bonding to
QCÀ and not protonation, which would manifest as irrever-
sibility in the CV traces.
To elucidate the equilibrium constants that describe the
binding of QCÀ to 1–3, the full set of electrochemical data for
these titrations was subjected to simulations.[23] This analysis
revealed that the experimental data are best described by
a mechanism in which two HBD molecules are involved in the
stabilization of QCÀ. This mechanistic interpretation provides
a good fit to the experimental data with respect to the overall
DE1/2 values, and also reproduces the distinct features of the
cyclic voltammogram at low HBD concentrations (e.g.,
Figure 3a, scan (c) and corresponding simulation
(a)).[24]
Figure 2. HBDs and additives examined in this study.
Chloranil (Q) was selected as the oxidant as it is an
electron-deficient quinone that nonetheless lacks the intrinsic
reactivity necessary to oxidize many organic substrates of
synthetic interest. Our examination of the influence of H-
bonding on the single-electron transfer chemistry of ortho-
chloranil has led to the discovery that dicationic bis(amidi-
nium) salts can exert a remarkable influence on the thermo-
dynamics and kinetics of ET. By taking advantage of this
effect, we demonstrate that these HBDs can also catalyze
a model oxidative transformation that is mediated by ortho-
chloranil.
In aprotic media, quinones undergo two sequential single-
electron transfers, proceeding via the semiquinone radical
anion QCÀ.[20] Protic and H-bonding molecules influence the
mechanism by which ET proceeds. This study is concerned
primarily with the effect of HBDs on the first ET step. To
quantify the ability of an HBD to modulate the thermody-
namics of ET, the association of the HBD with QCÀ must be
quantified; in other terms, we need to determine how strongly
the HBD favors the reduced state over the oxidized, neutral
state.
An HBD-coupled ET to Q that involves two binding
events requires the use of an expanded square scheme to
outline all mechanistic possibilities (Scheme 1b), wherein
K
K
provides a quantitative description of the stabili-
1QCÀ 2QCÀ
The mechanistic methods used to quantify HBD-coupled
ET are borrowed from the study of proton-coupled ET.[21]
Eq. (4), which is related to the Nernst equation, describes
HBD-coupled ET (Scheme 1a). The apparent potential of
a quinone involved in HBD-coupled ET will undergo a shift
(DE1/2) that is dependent on the HBD concentration and the
association constants for the binding of the quinone and
zation provided to QCÀ through binding, and a measure of the
oxidizing strength of Q in the presence of a given HBD.
The electrochemical simulations allow us to distinguish
between the pathways for HBD-coupled ET outlined in
Figure 1d and to determine the binding constants associated
with each individual step. The simulations for 1–3 reveal that
these HBDs all promote a mechanism in which binding of the
neutral quinone (K1Q) precedes ET (E2), and a second binding
semiquinone (KQ and K , respectively) to the HBD.
QCÀ
event follows (K ).[25] A simulation of this mechanism
explicitly determines values for these equilibrium constants,
2QCÀ
1 þ KQ ½HBDŠ
CÀ
ð4Þ
DE1=2 ¼ 0:059V log
1 þ KQ½HBDŠ
from which K
can be calculated. Independent determi-
1QCÀ
nation of K1Q using spectroscopic methods resulted in values
that were consistent with those obtained from the simulations
(Supporting Information, Figures S1–S4).
This relationship between DE1/2 and the association
constants shows that as long as K’ > K’Q, increasing the
QCÀ
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of the HBD can influ-
ence its interaction with
QCÀ. The enhanced bind-
ing of 2 relative to 1 can
be ascribed to a differ-
ence in acidity.[26] Such
an effect implicates
hydrogen-bonding inter-
actions in the modula-
tion of DGassoc and
increased favorability of
ET to 2. On the other
hand, neutral 3 and cat-
ionic 1 have similar pKa
values,[27] yet K
for 3 is smaller by one
K
1QCÀ 2QCÀ
order of magnitude,
demonstrating
the
importance of electro-
static effects in HBD-
coupled ET. Combined
with the required 2:1
stoichiometry between
the HBD and QCÀ, this
result has important im-
plications for the HBD-
coupled ET strategy, as
the data from the titra-
tion with 2 clearly indi-
cate that the most sub-
stantial stabilization of
QCÀ is achieved in a com-
plex that involves two
cationic HBDs. We con-
Figure 3. Experimental CV data and comparison with simulation. CVs (0.1 VsÀ1) recorded for 0.5 mm Q in 0.1m
nBu4NBArF24/CH2Cl2 (glovebox) in the presence of increasing concentrations of a) 1, b) 2, c) 3, and d) 4.
The values for K
K
were thus determined for the
clude that both H-bonding and electrostatic effects play
a crucial role in HBD-coupled ET.
1QCÀ 2QCÀ
HBDs 1–3 (Table 1). All three HBDs afforded similar results
with respect to mechanism and stoichiometry (Figure 3b,c).
Diphenylguanidinium 2 offers the greatest degree of stabili-
zation to QCÀ, and urea 3 offers the weakest, with a difference
of three orders of magnitude between them. A comparison of
these values provides insight into the ways in which the nature
The observation that the HBDs 1–3 all bind QCÀ in 2:1
complexes, with the charge of the HBD playing a critical role,
prompted us to examine bis(amidinium) salt 4,[28] which
features a covalent linkage between two cationic subunits
(Figure 3d). Reversible waves are obtained for the cyclo-
voltammetry of Q in the presence of 4, indicating that the
4·QCÀ complex is stable under the experimental conditions and
does not experience full proton transfer. Simulations repro-
duce the overall DE1/2 value and the observed reversibility
over the course of the titration. A mechanism involving
a single binding step (K1Q) with subsequent ET (E2) was
found to best describe the experimental data.[29]
Table 1: Equilibrium constants for HBD-coupled ET determined by CV.[a]
As noted above, these simulations revealed that bis(ami-
dinium) salt 4 binds QCÀ as a 1:1 complex, in contrast with
HBDs 1–3, which form 2:1 complexes with QCÀ. Because of
this change in stoichiometry, the efficacy of the different
HBDs in promoting ET to Q was gauged by comparing the
HBD[a]
K
[mÀ1 [b]
]
K
K
[mÀ2
]
1QCÀ
1QCÀ 2QCÀ
1
2
3
4
5
(3.4”104)
(3.5”105)
(5.6”104)
9.2”1010
5.7”105
6.1”108
1.8”1010
1.0”107
–
value of K for 4 to that of K
K
for 1–3. This analysis
QCÀ
1QCÀ 2QCÀ
reveals that 4 is exceptionally effective at promoting ET and
six orders of magnitude more potent than 2 at binding QCÀ.
Tetramethylated bis(amidinium) salt 5, which bears the
same net charge as 4 but lacks the ability to form H-bonds, has
–
[a] Parameters were determined by titrating 0.5 mm Q in 0.1m
nBu4NBArF24/CH2Cl2 (glovebox) with [HBD] and simulating the exper-
imental CVs obtained. [b] Values for K in parentheses are thermody-
1QCÀ
namically redundant and were calculated from E1, E2, and K1Q
.
a substantially smaller K
value than 4. The large difference
1QCÀ
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in the potencies of 4 and 5 shows that the pronounced effect of
4 in promoting HBD-coupled ET is not purely electrostatic in
nature. Instead, both the dual charge and the H-bonding
capability underlie the ability of 4 to modulate the thermo-
dynamics of ET to Q. Furthermore, the CVs recorded with 5
are best simulated by a pathway in which ET (E1) precedes
ability of these HBDs to thoroughly influence the energetics
of ET.
To further probe the mechanism of HBD-coupled ET and
provide independent verification for the stoichiometries
ascertained electrochemically, the reaction order with respect
to each HBD was determined. The ET reaction obeys
a second-order kinetic dependence on both guanidinium
salts 1 and 2 (Figure 4a), which is consistent with the
contention that two cationic HBDs act cooperatively to
stabilize QCÀ. ET promoted by urea 3, in contrast, was found
to follow a first-order dependence on HBD (Figure 4b). This
result may still be consistent with the formation of a 2:1
complex between 3 and QCÀ, as a rate-determining ET step
may precede complexation by the second urea molecule. The
kinetic order in 4 was not accurately quantified owing to the
extremely high reactivity observed with this HBD. However,
a Job plot obtained with excess reductant clearly shows that
the reaction stoichiometry between 4 and Q is 1:1 (Figure S6),
thereby corroborating the electrochemical thermodynamic
studies.
association (K
; Figure S5). This change in mechanism
1QCÀ
establishes that H-bonding is necessary for pre-association
between Q and the HBD, and thereby dictates the pathway by
which HBD-coupled ET occurs.
Having established that dicationic HBDs can exert
a strong influence on the thermodynamics of ET to an
electron-deficient quinone through tight binding of QCÀ, we
investigated whether HBDs can similarly affect the kinetics of
ET. This was addressed by measuring the rate of ET between
Q and ferrocene (Fc) derivatives in the presence of HBDs to
generate HBD·QCÀ Fc+ salts stoichiometrically (Table 2). The
reactions were monitored by UV/Vis spectrophotometry
under homogeneous conditions. The rate constants were
obtained under pseudo-first-order conditions, varying the
concentration of excess HBD. As the HBDs were found to
span a broad range of reactivity, multiple reductants with
Examining the free energy differences associated with
these homogenous ETs offers a different perspective on the
effectiveness of 4 as a promoter of
HBD-coupled ET. ET between 1,1’-
dibromoferrocene and Q is highly
Table 2: Relative rate constants for HBD-coupled ET.[a]
unfavorable in the absence of an
HBD (DGET =+ 15.3 kcalmolÀ1).[30]
Yet 4 modulates the kinetics and
thermodynamics of this inherently
disfavored process such that it pro-
ceeds rapidly. In comparison, DDQ,
HBD
Krel [sÀ1
Fc
]
krel [sÀ1
BrFc
]
krel [sÀ1
Br2Fc
]
krel
K
À
K
K
1QC
1QCÀ 2QCÀ
[sÀ1
]
[mÀ1
]
[m 2]
a more powerful oxidant than Q
that finds widespread use in organic
synthesis, lacks the intrinsic reactiv-
ity to perform this ET reaction
independently (DGET =+ 4.4 kcal
molÀ1).[31] The ability of 4 to partic-
ipate in HBD-coupled ET was
examined further with additional
electron donors, and it was found
3
1
2
4
1
486
–
–
1
124
–
–
–
1
1
5.6”104
3.4”104
3.5”105
9.2”1010
1.0”107
6.1”108
1.8”1010
–
4.9”102
2.3”107
9.0”1011
–
104
[a] Pseudo-first-order rate constants were determined at 258C by monitoring the reaction between Q
(2.5 mm) and the indicated ferrocene (0.5 mm) in CH2Cl2 in the presence of the indicated HBD
(5.0 mm).
a range of reduction potentials were
required for this study. Two reduc-
tants were studied with each HBD,
and the relative rates were scaled
according to the intrinsic reactivity
differences of those reductants.
Bis(amidinium) salt 4 is found
to provide remarkable acceleration
of the rate of ET, with a relative
rate constant that is twelve orders
of magnitude larger than that for
urea 3 (Table 2). A comparison of
the relative rate constants with the
corresponding equilibrium con-
stants revealed a good correlation
between the thermodynamics and
Figure 4. Initial rate constants (kobs) vs. [HBD]2 or [HBD] for ET from ferrocene derivatives to Q in
CH2Cl2 at 258C under N2 atmosphere. a) Second-order plots for 1 (10–1.0 mm), Q (1.0 mm), and
bromoferrocene (BrFc; 1.0 mm); and 2 (10–1.0 mm), Q (1.0 mm), and 1,1’-dibromoferrocene (Br2Fc;
1.0 mm). b) First-order plot for 3 (5.0–0.5 mm), Q (0.5 mm), and 1,1’-dimethylferrocene (Me2Fc;
kinetics of ET, demonstrating the 0.5 mm).
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to facilitate oxidation of perylene in a yet more unfavorable
process (DGET =+ 19.8 kcalmolÀ1 [32]
Figure S7).
catalysts for promoting ET. The evidence that association of
;
the HBD occurs prior to ET demonstrates the potential of
this strategy for application in enantioselective processes,
wherein binding to the chiral catalyst prior to generation of
reactive intermediates would be expected to be crucial. We
anticipate that the findings outlined here will help guide the
discovery of new catalysts that are capable of promoting
highly efficient and selective ET reactions mediated by
quinone oxidants.
Having identified HBDs capable of promoting ET to
electron-deficient quinones, we sought to probe their possible
utility as catalysts for synthetic reactions involving ET. An
oxidative lactonization was selected as a model transforma-
tion that would illustrate the catalytic use of HBDs to
promote quinone-mediated ET (Scheme 2a). The HBDs 1–4
Acknowledgements
This work was supported by the NIH (GM043214 to E.N.J.)
and the DOE (DE-SC0009565 to D.G.N.), by an NSF pre-
doctoral fellowship to A.K.T., and by an NIH post-doctoral
fellowship to D.J.H. We thank Robert Knowles for many
helpful discussions.
Keywords: catalysis · electron transfer · hydrogen bonding ·
oxidation · quinones
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Angew. Chem. 2016, 128, 549–554
Scheme 2. a) Proposed oxidative lactonization mechanism and yields
obtained at 24 hours. b) Kinetic isotope effect experiment.
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time of 24 hours are found to correlate well with both the
thermodynamic and kinetic trends discussed previously.
Bis(amidinium) salt 4 is the most effective catalyst, affording
the product in 70% yield, whereas urea 3 provides no
acceleration over background. The bis(amidinium) salt 6,
which lacks the tert-butyl substituent of 4, is even more
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À
C H bond. This finding can be reconciled with rapid and
reversible single-electron transfer preceding a subsequent,
rate-limiting H-atom abstraction (Scheme 2b), although
a direct hydride abstraction mechanism cannot be ruled out
unambiguously.[34] Nonetheless, the strong correlation
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lactonization is consistent with a mechanism in which the
HBD affects a pre-equilibrium ET by binding Q and remains
associated with QCÀ throughout the H-atom transfer.
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as an effective strategy to activate electron-deficient qui-
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[24] Discrepancies in the current magnitude may be attributed to
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involved in the simulation, which have no bearing on DE1/2 (see
the Supporting Information for a discussion).
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formation of quinone dimers, which have been observed with
some ortho-quinones containing electron-withdrawing groups,
may also play a role in the appearance of this extra current; see:
b) N. A. Macías-Ruvalcaba, D. H. Evans, J. Phys. Chem. C 2010,
114, 1285 – 1292.
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[25] Efforts to simulate alternative mechanisms are described in the
Supporting Information.
[26] The pKa values in DMSO for N,N’-dialkylguanidinium ions and 2
are 14.1 and 10.1, respectively; see: C. H. Uyeda, Catalysis of the
Claisen Rearrangement by Hydrogen Bond Donors, Ph.D. Thesis,
Harvard University, Cambridge, MA 2010.
[31] N. G. Connelly, W. E. Geiger, Chem. Rev. 1996, 96, 877 – 910.
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Jacquemin, J. Org. Chem. 2014, 79, 2038 – 2048.
[33] A rigorous comparison of the abilities of 4 and 6 to promote ET
was not possible because of the very low solubility of 6 in
dichloromethane.
[27] The pKa value of 3 is 13.8 in DMSO; see: F. Jakab, C. Tancon, Z.
Zhang, K. M. Lippert, P. R. Schreiner, Org. Lett. 2012, 14, 1724 –
1727.
[34] X. Guo, H. Zipse, H. Mayr, J. Am. Chem. Soc. 2014, 136, 13863 –
13873.
[28] V. R. Annamalai, E. C. Linton, M. C. Kozlowski, Org. Lett. 2009,
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Received: August 27, 2015
[29] The current that appears at 0.1 V in scan (c) is not reproduced by
this mechanism. This extra current has been observed in cyclic
Revised: October 23, 2015
Published online: November 27, 2015
544
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