Mechanisms of hydride abstractions by quinones

Article abstract of DOI:10.1021/ja507598y

The kinetics of the hydride abstractions by 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) from 13 C-H hydride donors (acyclic 1,4-dienes, cyclohexa-1,4-dienes, dihydropyridines), tributylstannane, triphenylstannane, and five borane complexes (amine-boranes, carbene-boranes) have been studied photometrically in dichloromethane solution at 20 °C. Analysis of the resulting second-order rate constants by the correlation log k₂(20°C) = s_N(E + N) (J. Am. Chem. Soc. 2001, 123, 9500) showed that the hydride abstractions from the C-H donors on one side and the Sn-H and B-H hydride donors on the other follow separate correlations, indicating different mechanisms for the two reaction series. The interpretation that the C-H donors transfer hydrogen to the carbonyl oxygen of DDQ while Sn-H and B-H hydride donors transfer hydride to a cyano-substituted carbon of DDQ is supported by quantum-chemical intrinsic reaction coordinate calculations and isotope labeling experiments of the reactions of D₈-cyclohexa-1,4-diene, Bu₃SnD, and pyridine·BD₃ with 2,5-dichloro-p-benzoquinone. The second-order rate constants of the reactions of tributylstannane with different quinones correlate linearly with the electrophilicity parameters E of the quinones, which have previously been derived from the reactions of quinones with -nucleophiles. The fact that the reactions of Bu₃SnH with quinones and benzhydrylium ions are on the same log k₂ vs E (electrophilicity) correlation shows that both reaction series proceed by the same mechanism and illustrates the general significance of the reactivity parameters E, N, and s_N for predicting rates of polar organic reactions.

Full text of DOI:10.1021/ja507598y

Article
pubs.acs.org/JACS
Mechanisms of Hydride Abstractions by Quinones
Xingwei Guo, Hendrik Zipse, and Herbert Mayr*
̈
̈ ̈
Department Chemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstraße 5-13 (Haus F), 81377 Munchen, Germany
*
S Supporting Information
ABSTRACT: The kinetics of the hydride abstractions by 2,3-dichloro-5,6-
dicyano-p-benzoquinone (DDQ) from 13 C−H hydride donors (acyclic
1
,4-dienes, cyclohexa-1,4-dienes, dihydropyridines), tributylstannane, tri-
phenylstannane, and five borane complexes (amine−boranes, carbene−
boranes) have been studied photometrically in dichloromethane solution at
2
0 °C. Analysis of the resulting second-order rate constants by the
correlation log k (20 °C) = s (E + N) (J. Am. Chem. Soc. 2001, 123, 9500)
2
N
showed that the hydride abstractions from the C−H donors on one side and the Sn−H and B−H hydride donors on the other
follow separate correlations, indicating different mechanisms for the two reaction series. The interpretation that the C−H donors
transfer hydrogen to the carbonyl oxygen of DDQ while Sn−H and B−H hydride donors transfer hydride to a cyano-substituted
carbon of DDQ is supported by quantum-chemical intrinsic reaction coordinate calculations and isotope labeling experiments of
the reactions of D -cyclohexa-1,4-diene, Bu SnD, and pyridine·BD with 2,5-dichloro-p-benzoquinone. The second-order rate
8
3
3
constants of the reactions of tributylstannane with different quinones correlate linearly with the electrophilicity parameters E of
the quinones, which have previously been derived from the reactions of quinones with π-nucleophiles. The fact that the reactions
of Bu SnH with quinones and benzhydrylium ions are on the same log k vs E (electrophilicity) correlation shows that both
3
2
reaction series proceed by the same mechanism and illustrates the general significance of the reactivity parameters E, N, and sN
for predicting rates of polar organic reactions.
INTRODUCTION
Scheme 1. Possible Hydride Transfer Mechanisms of
Quinones
■
Quinones belong to the most important oxidizing reagents in
1
organic chemistry and play an important role as hydrogen
2
acceptors in biological processes. However, mechanistic details
of these processes are still discussed controversially. Detailed
studies by Linstead, Jackman, and co-workers came to the
3
4
conclusion that the oxidations of hydrocarbons by quinones
usually occur via rate-determining hydride transfer, leading to
delocalized carbocations, which rapidly lose a proton or are
trapped by a nucleophile in a subsequent step. While this view
3
h,i
was supported by Heesing et al., Ru
̈
chardt et al. proposed a
mechanism in which an initial hydrogen atom transfer leads to
the formation of radicals. This view was supported by spin
trapping of the intermediary radicals by nitrosobenzene.
3l
3m,n
Chan and Radom pointed out, however, that the detection of a
trapping product with nitrosobenzene cannot be considered as
3o
a proof for the operation of the radical mechanism. In a
detailed computational investigation, they demonstrated that
the course of the reaction depends on the solvent and that, in
the reaction of 2,3-dichloro-5,6-dicyano-p-benzoquinone
(
DDQ; 1a) with cyclohexa-1,4-diene, a radical mechanism
proceeds in the gas phase and in heptane solution, whereas an
ionic process with initial hydride transfer dominates in acetone
and acetonitrile.
3
o
Among quinones, DDQ (1a) is the most frequently used
6
hydride acceptor for oxidations of hydrocarbons and
As depicted in Scheme 1, several mechanistic pathways are
conceivable, e.g., (a) initial single electron transfer (SET),
followed by hydrogen atom transfer (HAT), (b) initial
hydrogen atom transfer, followed by an electron transfer, (c)
one-step hydride transfer via O attack, and (d) one-step
hydride transfer via C attack.
7
dehydrogenative cross-coupling reactions. We have previously
demonstrated that the reactions of DDQ (1a) and of the
Received: July 25, 2014
Published: September 8, 2014
©
2014 American Chemical Society
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Article
quinones 1b−f (Scheme 2) with π-nucleophiles and amines
5
most often proceed by polar pathways, the rates of which can
Scheme 2. Quinones Investigated in This Work and Their
Electrophilicity Parameters E (from Ref 5)
Figure 1. UV−vis spectroscopic monitoring of the reaction of DDQ
−3
−1
−2
−1
(
c = 1.0 × 10 mol L ) with 2j (c = 1.0 × 10 mol L ) at 390 nm
0 0
in CH Cl at 20 °C. Inset: determination of the second-order rate
2
2
−
1 −1
constant k = 6.6 L mol
s
from the dependence of the first-order
2
rate constant kobs on the concentration of 2j.
the correlations between the first-order rate constants kobs and
the concentrations of the hydride donors, which were linear
with negligible intercepts (Figure 1, inset).
8
be described by eq 1, which was developed to predict rates and
selectivities of polar reactions.
Correlation Analysis. In previous work we have
determined the electrophilicity parameter of DDQ (E =
log k(20 °C) = s (E + N)
In eq 1 the second-order rate constants (log k) are described
by two solvent-dependent, nucleophile-specific parameters (sN,
N) and one electrophile-specific parameter (E). Using a series
(1)
N
−
3.66 at C-5 or C-6) from the rates of its reactions with π-
5a
nucleophiles. By insertion of this electrophilicity parameter
and the previously reported N and sN parameters for the
hydride donors 2 (Table 1) into eq 1, one obtains the
calculated rate constants kcal for hydride transfer to C-5 of
DDQ, which are also given in Table 1. The last column of
Table 1 shows that all C−H hydride donors investigated (2a−
m) react 2−5 orders of magnitude faster than calculated, while
the tin hydrides 2n,o and the borane complexes 2p−t react 1−
of benzhydrylium ions and structurally related quinone
methides as reference electrophiles, comprehensive nucleophil-
9
icity scales have been established for different types of
1
0
nucleophiles, including a variety of hydride donors.
We now will report how eq 1 and the previously determined
electrophilicity parameters E of the quinones 1a−f (Scheme 2)
can be employed to elucidate the mechanisms of hydrogen
abstractions from structurally diverse hydride donors, as the
allylic and benzylic C−H hydride donors 2a−l, the tin hydrides
2
orders of magnitude slower than calculated. This situation is
illustrated in Figure 2 by the plot of (log k)/sN against the
nucleophilicity parameters N of hydride donors. One can see a
fair linear correlation line (r = 0.91) for the C−H hydride
2
2
n,o, and the boron hydrides 2p−t (Table 1).
donors which is 3−4 units higher than the calculated
correlation line and a second correlation for B−H or Sn−H
hydride donors which is slightly below the calculated
correlation line but still is within the confidence limits of eq
1. Two different mechanisms are thus indicated.
RESULTS AND DISCUSSION
Kinetic Studies. Most kinetic investigations of the reactions
■
of DDQ (1a) with the hydride donors 2 were performed in
CH Cl solution at 20 °C, and for some reactions of DDQ,
As the nucleophile-specific parameters N and s of eq 1 have
2
2
N
solvent effects were investigated. CH CN and CD CN were
employed as solvents for the kinetic investigations of the
been derived from the reactivities of various types of
nucleophiles toward C electrophiles (benzhydrylium ions and
quinone methides) and the electrophilicity parameters E have
been derived from reactions of various electrophiles with C
nucleophiles, eq 1 should only hold for reactions where a new
C−X bond (X = C, H, heteroatom) is formed in the rate-
determining step. Thus, eq 1 should be applicable to
mechanism d of Scheme 1 (polar hydride transfer to C) but
not to mechanism c (polar hydride transfer to O).
Subsequently, we will show that the reactions of the B−H
and Sn−H hydride donors actually follow mechanism d with
rate constants close to those predicted by eq 1, while C−H
3
3
reactions of Bu SnH (2n) with 1b−f. Most reactions were
3
monitored by UV−vis spectroscopy at or close to the
absorption maxima of the quinones (DDQ (1a), 286 or 390
nm; 2,5-dichloro-p-benzoquinone (1b), 275 nm; p-chloranil
(
1c), 290 nm; tetrafluoro-p-benzoquinone (1d), 256 nm; o-
chloranil (1e), 457 nm). When acetone was used as a solvent,
the formation of the hydroquinone DDQH was monitored at
50 nm, because the absorption of the solvent covered that of
2
3
the quinone. In all runs, at least 10 equiv of hydride donors was
used to achieve pseudo-first-order kinetics; the rate constants
were obtained by least-squares fitting of the monoexponential
−
hydride donors transfer H to the carbonyl oxygen much faster
obs
−k t
functions A = A e
+ C (for decrease) or A = A (1 −
than calculated by eq 1.
t
0
t
0
obs
−k t
e
1
) + C (for increase) to the observed absorbances (Figure
). H NMR spectroscopy was employed to study the slow
As tributylstannane (2n) reacted 300 times faster with DDQ
than triphenylstannane (2o), we excluded rate-determining
hydrogen atom transfer for these reactions (mechanism b,
Scheme 1), because Ingold reported that homolytic Sn−H
1
reaction of tributylstannane (2n) with p-benzoquinone (1f),
which was used in excess over 2n. The second-order rate
11
constants k given in Table 1 were derived from the slopes of
cleavage is faster in Ph SnH than in Bu SnH.
3 3
2
1
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Table 1. Experimental Rate Constants of the Reactions of DDQ (1a) with the Reducing Agents 2a−t in CH Cl at 20 °C and
2
2
Calculated Rate Constants for C Attack from Eq 1 by Using the Electrophilicity Parameter of E(1a) = −3.66 (from Ref 5a)
a
From ref 10. k = 2.91 × 10 M−1 s−1 has been reported in AcOH at 25 °C. k2 = 1.22 × 10−4 M−1 s−1 has been reported in AcOH at 25 °C.
b
−5
3c
c
3c
2
d
−1 −1
3c
e
−2
−1 −1
3c
−2
−1 −1
k2 = 0.20 M
s
has been reported in AcOH at 25 °C. k = 5.4 × 10
M
s
has been reported in AcOH at 25 °C; k2 = 1.3 × 10
M
s
2
has been reported in dioxane at 25 °C; k = 7.8 × 10 M−1
3i
−3
s
−1
(20 °C) in dioxane has been calculated from activation parameters given in ref 3n.
2
f
Determined in this work using our standard procedure (Supporting Information, pp S20−S24). As only two reference electrophiles of similar
g
−1 −1
reactivity were employed, the splitting up of log k into N and s has not been independently justified. k = 9.0 M
s
has been reported in AcOH
2
N
2
3d
h
−1 −1
3d
i
−1 −1
3m j
6
at 25 °C. k2 = 61.4 M
M
s
has been reported in AcOH at 25 °C. k = 0.46 M
s
has been reported in CH CN at 25 °C. k2 = 1.5 × 10
3
3j
2
s
−1
−1
3j
k
6
−1 −1
s
has been reported in CH CN at 25 °C. k = 8.3 × 10 M
has been reported in CH CN at 25 °C.
3
2
3
Solvent and Kinetic Isotope Effects. Table 2 and Figure
show that the rates of hydride abstraction from cyclohexa-1,4-
diene (2e) do not correlate with Reichardt’s solvent polarity
In line with an earlier report on dehydrogenations of
3e
3
hydroaromatic compounds with quinones, large primary
isotope effects of k /k
= 5.8−9.0 were observed for the
H
D
1
2
reactions of DDQ with cyclohexa-1,4-diene (Table 2). The
small, solvent-dependent kinetic isotope effects which were
observed for the corresponding reactions with tributylstannane
parameter ET. In contrast, the rate constants for the reactions
of DDQ with Bu SnH (2n) increase linearly with E , while the
3
T
hydride abstractions from pyridine−borane become slightly
slower with increasing ET.
The large solvent effect for the reaction of DDQ with
(
k /k = 0.94−2.2) and the borane−pyridine complex 2r (k /
H
D
H
As
13,14
k = 1.5−2.5) also have precedents in the literature.
D
14b
summarized by Wigfield et al., the rather low and, in part
even inverse, primary KIE data for borohydride reductions of
ketones have qualitatively been rationalized with product-like
transition states. This interpretation has also been supported by
tributylstannane (2n) indicates charge separation in the
transition state, as shown in Figure 4, where C attack of 2n
on DDQ forms an ion pair, which can be stabilized by a polar
solvent. From Hammond’s postulate, we can expect a large
solvent effect based on a late transition state (see also the
quantum chemical calculations below). The slight decrease of
the reaction rates with increasing solvent polarity in the
corresponding reaction with the borane−pyridine complex 2r
can be attributed to the dipolar character of 2r that is stabilized
by a polar solvent.
14c
Yamataka and Hanafusa, whose calculations with quantitative
transition state models document the possibility of very small
primary H/D isotope effects in ketone reductions for very late
that is, product-like) transition states. That primary KIE values
can actually become inverse for these reactions can be explained
by the smaller stretching force constants of B−H and Sn−H in
comparison to C−H bonds.
(
1
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Figure 3. Solvent effects for the reactions of DDQ (1a) with 2e,n,r.
Figure 2. Correlations of (log k)/sN vs N for the reactions of DDQ
(1a) with hydride donors 2. The broken line represents the calculated
line according to eq 1 using the electrophilicity parameter E = −3.66,
which was derived from reactions of DDQ with C nucleophiles, and
the N/s parameters of the hydride donors, which were derived from
N
their reactions with benzhydrylium ions.
Table 2. Solvent and Kinetic Isotope Effects for Reactions of
DDQ (1a) with 2e,n,r (20 °C)
a
kH/M−1 s−1
kD/M−1 s−1
solvent
ET
k /k
H
D
DDQ + Cyclohexa-1,4-diene/D (2e)
8
1
cyclohexane
31.2
32.0
37.4
41.1
42.2
46.0
1.4 × 10−
4.6 × 10−
4.2 × 10
4.9 × 10−
1.2 × 10
6.2 × 10−
2
3
1
2
2
−3
−4
−2
n-Bu O
5.1 × 10
7.3 × 10
6.8 × 10
9.0
5.8
7.2
2
−
THF
CH Cl2
2
−
acetone
Figure 4. Solvent effect on the reaction of DDQ (1a) with
tributylstannane (2n).
CH CN
9.7 × 10−3
6.4
3
DDQ + Bu SnH/D (2n)
3
1
1
cyclohexane
31.2
32.0
37.4
41.1
42.2
46.0
1.5 × 10
1.6 × 10
1.4 × 10
3.7 × 10
3.7 × 10
2.7 × 10
2.7 × 10
0.94
1.8
1.3
1.7
1.3
2.2
Table 3. Comparison of Rate Constants of the Reactions of
1
1
n-Bu O
2.5 × 10
Tributylstannane (2n) with Quinones in CH CN and
2
3
1
1
THF
4.8 × 10
Benzhydrylium Ions in CH Cl
2
2
2
2
CH Cl2
6.2 × 10
2
a
/M−1 s −1
calc /M−1 s −1 log (k
b
2
2
electrophile
E
k
2
k /kcalc)
2
acetone
3.6 × 10
(dpa) CH+
−4.72
−7.02
−7.69
−9.45
−3.66
−12.28
7.2 × 102
5.4 × 101
c
7.6 × 102
−0.03
0.12
3
3
CH CN
6.0 × 10
2
3
+
c
c
1
(
dma) CH
4.1 × 10
DDQ + pyridine·BH /D (2r)
2
3
3
+
1
1.8 × 101
1.9
4
3
2
3
3
3
4
3
2
3
2
3
(pyr) CH
1.7 × 10
−0.02
−0.03
0.31
cyclohexane
31.2
32.0
37.4
41.1
42.2
46.0
3.0 × 10
6.4 × 10
5.4 × 10
5.1 × 10
1.7 × 10
2.2 × 10
1.3 × 10
4.2 × 10
2.2 × 10
2.8 × 10
7.9 × 10
1.0 × 10
2.3
1.5
2.5
1.8
2.2
2.2
2
+
c
(jul) CH
1.8
n-Bu O
2
2
DDQ (1a)
6.0 × 103
2.5 × 10−
2.9 × 103
THF
2
−2
2,5-dichloro-p-
5.3 × 10
−0.33
CH Cl2
2
benzoquinone
acetone
(1b)
CH CN
9.3 × 10−1
6.4 × 10−2
2.1
3
p-chloranil (1c)
−12.13
−9.37
1.16
a
From ref 12.
tetrafluoro-p-
1.5
−0.15
benzoquinone
(1d)
o-chloranil (1e)
−8.77
−16.19
3.0 × 102
9.4 × 10
4.5
1.82
Reactions of Tributylstannane with Different Oxi-
dants. Table 3 and Figure 5 show that the rate constants (log
k ) for the reactions of Bu SnH with quinones and
benzhydrylium ions follow a common correlation with the
electrophilicity parameters of quinones and benzhydrylium
ions, which were derived from reactions with π-nucleophiles. As
the reactions of stannanes with benzhydrylium ions have
−5
−4
p-benzoquinone
(1f)
3.7 × 10
−0.60
a
b
2
3
For structures see Figure 5. Calculated by substituting N = 9.96 and
s = 0.55 of Bu SnH (from ref 15) and the electrophilicities E of the
N
3
c
reaction partners into eq 1. From ref 15.
10
previously been shown to proceed by a polar mechanism, the
correlation in Figure 5 supports a polar reaction mechanism via
C attack for the reactions of Sn−H hydride donors with
quinones.
1
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Scheme 4. Reaction of 2,5-Dichlorobenzoquinone (1b) with
the Pyridine−Borane Deuteride Complex (D -2r)
3
Scheme 5. Reaction of 2,5-Dichloro-p-benzoquinone (1b)
with D -Cyclohexadiene (D -2e)
8
8
Figure 5. Correlation of log k vs E for the reactions of Bu SnH (2n)
2
3
with quinones (in MeCN) and benzhydrylium ions (in CH Cl ). Data
2
2
are taken from Table 3.
Deuterium labeling experiments with 2,5-dichlorobenzoqui-
none (1b) provide a further tool to differentiate between C and
O attack of different hydride donors. When 1b was treated with
Bu SnD in CH Cl at 20 °C, a ∼1:1 mixture of the deuterated
3
2
2
and nondeuterated hydroquinones 3-D and 3-H was isolated in
0% yield (Scheme 3). The formation of 3-D, i.e., a product
8
with deuterium at C-3, indicates a C attack pathway, e.g., via
intermediates 4 and 5.
Scheme 3. Reaction of 2,5-Dichloro-p-benzoquinone (1b)
with Bu SnD
3
the rate of O attack, the formation of a small yield of 3 from 1b
and D -2e is surprising in view of the fact that a rate constant of
8
M
−12
−1 −1
1
0
s
can be calculated for the formation of 9 by attack
of cyclohexa-1,4-diene (2e) at the CH position of 1b, which is
far too small to explain the observed traces of 3-D.
In order to examine the origin of 3-D, O-deuterated 2,5-
dichlorohydroquinone was prepared by deuterium exchange
with heavy water and dissolved in CH Cl , the solvent used for
2
2
the hydride transfer reaction. Scheme 6 shows that the
exchange of deuterium at the C-3 position occurs slowly at
2
0 °C. The small amount (4%) of 3-D observed after 48 h,
therefore, suggests that the trace amount (3%) of 3-D found in
Similarly, when 2,5-dichlorobenzoquinone (1b) reacted with
the deuterated borane pyridine complex D -2r, a 3:7 mixture of
3
Scheme 6. Examination of Deuterium Exchange at the
Product Stage
3
-D and 3-H was isolated in 87% yield (Scheme 4), which also
supports a C attack pathway via intermediates 6 and 7. The
smaller ratio 3-D/3-H may be due to the proton exchange of
pyridine·BD with the phenolic proton of 8, as an earlier study
3
showed that amine−borane complexes undergo a rapid
proton−deuterium exchange with heavy water under acidic
1
6
conditions.
In contrast, only a trace amount of deuterium was found in
the hydroquinone, which was obtained in 17% yield from the
reaction of 1b with perdeuterated cyclohexa-1,4-diene (D -2e)
8
17
in CH Cl at 20 °C after 48 h (Scheme 5). While the E
2
2
parameters for C attack at quinones cannot be applied to derive
1
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Figure 6. Free energy profile for the reaction of DDQ (1a) with cyclohexadiene (2e) (RM06-2X/def2-TZVPP//B97D/6-31+G(d,p)//PCM/UFF)
in CH Cl together with selected transition structures.
2
2
the reaction of 1b with C D comes from deuterium exchange
at the product stage and not from the intermediacy of 9.
Computational Studies. DFT studies of the reactions of
and RM06-2X) have been checked for all transition states. An
ultrafine grid was used throughout this study for numerical
integration of the density.
6
8
DDQ with cyclohexa-1,4-diene (2e), Me SnH (2n′), and
The energy profile as well as the optimized transition
structures for the different modes of reaction of DDQ (1a)
with cyclohexadiene (2e) are shown in Figure 6. The geometry
of TS1, the most favorable pathway, closely resembles that
3
trimethylamine−borane complex (2p) were performed using
1
8
Gaussian 09. The B97D functional was used in combination
with the 6-31+G(d,p) basis set (LANL2DZ ECP for Sn atoms)
for structure optimization and frequency calculations. Since
Radom has shown that transition structures obtained in the
presence of a solvent model may deviate significantly from the
3o
previously calculated by Chan and Radom for polar solvents.
The formation of the CT complex CT1 between DDQ (1a)
−1
and 2e is endergonic by 22 kJ mol . From CT1, hydride
transfer to O of DDQ via TS1 requires an activation free energy
3o
gas-phase structures, the PCM/UFF model for CH Cl has
2
2
−
1
−1
been used for all geometry optimizations in this study.
Geometries of the transition states were verified by vibrational
frequency calculations. The nature of the most favorable
transition states was further verified by IRC calculations (50
steps in each direction) and subsequent structure optimizations
to the next local minimum energy structure. Thermal
corrections were calculated from unscaled frequencies at
of 60 kJ mol , resulting in an overall barrier of 82 kJ mol .
Surprisingly, the generation of the ion pair intermediate IM1
from DDQ (1a) and cyclohexa-1,4-diene (2e) is exergonic by
−
1
16 kJ mol . Further stabilization by proton transfer and
separation of the product complex gives the final products P1
and P2.
The barrier for hydride transfer from 2e to C-5 of DDQ via
TS2 is 44 kJ mol− higher than that for O attack, and the free
energy of the generated ion pair intermediate IM2 is 87 kJ
1
298.15 K and 1 atm. Refined electronic energies were obtained
from single-point calculations on the B97D geometries using
Truhlar’s meta hybrid exchange-correlation functional M06-2X
with the triple-ζ quality def2-TZVPP basis sets, again using the
PCM/UFF model for CH Cl . All free energies in solution have
−1
mol higher than that of IM1. In addition, the transition state
−1
of the ene reaction TS3 is favored by 28 kJ mol over TS2,
and the formation of the ene adduct IM4 is exergonic by 24 kJ
2
2
−1
been corrected to correspond to a standard state of 1 mol
mol . Further elimination of benzene from IM4 requires an
−1
19
−1
L . The stabilities of the restricted wave functions (RB97D
activation free energy of 86 kJ mol (for the structure of TS4
1
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Figure 7. Free energy profile for the reaction of DDQ (1a) with trimethylstannane (2n′) (RM06-2X/def2-TZVPP//B97D/6-31+G(d,p)//PCM/
UFF) in CH Cl together with selected transition structures.
2
2
−
1
see the Supporting Information, p S50). Interestingly,
kJ mol . The formation of IM9 is a highly endergonic process
−1
−1
concerted transfer of two hydrogen atoms via TS5 faces a
by 61 kJ mol : i.e., IM9 is only 8 kJ mol more stable than the
transition state TS9. As in the reaction with the stannane, the
major stabilization comes through migration of boron to the
oxygen.
−1
reaction barrier (99 kJ mol ) comparable to that of the
stepwise process through TS3 and IM4. The restricted wave
functions were examined to be stable for the structures in
Figure 6, which indicates that these stationary points are not of
biradical type. The charge distributions in these structures
further confirm the polar character of these pathways (see the
Supporting Information, pp S35−S36).
The activation Gibbs free energies for C- and O-attack
pathways of the reaction of DDQ (1a) with various hydride
donors 2, which were analogously calculated on the same level
of theory (Supporting Information, Table S64) were converted
into second-order rate constants by the Eyring equation. The
numbers given in Table 4 include statistical corrections,
considering the number of equivalent positions in the quinones
and the hydride donors. As shown in Table 4, O attack is
favored for all computationally examined C−H hydride
Figure 7 shows the free energy profiles of the two different
reaction pathways for the reaction of DDQ (1a) with
trimethylstannane (2n′), a model for the experimentally studied
tributylstannane 2n. The O-attack pathway, i.e., hydride transfer
via TS6, requires an overall activation free energy of 103 kJ
−
1
20
mol to form the zwitterionic intermediate IM5. The
formation of IM5 from DDQ (1a) and 2n′ is exergonic by
donors, while C attack is favored for all computationally
examined B−H and Sn−H hydride donors, in agreement with
the interpretation of our experimental observations. Efforts to
rationalize the different behaviors of these two groups of
hydride donors by analysis of transition state charge
−1
1
33 kJ mol , and a subsequent proton shift leads to the more
stable final product P3. The competing hydride transfer to C-5
of DDQ (1a) via TS7 is favored by 42 kJ mol− over the O-
attack pathway. While the generation of the ion pair
intermediate IM6 from 1a and 2n′ is endergonic by 36 kJ
1
21
distribution or distortion/interaction energy analysis (see
the Supporting Information, pp S32−S34) have, unfortunately,
not been successful. Obviously, there is not one dominant
component which accounts for the variations of the barriers,
and the different selectivities of C−H and Sn−H/B−H donors
−1
mol , stabilization comes from the following migration of the
SnMe group to the adjacent oxygen atom and the subsequent
3
proton transfer, which gives the final product P3. Though there
−1
30
seems to be a small barrier of ∼10 kJ mol , the transition state
are not due to a single factor.
for the migration of the SnMe group could not be located due
As shown in Figure 9, the rate constants derived from
quantum chemically calculated activation free energies for O
attack of C−H hydride donors and for C attack of tin and
boron hydrides correlate well with the experimental values,
which demonstrates the consistency of the computational
method employed in this work.
3
to the exceedingly flat potential energy surface.
As illustrated in Figure 8, the O- and C-attack pathways of
the reaction of DDQ (1a) with trimethylamine−borane
complex (2p) show a pattern similar to that of the reactions
with trimethylstannane. C attack is favored over O attack by 47
1
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Figure 8. Free energy profile for the reaction of DDQ (1a) with trimethylamine−borane (2p) (RM06-2X/def2-TZVPP//B97D/6-31+G(d,p)//
PCM/UFF) in CH Cl together with selected transition structures.
2
2
Table 4. Rate Constants Derived from Activation Gibbs Free
Energies (RM06-2X/def2-TZVPP//B97D/6-31+G(d,p)//
PCM/UFF) for O-Attack and C-Attack Pathways of
Reactions of DDQ with 2 in CH Cl at 25 °C and
2
2
Experimental Values in CH Cl at 20 °C
2
2
log (k /M− s−1
1
)
2
RM06-2X, 25 °C
log (k /M− s−1
1
)
2
a
a
nucleophile
O attack
C attack
exptl, 20 °C
2
2
2
2
2
2
2
2
2
a
−4.79 (8)
−4.54 (4)
−4.47 (4)
0.38 (8)
−7.50 (8)
−6.49 (4)
−4.60 (4)
−2.00 (8)
−3.21 (16)
−0.23 (16)
2.43 (4)
−3.28
−2.66
−2.12
0.34
b
c
d
e
f
−0.35 (16)
2.86 (16)
3.67 (4)
−0.31
2.04
Figure 9. Correlation of quantum chemically calculated rate constants
(log k (RM06-2X, 25 °C), from Table 4) for the reactions of DDQ
2
(
1a) with C−H hydride donors (O attack, red circles) and Sn−H and
g
h
j
3.08
B−H hydride donors (C attack, blue squares) with the experimental
5.15 (16)
0.28 (8)
2.08 (16)
−3.02 (8)
4.77
values from Table 1.
0.82
Bu SnH (2n)
2.79
3
b
Me SnH (2n′) −4.67 (4)
2.62 (4)
2.10
3
was explained by the fact that the experimental data refer to
transfer of H to the quinone oxygen, while the E parameters of
2
2
2
2
p
q
r
−6.40 (12)
−5.98 (12)
−1.98 (12)
−0.25 (12)
1.80 (12)
3.01 (12)
6.27 (12)
0.49
2.23
3.71
4.23
−
quinones refer to the quinone carbons, with the consequence
−
that eq 1 calculates the transfer of H to the quinone carbon
t
6.83 (12)
b
a
atoms. For that reason we have compared the quantum
chemically calculated rate constants for the nonobserved
transfer of hydride from C−H to C-5 of DDQ (1a) with the
corresponding rate constants obtained from the linear free
energy relationship (eq 1). Figure 10 shows a remarkably good
agreement of the absolute rate constants obtained by two
completely different approaches. The applicability of eq 1 also
Statistical factor in parentheses. Calculated from the rate constant k
2
−1
−1
=
125 M
s
in CH CN at 25 °C reported in ref 22.
3
The deviation of the experimental rate constants for the
reactions of DDQ (1a) with C−H hydride donors from those
calculated from the reactivity parameters E, N, and s by eq 1
N
1
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Journal of the American Chemical Society
Article
can be combined with the benzhydrylium-derived N and sN
parameters of Sn−H and B−H hydride donors to calculate the
rate constants for the reactions of quinones with these hydride
donors. The analogy of the involved mechanisms is thus
demonstrated. The polar nature of these processes is further
supported by the higher reactivity of Bu SnH in comparison to
3
Ph SnH, which would not be the case if the Sn−H bond would
3
11
be cleaved homolytically.
As the E parameters of electrophiles are based on their
reactivities toward C-centered reference nucleophiles, and the
N and sN parameters of nucleophiles are based on their
reactivities toward C-centered reference electrophiles (typically
benzhydrylium ions and quinone methides), the applicability of
eq 1 is limited to electrophile−nucleophile combinations, in
which at least one of the reaction centers is carbon. Since this
condition is not fulfilled for the hydride shift from C−H groups
to the carbonyl oxygen of quinones (formation of an O−H
bond), the failure of eq 1 to reproduce the rate constants for
this reaction series can be rationalized. Figure 10 shows,
however, that eq 1 accurately predicts the quantum chemically
derived rate constants for the nonobserved transfer of hydride
from C−H groups to C-5 of DDQ (1a).
Figure 10. Rate constants for the nonobserved reactions of C−H
hydride donors with C-5 of DDQ (1a): comparison of quantum
chemically calculated rate constants (log k (RM06-2X, 25 °C), from
2
Table 4) with the log k (20 °C) values derived from eq 1, by using the
2
electrophilicity parameter E(1a) = −3.66 and the N and s parameters
N
from Table 1.
for hydride transfer reactions from C−H hydride donors to
quinones has thus been demonstrated.
The calculated energy profiles also provide an explanation for
the largely differing kinetic isotope effects for the different
systems. From the reaction profile shown in Figure 6 for the
reaction of DDQ (1a) with cyclohexadiene (2e) we can see
that the lowest-lying transition state TS1 describes the
exothermic/exergonic conversion of reactant complex CT1 to
ion pair IM1. This is not so for the reaction of DDQ (1a) with
stannane 2n′, where the lowest-lying transition state TS7
characterizes the endergonic formation of ion pair IM6 from
reactant complex CT2 (Figure 7). Similar observations can also
be made for the borane reduction reaction in Figure 8, and we
therefore believe that the rather small KIE values for reactions
of stannanes and boranes indicate systematically later transition
states connected to the formation of energetically high lying ion
pair intermediates.
EXPERIMENTAL SECTION
■
Materials. The cyclohexa-1,4-diene derivatives 2f−h were synthe-
23
sized by Birch reduction according to a literature procedure. 2i was
prepared through reduction of 4,4′-dimethoxybenzophenone with
triethylsilane in the presence of HBF . 2k,l were synthesized by
4
reduction of the corresponding acridinium and pyridinium salts with
NaS O4 according to refs 24 and 25. 2s,t were prepared by
2
deprotonation of their carbene precursors and treated with THF−
26
borane complex according to literature procedures. D -1,4-cyclo-
8
hexadiene was prepared by Birch reduction of D -benzene in liquid
6
deuterated ammonia according to ref 27. Bu SnD was synthesized
3
from the reaction of tributyltin chloride with LiAlD . The pyridine·
4
BD3 complex was obtained in pyridine solution by treatment of
NaBD with pyridine deuterium chloride, which was prepared from
4
the deuterium exchange of pyridine hydrogen chloride with heavy
water. 1b was prepared by chlorination and subsequent oxidation of
2
8
1
,4-dimethoxybenzene as reported in the literature. All other
CONCLUSION
■
compounds were purchased from commercial sources and (if
necessary) purified by crystallization, sublimation (for benzoquinone),
or distillation prior to use.
Correlation eq 1, which has previously been demonstrated to
hold for a large variety of reactions of carbocations and Michael
acceptors with π, n, and σ nucleophiles, has now been
demonstrated also to hold for the reactions of quinones with
Sn−H and B−H hydride donors, but not for the corresponding
reactions with C−H hydride donors. The contrasting behavior
of the different hydride donors turned out to be due to the fact
that Sn−H and B−H groups transfer hydrogen to the conjugate
carbons of the investigated quinones, while C−H hydride
donors transfer hydrogen to the carbonyl oxygens. This
conclusion is supported by deuterium labeling experiments
and quantum chemical intrinsic reaction coordinate calcu-
lations.
Kinetics. Dichloromethane was freshly distilled over CaH before
2
use. Commercially available cyclohexane, n-Bu O, and THF were
2
further purified by distillation over DDQ to remove the impurities
which may react with DDQ. Acetone and acetonitrile were purchased
from Acros and used without further purification. Most rate constants
were determined photometrically as described previously. Fast
reactions were determined by using the stopped-flow technique.
Slow reactions were measured by UV−vis (conventional photodiode
1
array) or H NMR spectroscopy (200 MHz, in CD CN) under
3
29
nitrogen. The temperature of the solutions during all kinetic studies
was kept constant (20.0 ± 0.1 °C) by using a circulating bath
thermostat.
Figures 6−8 show that the hydride transfer step from 1,4-
cyclohexadiene to the DDQ oxygen is exergonic, resulting in
large kinetic isotope effects (k /k = 6−9). In the reactions of
ASSOCIATED CONTENT
■
H
D
*
S
Supporting Information
DDQ with B−H and Sn−H hydride donors, on the other hand,
the rate-determining hydride transfers to C-5 of DDQ lead to
high-energy intermediates with late, product-like transition
states, resulting in small and even inverse H/D kinetic isotope
effects because of the smaller stretching force constants of B−H
and Sn−H bonds in comparison to C−H bonds.
Text, figures, and tables giving details of the kinetic experiments
and quantum chemical calculations. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
The electrophilicity parameters E of quinones, which have
Corresponding Author
*herbert.mayr@cup.uni-muenchen.de
5
been derived from their reactivities toward πCC nucleophiles,
1
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Journal of the American Chemical Society
Article
Notes
Chem., Int. Ed. 2010, 49, 5558−5562. (f) Hayashi, Y.; Itoh, T.;
Ishikawa, H. Angew. Chem., Int. Ed. 2011, 50, 3920−3924. (g) Tsang,
A. S.-K.; Jensen, P.; Hook, J. M.; Hashmi, A. S. K.; Todd, M. H. Pure
Appl. Chem. 2011, 83, 655−665. (h) Alagiri, K.; Devadig, P.; Prabhu,
K. R. Chem. Eur. J. 2012, 18, 5160−5164. (i) Rohlmann, R.; Garcia
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Deutsche Forschungsgemeinschaft (SFB 749,
Project B1) and the China Scholarship Council (fellowship to
X.G.) for financial support. We are grateful to Prof. Sason S.
Shaik for helpful discussions and Dr. Armin R. Ofial for help
during the preparation of this manuscript. Dedicated to
Professor Yitzhak Apeloig on the occasion of his 70th birthday.
̃
Mancheno, O. Synlett 2013, 24, 6−10. (j) Singh, K. N.; Singh, P.;
Singh, P.; Maheshwary, Y.; Kessar, S. V.; Batra, A. Synlett 2013, 24,
1
963−1967.
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9) For a comprehensive database of nucleophilicity parameters N
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Article
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29) For the slow reactions with tributylstannane, contact with
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oxygen should be avoided, because it might initiate radical chain
reactions. For general principles of radical chain reactions of stannanes,
see: Zard, S. Z. Radical Reactions in Organic Synthesis; Oxford
University Press: New York, 2003.
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30) One reviewer, though agreeing with our conclusions, missed a
simple chemical rationale for the different behaviors of the C−H
hydride donors on one side and B−H and Sn−H on the other. We
regret that we cannot provide such a rationale, but instead of
presenting an ostensible explanation, we prefer to follow the advice of
our senior colleague Rolf Huisgen: “Do not detract the excitement of
mystery from unsolved problems.”
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