Quantification of the ambident electrophilicities of halogen-substituted quinones

Article abstract of DOI:10.1021/ja505613b

Kinetics and mechanisms of the reactions of p-quinone, 2,5-dichloro-p- quinone, 2,3,4,5-tetrachloro-p-quinone (chloranil), 2,3,4,5-tetrafluoro-p- quinone (fluoranil), and 3,4,5,6-tetrachloro-o-quinone with π-nucleophiles (siloxyalkenes, enamines) and amin

Full text of DOI:10.1021/ja505613b

Article
pubs.acs.org/JACS
Quantification of the Ambident Electrophilicities of Halogen-
Substituted Quinones
Xingwei Guo and Herbert Mayr*
Department Chemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstraße 5-13 (Haus F), 81377 Munchen, Germany
̈
̈
̈
S
* Supporting Information
ABSTRACT: Kinetics and mechanisms of the reactions of p-quinone,
2,5-dichloro-p-quinone, 2,3,4,5-tetrachloro-p-quinone (chloranil),
2,3,4,5-tetrafluoro-p-quinone (fluoranil), and 3,4,5,6-tetrachloro-o-
quinone with π-nucleophiles (siloxyalkenes, enamines) and amines
have been investigated. Products arising from nucleophilic attack at all
conceivable sites, that is, at C and O of the carbonyl groups (pathways
a, b) as well as at halogenated and nonhalogenated conjugate positions
(pathways c, d), were observed. The partial rate constants for the C-
attack pathways (a, c, d), which are derived from the photometrically
determined second-order rate constants and the product ratios followed
the linear free energy relationship log k (20 °C) = sN(E + N) (Mayr, H.;
et al. J. Am. Chem. Soc. 2001, 123, 9500−9512). It was, therefore,
possible to calculate the electrophilicity parameters E of the different positions of the quinones from log k (20 °C) and the N and
sN parameters of the nucleophilic reaction partners, which have previously been derived from their reactions with benzhydrylium
ions. Almost all rate constants for the C-attack pathways (a, c, d) were considerably larger than those calculated for the
corresponding SET processes, indicating the operation of polar mechanisms. SET mechanisms may only account for the
formation of the products formed via O-attack. With the E parameters determined in this work, it is now possible to predict rate
constants for the reactions of these quinones with a large variety of nucleophiles and, thus, envisage unprecedented reactions of
quinones.
quinone reactivity with the potential to predict unprecedented
reactions.
Nucleophilic attack at quinones may either occur at the
carbonyl group (paths a, b, Scheme 1) or at conjugate positions
(paths c, d). Depending on the substitution pattern of the
quinone, one or more types of conjugate attack are conceivable.
INTRODUCTION
■
Since Wohler carried out the first 1,4-addition of HCl to p-
̈
benzoquinone in 1844,1 the chemistry of quinones has
continuously been attracting the attention of chemists.2 The
realization of the oxidizing properties of quinones in the early
20th century3 also paved the way to understanding the
important role of quinones in biological processes.4 In spite
of this long history, quantitative mechanistic studies concerning
the reactivities and selectivities of quinones in organic synthesis
are still missing, especially in the border area between electron
transfer and polar reaction pathways.
Scheme 1. Ambident Reactivities of 2,5-Disubstituted
Quinones
We have previously reported that the reactions of DDQ with
π-nucleophiles usually proceed by polar pathways,5 the rates of
which can be described by eq 1, which had been developed to
predict rates and selectivities of polar reactions.6
log k(20°C) = sN(E + N)
(1)
In eq 1, the second-order rate constant (log k) is calculated by
two solvent-dependent nucleophile-specific parameters (sN, N)
and one electrophile-specific parameter (E). A comprehensive
nucleophilicity scale covering more than 30 orders of
magnitude7 has been created by using a series of benzhydrylium
ions and structurally related quinone methides as reference
electrophiles.8 In this work, we will derive electrophilicity
parameters E for five synthetically important quinones and
show that they can be used as an organizing principle of
Received: June 11, 2014
Published: July 23, 2014
© 2014 American Chemical Society
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We have now used the linear free energy relationship (1) to
elucidate the mechanisms of the reactions of different halogen-
substituted quinones (Figure 1) with π-systems and amines
(Table 1) and quantified their ambident electrophilicities and
selectivities.
(Scheme 2), which were fully characterized. Due to the low
electrophilicity of 1a, the reactions with less reactive silyl ketene
acetals are rather slow and were not studied in this work.
Scheme 2. Reactions of Benzoquinone (1a) with Silyl Ketene
Acetals
a
Yield includes traces of impurities which could not be removed by
chromatography.
2,5-Dichlorobenzoquinone (1b) reacted analogously with the
silyl ketene acetals 2(a,d,e) and gave 3ba, 3bd, and 3be,
respectively (Scheme 3). As significant amounts of other
products were not detected in the NMR spectra of the crude
products, the moderate yields are due to nonoptimized workup
procedures. In the reaction of 1b with 2c, the [3 + 2]
cyclization products 4bc (18%) and 5bc (40%) were formed
along with 19% of 6bc, a product of O attack.
Figure 1. Quinones 1a−e studied in this work and their reduction
potentials Ered (vs SCE)9 in acetonitrile.
RESULTS
■
Product Studies: Reactions with π-Nucleophiles. 1,4-
Benzoquinone 1a reacted with the silyl ketene acetals 2d and
2e to give products of conjugate attack selectively. Chromatog-
raphy of the crude mixture on silica gel led to hydrolysis with
formation of the substituted hydroquinones 3ad and 3ae
In line with Fukuzumi’s and Otera’s report,9 the tetrachloro-
and tetrafluoro-substituted para-quinones 1c and 1d were
found to give 1,2-addition products (7) with the terminal silyl
ketene acetal 2a, and products of O attack (6) with 2c (Scheme
4).
Table 1. Nucleophiles 2a−o and Their Reactivity Parameters N and sN in CH2Cl2 (2a−h) or CH3CN (2i−o) and Their
Oxidation Potentials in CH3CN (vs SCE)
a
b
c
d
e
Calculated values from ref 5. From ref 10. Peak potentials from ref 11. From ref 12. From ref 13.
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The reaction of 1e with silyl enol ether 2f proceeded with
attack at the carbonyl oxygen and gave hydroxyacetophenone
(12ef) after chromatography on silica gel. NMR-spectroscopic
investigation of the reaction of 1e with enamine 2h showed the
exclusive formation of the [4 + 2] cycloaddition product 10eh-
1; its chromatography on silica gel led to hydrolysis, and 10eh-
2 was isolated in 61% yield as a 1:1 mixture of diastereomers.
Reactions with Amines. In agreement with earlier
reports,2b,14 pyrrolidine was found to react with 1,4-
benzoquinone with formation of the monosubstituted
benzoquinone 13ai in 85% yield, when 4 equiv of quinone
was used (Scheme 6).
Scheme 3. Reactions of 2,5-Dichlorobenzoquinone (1b)
with Silyl Ketene Acetals
Products arising from C-2 and C-3 attack were formed by the
reaction of 2,5-dichloroquinone (1b) with pyrrolidine.2b,15
Scheme 7 shows that the ratio 13bi/8bi depends strongly on
the concentration of the reactants. The ratio 13bi/8bi
decreases from 58/26 to 3/82 when reducing the concentration
of quinone 1b from 0.25 to 0.001 mol L−1 in CH3CN while
keeping the ratio [1b]/[2i] = 5 constant.
As chloranil 1c has previously been reported to react with
more than one molecule of amine,2g the reactions of 1c−e with
2i and 2j have been performed with 4 equiv of quinones
(Schemes 8 and 9).
The 13C NMR spectrum of pyrrolidine-substituted ortho-
quinone 8ei shows a similar pattern as that of 8ci, that is, only
one carbon signal (C-3) is significantly shifted to high field
because of the mesomeric electron donation of the lone pair of
the nitrogen atom, in line with structure 8ei, where the
pyrrolidino group is located at the C-4 position. The
corresponding C-3 substitution by pyrrolidine would result in
an NMR spectrum in which two carbon signals (conjugate C-4
and C-6 positions) are shifted to higher field. This assignment
is in line with Koch’s report16 that the reaction of o-chloranil
with 2,2′-bipyridine proceeds via C-4,5 substitution (Scheme
10).
Reaction Mechanism. From the fact that p-benzoquinone
1a as well as 2,5-dichloro-benzoquinone 1b do not give
products of C-1 attack with any of the investigated
nucleophiles, we can conclude that conjugate attack at these
quinones is generally preferred over attack at the carbonyl
carbon C-1. For that reason, the nucleophilic attack at the
carbonyl carbon of 1b is not considered in Scheme 11.
As summarized in Scheme 11, ketene acetals attack
exclusively at O or C-6 (C−H) of 1b with formation of the
zwitterions 15 or 14, respectively, which undergo subsequent
desilylation to give the isolated products 6 and 3; nucleophilic
attack at the chlorinated carbon is not observed. Analogously,
amines also attack faster at C−H than at the chlorinated carbon
to give the zwitterion 16. However, the intermediate 16 may
undergo retroaddition, and the subsequent slower attack at C-2
leads to nucleophilic substitution of the chloride with formation
of 8. Only in the presence of high concentrations of quinone,
oxidation of 16 can take place to give the amino-substituted
quinones 13. This situation−fast reversible nucleophilic attack
at a C−H position followed by slow irreversible attack at the
chlorinated position−reminds of the mechanisms of nucleo-
philic aromatic substitution of Cl− in acceptor substituted
chlorobenzenes, where the initial nucleophilic attack also occurs
at a C−H group.17
Mixtures of products were formed with cyclic silyl ketene
acetals. When 2d was combined with p-chloranil 1c, products
from C-1 addition (7cd) and C-2 monosubstitution (8cd), and
traces of a disubstitution product (9cd) were formed. The C-1
addition product 7dd was the major product of the reaction of
2d with tetrafluoro-benzoquinone 1d. Although only a trace of
the monosubstitution product (8dd) was observed, the
disubstitution product 9dd was isolated in 27% yield as a 1:2
mixture of diastereomers.
Concomitant C- and O-attack were observed in the reaction
of the six-membered ring silyl ketene acetal 2e with p-chloranil
1c, to give the quinone 8ce and the hydroquinone 6ce. In the
reaction of 2e with tetrafluoro-p-benzoquinone (1d), only the
substitution product 8de was obtained.
Though 1c reacted with enamine 2h in the same way as with
2c to give 6ch by O-attack, the corresponding reaction of 1d
with 2h gave a complex mixture of products, which was not
analyzed.
o-Chloranil (1e) reacted with the terminal silyl ketene acetals
2a and 2b to give the C-1 addition products 7ea and 7eb,
respectively, whereas its reaction with 2c yielded the [4 + 2]
cycloaddition product 10ec exclusively (Scheme 5).
The reaction of 1e with 2d gave a mixture, from which the C-
1 addition product 7ed, the product of O-attack 6ed (for the X-
ray structure, see Supporting Information, page S20), and the
tricyclic compound 11ed were isolated in 13%, and 31%, and
11% yield, respectively. Only a single diastereomer of 11ed was
1
observed and characterized by H NMR, 13C NMR, and high-
If a highly electrophilic C−H position is not available, as in
the tetrahalo-substituted quinones 1c−e, attack of π-nucleo-
philes at the carbonyl carbon, which was not observed in the
reactions with 1a and 1b, becomes competitive. As shown in
resolution mass spectroscopy. The analogous tricyclic com-
pound 11ee, which was the only product obtained in the
reaction of 1e with 2e, was characterized by X-ray
crystallography (page S21, in Supporting Information).
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Scheme 4. Isolated and (in Parentheses) NMR Yields for the Reactions of Chloranil (1c) and Fluoranil (1d) with Silyl Ketene
Acetals and an Enamine
Scheme 12, nucleophiles may either attack at a halogen-
substituted position (Scheme 12, path c) or at the carbonyl
group, where C or O attack may occur (paths a and b).
Pathway a (C-1 attack) is only followed by the terminal
ketene acetal 2a, and it is the only pathway followed by this
nucleophile. Pathway b (O attack) is partially followed by the
cyclic ketene acetal 2e, and it is the only pathway followed by
the enamine 2h and the sterically demanding ketene acetal 2c.
Pathway c (C-2 attack), which leads to substitution via initial
conjugate addition, is the exclusive process for all amines and is
partially followed by the ketene acetals 2d and 2e, which
concomitantly react via pathways a or b.
The presence of an s-cis configurated heterodiene system in
the ortho-quinone 1e provides additional reaction pathways.
Although amines selectively substitute 4-Cl of chloranil (1c)
according to reaction pathway c in Scheme 12, and the terminal
ketene acetal 2a attacks the carbonyl carbon C-1 according to
pathway a in Scheme 12. All other investigated π-nucleophiles
2c-e,h behave partially or exclusively as dienophiles in Diels−
Alder reactions with inverse electron demand. The formation of
the tricyclic compounds can be rationalized by the mechanism
shown in Scheme 13. Initial [4 + 2] cycloaddition gives
intermediate 17, which undergoes ring-opening and proton
transfer to form the silyl ketene acetal 18. Its Diels−Alder
reaction with 1e and subsequent silylation of the hydroxyl
group gives the isolated product 11ee. Alternatively, silylation
of the hydroxyl group may occur at an earlier stage of the
reaction cascade.
Kinetic Studies: Reactions with π-Nucleophiles. Kinetic
investigations of the reactions of the quinones 1a−e with the π-
nucleophiles 2a−h were performed in dichloromethane
solution at 20 °C. Most of these reactions were monitored
by UV−vis spectroscopy at or close to the absorption maxima
of the quinones (2,5-dichloro-p-benzoquinone (1b), 275 nm;
p-chloranil (1c), 290 nm; tetrafluoro-benzoquinone (1d), 256
nm; o-chloranil (1e), 457 nm). Only the reaction of 1a with 2d
as well as the reaction of 1d with 2b were monitored by UV−
vis spectroscopy at or close to the absorption maxima of the
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Scheme 5. Reactions of Ortho-Chloranil (1e) with Silyl Ketene Acetals and an Enamine
products (at ∼290 nm), and the reaction of 1a with 2e was
followed by 1H NMR spectroscopy. In all runs, an excess of the
nucleophiles (at least 10-fold) over the quinones was used to
achieve pseudo-first-order kinetics. The pseudo-first-order rate
constants kobs were obtained by least-squares fitting of the
Scheme 6. Reaction of Pyrrolidine with p-Benzoquinone
(1a)
obst
monoexponential function At = A0 e−k + C (for decrease) or
obst
At = A0 (1 − e−k ) + C (for increase) to the absorbances. The
second-order rate constants k2 (summarized in Table 2) were
derived from the linear correlations of kobs (s−1) with the
concentrations of the nucleophiles as illustrated in Figure 2.
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Scheme 7. Reactions of Pyrrolidine with 2,5-Dichloroquinone (1b) in Acetonitrile
a
Yield based on 2i, considering the fact that two amine molecules are needed per quinone.
These observations confirm that the low yields isolated in some
cases are not due to oxidations of the initial products by
quinones because in this case the order in quinone would
increase during the course of the reactions. As reductions of the
quinones by the products only take place at higher
concentrations, the measured second-order rate constants can
be assigned to the bimolecular reactions with the π-
nucleophiles, which are used in high excess.
Scheme 8. Reactions of Quinones 1c and 1d with Amines 2i,j
Reactions with Amines. Kinetic investigations of the
reactions of the quinones with the amines 2i−o were
performed in CH3CN solution at 20 °C. The formations of
the colored amino-substituted benzoquinones were monitored
by UV−vis spectroscopy. In all runs, an excess of the quinones
(at least 10-fold) over the amines was used to achieve pseudo-
first-order kinetics and to avoid multiple substitutions. The
pseudo-first-order rate constants kobs were obtained by least-
squares fitting of the monoexponential function At = A0 (1 −
a
Isolated yield based on 2i or 2j, considering the fact that two amine
molecules are needed per quinone.
Scheme 9. Reaction of ortho-Quinone 1e with Pyrrolidine 2i
obst
e−k ) + C to the increasing absorbances.
Like the reactions with π-nucleophiles, the reactions of the
quinones 1b−e with the amines 2i−o also followed second-
order kinetics. The second-order rate constants k2 (summarized
in Table 2) were derived from the linear correlations of kobs
(s−1) against the concentrations of the nucleophiles (Figure 3).
As two amine molecules are consumed by each substitution
process, the slopes of the plots of kobs vs [quinone] have been
multiplied by a factor of 0.5 to give the second-order rate
constants k2, which are listed in Table 2.
a
Isolated yield based on 2i, considering the fact that two amine
molecules are needed per quinone.
Scheme 10. Reactions of o-Chloranil with Pyridine
Derivatives Reported in Ref 16
Only the reaction of p-benzoquinone 1a with pyrrolidine 2i
did not follow a second-order rate law. As shown in Figure 4, a
reaction order of 2.6 (1 for 2i and 1.6 for 1a) was observed,
indicating that a second molecule of quinone is needed for the
oxidation of the reversibly generated initial adduct.
DISCUSSION
■
Linear Free Energy Relationships. The changes of
selectivity due to increasing steric hindrance of the silyl ketene
acetals are shown in Figure 5. In the reactions with 1a and 1b
conjugate addition at the C−H positions is always favored; only
the sterically demanding ketene acetal 2c also attacks at the
carbonyl oxygen. Both tetrahalogen-substituted quinones 1c,d
react with the terminal ketene acetal 2a exclusively at the
carbonyl carbon, but increasing steric shielding of the
nucleophiles (2d, 2e) leads to C-2 attack (substitution), and
further increase of steric demand results in attack at O, which is
the least shielded position and gives the thermodynamically
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Scheme 11. Reaction Pathways of 2,5-Dichlorobenzoquinone (1b)
most stable product. Like the para-quinones 1c,d, the ortho-
quinone 1e also reacts exclusively at C-1 with the terminal
ketene acetal 2a, but increasing steric shielding now leads to
Diels−Alder reactions.
Scheme 12. Reaction Pathways of Tetrahalogen-Substituted
Quinones
The linear plot of (log k)/sN vs the benzhydrylium-derived
nucleophilicity parameters N of the ketene acetals 2 in Figure 6
shows that the conjugate attack of the ketene acetals at a C−H
position of 1a and 1b follows eq 1. Please note that also the
two-point correlation for the parent quinone 1a has significance
because a slope of 1.0, as required by eq 1, was enforced for the
least-squares minimizations. The similar reactivities of the
trimethylsilyl (2a) and tert-butyldimethylsilyl (2a′) ketene
acetals indicate that the silyl transfer must occur after the
rate-determining step. Comparison of the reactivities of 1a and
1b shows that the dichloro-substitution in 1b increases the
electrophilicities of the C−H positions by approximately 3
orders of magnitude. It should be noted, however, that the high
electrophilicities of these positions can only become effective
when the initially formed zwitterions undergo fast subsequent
reactions, for example, silyl transfer in the reactions with
silylated ketene acetals or oxidation by a second molecule of
quinone in the reactions with amines.
Scheme 13. Possible Mechanism for the Reaction of 1e with
2e
When studying the kinetics of the reactions of 1b with
amines, the concentrations of the quinone 1b were rather small,
with the consequence that the measured rate constants referred
to the attack at the chlorinated position and formation of 8.
From the fact that second-order kinetics were observed from
low to high degree of conversion, we conclude that the
concentration of the rapidly formed zwitterion 16 (Scheme 11)
remains so small under the conditions of the kinetic
experiments that its intermediacy is not relevant for the
kinetics.
The linear correlations for the attack at the C−Cl or C−F
positions of 1b−e show (Figure 7) that also for these reactions,
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d
Table 2. Rate Constants for the Reactions of the Quinones 1a−e with the Nucleophiles 2a−o
a
b
calcd
max
k2
are rate constants calculated by eq 1 from the E parameters in this table and N/sN from Table 1. ket are the maximal rate constants
c d
calculated by eq 4 for single electron transfer. Calculated from overall rate constant and the ratio of products. 20 °C, L mol−1 s−1.
eq 1 and the benzhydrylium-derived nucleophile-specific
reactivity parameters N and sN are applicable; as mentioned
above, a slope of 1.0 is enforced in this type of plot. Since the
partial rate constants18 for the attack of the ketene acetals 2d
and 2e at the C-Halogen positions of 1c and 1d are on the
same correlation line (deviation less than a factor of 20, see
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from Table 1, which have been derived from reactions with
benzhydrylium ions.6−8
SET vs Polar Reaction. In previous work we have shown
that DDQ reacts much more slowly with π-nucleophiles than
expected from the correlation between electrophilicity and
redox potential of benzhydrylium ions and quinone methides,19
that is, DDQ was found to be far below the correlation line for
benzhydrylium ions and quinone methides. By adding data for
the quinones studied in this work to the plot (Figure 9), one
can see that the electrophilic reactivities of the most reactive
positions of quinones also correlate linearly with their redox
potentials. The correlation line for quinones is ∼10 orders of
magnitude below the line for benzhydrylium ions and quinone
methides.
As the rate constant for electron transfer can be calculated by
⧧
the Eyring equation (eq 2), and ΔGet must be greater than
ΔGet° (eq 3) according to Figure 10, the maximal accessible
rate constants for electron transfer from nucleophiles to
quinones are given by eq 4, where c is the Coulomb term,
that is, the energy needed to separate the radical ion pair to
infinite distance in CH2Cl2 solution; a value of c = 9.6 kJ/mol as
suggested by Fukuzumi and Otera was used for the Coulomb
term in the following analyses:9
Figure 2. UV−vis spectroscopic monitoring of the reaction of o-
chloranil (1e, 1.0 × 10−4 mol L−1) with 2a (3.0 × 10−3 mol L−1) at 457
nm in CH3CN at 20 °C. Determination of the second-order rate
constant k2 = 40 L mol−1 s−1 from the dependence of the first-order
rate constants kobs on the concentrations of 2a.
ket = (kbT/h)exp(−ΔGet⧧/RT)
(2)
⧧
ΔGet > ΔGet° = F(Eox − Ered) − c
(3)
max
ket = (kbT/h)exp{[−F(Eox − Ered) + c]/RT}
(4)
The comparison of the experimental rate constants with the
⧧
maximal rate constants for electron transfer (i.e., for ΔGet
=
ΔGet°), which is given in the last column of Table 2, is
illustrated in Figure 11. Because the drawn diagonal character-
izes reactions of quinones with nucleophiles, which proceed
with the same rate as the fastest conceivable SET processes, one
can derive that the operation of SET processes can certainly be
excluded for the reactions of quinones with amines (▲). As all
amines react several orders of magnitude faster than the SETs
can proceed, they must react via polar processes. Most of the
reactions of π-nucleophiles with a carbon center of the
quinones are also 4−7 orders of magnitude faster than the
fastest conceivable SET processes (●, exception 1b + 2c which
gives both C- and O-attack products), and only the reactions
that involve O attack at the quinones (○) proceed with rate
constants which are compatible with SET processes.
Computational Studies: Stepwise or Concerted
Substitution? The question whether conjugate addition or
elimination of chloride is rate-determining in the reaction of
2,5-dichloro-benzoquinone (1b) with pyrrolidine (2i) was
studied by quantum chemical calculations using Gaussian 0920
at B97D/6-31+G(d,p)//B97D/6-31+G(d,p)//PCM/UFF level
of theory in CH3CN. The potential energy surface for the
substitution process was calculated by a relaxed PES scan (with
geometry optimization at each point) on the bond length of
C−N and C−Cl.
Figure 3. UV−vis spectroscopic monitoring of the reaction of 2,5-
dichloro-benzoquinone (1b, 5.0 × 10−3 mol L−1) with 2i (1.0 × 10−4
mol L−1) at 500 nm in CH3CN at 20 °C. Determination of the
second-order rate constant k2 = 54 L mol−1 s−1 from the dependence
of the first-order rate constants kobs on the concentrations of 1b.
Table 2) as the rate constants for the reactions with amines, it is
demonstrated that the electrophilic reactivities (E) of the
halogen-substituted positions of the quinones are again almost
independent of the nature of the nucleophilic reaction partner.
The absence of a kinetic isotope effect (kH/kD = 1.0, Scheme
14) in the reaction of 2,5-dichloro-benzoquinone (1b) with N-
deuterated-morpholine (90% D) indicates that proton transfer
is not involved in the rate-determining-step.
Analogous correlations in Figure 8 show that the carbonyl
carbons of tetrachloro-o-quinone (1e) and fluoranil (1d) have
similar electrophilicities, 2−3 orders of magnitude greater than
that of the carbonyl carbon of chloranil (1c).
According to eq 1, the electrophilicity parameters of the C-1,
C-2, and C-3 positions of the quinones listed in Table 2 were
determined by least-squares minimization of Δ2 = Σ (log k2 −
sN(N + E))2 using the second-order rate constants k2 given in
Table 2 and the N and sN parameters of the nucleophiles 2a−o
Interestingly, the potential energy surface for the substitution
reaction of 1b with 2i shows that there is no intermediate
between the reactants and products (Figure 12). The
substitution proceeds via an asymmetric concerted process, in
which breaking of the C−Cl bond starts before the formation
of C−N bond is complete.21
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Figure 4. (a) UV−vis spectroscopic monitoring of the reaction of 2i (1.0 × 10−3 mol L−1) with 1a (2.0 × 10−2 mol L−1) at 500 nm in CH3CN at 20
°C. (b) Correlation of the observed pseudo-first-order rate constant kobs with the concentration of 1a. (c) Correlation of log kobs vs log [1a].
Figure 6. Plot of (log k2)/sN vs N for the addition reactions (at
C(−H)) of 1a,b with π-nucleophiles in CH2Cl2 at 20 °C (the slope is
enforced to 1).
Figure 5. Steric effect on the product selectivities of quinones with
silyl ketene acetals.
CONCLUSION
■
Figure 13 summarizes the behavior of the quinones 1(a−e)
toward nucleophiles. In the right part, quinones are ordered
according to their electrophilicity at the different C-centers. O-
Reactivity is not included because eq 1 is only applicable for
Figure 7. Plot of (log k2)/sN vs N for the substitution or addition
reactions of 1b−e (at C-Halogen) with amines 2i−o in CH3CN and
silyl ketene acetals 2d and 2e in CH2Cl2 at 20 °C (the slope is
enforced to 1).
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Scheme 14. Kinetic Isotope Effect for the Reaction of 1b
with Morpholine
Figure 10. Energy profile for electron transfer processes.
Figure 11. Correlation of measured rate constants (log kexp) with
calculated maximal rate constants of SET (log ket,max) for the reactions
Figure 8. Plot of (log k2)/sN vs N for the attack of π-nucleophiles at
the carbonyl carbon of 1c−e in CH2Cl2 at 20 °C (the slope is enforced
to 1).
●
▲
of quinones with amines ( ) and π-nucleophiles via C attack ( ) and
○
π-nucleophiles via O attack ( ).
Introduction of two chlorine atoms, as in 1b, increases the
electrophilicities of the C−H-positions by 3−4 units, whereas
the electrophilicities of the chlorine substituted positions
remain the same as in the parent 1a. As a consequence,
products arising from attack at a C−H-position of 1b are
formed, when the initially formed adduct can undergo
subsequent reactions. Otherwise, the C−H attack is reversible,
and the final product is formed by the slower attack at the
chloro-substituted position.
The additional chlorine substituents in 1c increase the
electrophilicities of the C−Cl positions in 1c relative to those of
1b by more than two units of E. Four halogen substituents in
chloranil 1c or fluoranil 1d activate the carbonyl groups so
strongly, however, that now the carbonyl carbons adopt similar
electrophilicities as the halogen-substituted positions, and it
depends on the nature of the nucleophile and the rate of the
subsequent reactions, where products will eventually be formed.
It is interesting to note that the C−Cl positions in chloranil 1c
are still less reactive than the C−H positions of dichloro-
quinone 1b.
The higher electrophilicities of both positions of fluoranil 1d
compared to those of chloranil 1c are analogous to the relative
reactivities of nitrated fluoro- and chlorobenzenes in
nucleophilic aromatic substitutions.17
Both, C-1 and C-4 of ortho-chloranil 1e are more
electrophilic than the corresponding positions in para-chloranil
1c, and the regioselectivity of nucleophilic attack at 1e is again
controlled by the feasibility of subsequent reactions.
Figure 9. Correlation between the electrophilicity parameters E and
the reduction potentials Ered of benzhydrylium ions and quinone
methides (reference electrophiles)19 and quinones.
predicting electrophile−nucleophile combinations, when at
least one of the reaction centers is carbon. Figure 13 shows
that the most electrophilic position of the parent compound 1a
is the C−H-group. Attack at this position can only lead to
products, however, when the initially formed adduct can be
stabilized, for example, by silyl migration, as in the reactions
with silyl ketene acetals, or by subsequent proton transfer or
oxidative hydride abstraction, as in the reactions with amines.
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Figure 12. Potential energy surface of the reaction of 1b with 2i.
Figure 13. Synthetic potential of halogen-substituted quinones.
Comparison with the previously reported electrophilicity of
DDQ5 reveals the enormous activating effect of the cyano
groupsten units in E compared with chloranil 1c.
reactionsmuch faster than calculated for SET processes
from the corresponding redox potentials. Only for the reactions
that involve O-attack at the quinones, the measured rate
constants do not allow to differentiate between the two
mechanisms because the measured rate constants were close to
In summary, most reactions of quinones with amines and π-
nucleophiles investigated in this work proceed via polar
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those expected for SET processes. However, because in all
cases, the measured rate constants agreed with those calculated
by eq 1, our rule of thumb applies, which states that reactions of
electrophiles with nucleophiles can be expected to take place at
20 °C if E + N > −5.6 The electrophilicity parameters E derived
in this work, thus, provide a semiquantitative basis for
characterizing the synthetic potential of additions of
nucleophiles to 1,4-benzoquinone 1a and its halogen-
substituted derivatives 1b−e.
In Figure 13, the E-scale for quinones is complemented by an
inversely ordered N-scale, and the two scales are arranged in a
way that quinones and nucleophiles, which are positioned at the
same level (E + N = −5), are calculated by eq 1 to combine
with rate constants of log (k/M−1 s−1) = −5sN. For typical
values of sN (0.6 to 1.0), this term translates into second-order
rate constants in the range of 10−5 < k(M−1 s−1) < 10−3 at 20
°C, corresponding to slow reactions at typical concentrations
for synthetic transformations. One can, therefore, expect the
quinones 1a−e to react at room temperature with the
nucleophiles located below them in Figure 13, whereas
reactions with nucleophiles positioned above the corresponding
quinones should not occur readily.
This qualitative rule summarizes not only the reactions
described in this work but also various results reported in the
literature. Thus, Figure 13 explains, why 2,4-dimethylpyrrole,
but not 2-ethylpyrrole and 1,2,5-trimethylpyrrole, react with
1,4-benzoquinone (1a) at room temperature.22 From the
calculated rate constant of 6 × 10−10 M−1 s−1 for the reaction of
pyrrole (N = 4.61, sN = 1.0) with a conjugate position of
chloranil (1c), one would derive that 20% conversion of the
reaction in neat pyrrole would take about 7000 h [c(pyrrole) =
14 M in neat pyrrole], if the solvent effect on N is neglected;
this number is in reasonable agreement with the experimental
value of 150 h.23 Horner’s observation of the formation of
adduct 19 in the uncatalyzed reaction of indole with
tetrachloro-o-quinone (1e) at ambient temperature (Scheme
15) is also in line with the relative position of these substrates
in Figure 13.24
tautomerization; alternatively, the initial adducts are oxidized to
give amino-substituted quinones.
From the nucleophilicity parameters for isocyanides (N ≈
5),7 one can derive that they will not react at room temperature
with 1a. Reactions of 1a with phenylisocyanide in boiling
toluene or xylene have been reported, however.29
A three-parameter equation cannot be expected to give an
accurate description of the whole field of organic reactivity, and
we have repeatedly emphasized the semiquantitive character of
eq 1.6 However, with a typical confidence limit of a factor of
10−100, eq 1 allows the prediction of the rates of polar organic
reactions in a range of 40 orders of magnitude.30 We were
delighted to find that the reactions of quinones with n- and π-
nucleophiles also follow eq 1, which could not a priori be
expected because of the known tendency of quinones to act as
one-electron oxidants. As a consequence, it is now possible to
predict unprecedented reactions of quinones with nucleophiles
by combining the E parameters reported in this work with the
manifold of N and sN parameters listed in our database.7
Hydride abstractions belong to the most important
applications of quinones.3 In a subsequent article, we will
demonstrate that the E-parameters reported in this work can
furthermore be used to analyze the mechanisms involved in
these reactions and to predict the corresponding rate constants.
EXPERIMENTAL SECTION
■
Materials. Commercially available 1a was purified by sublimation
before use. 1b was prepared by chlorination and subsequent oxidation
of 1,4-dimethoxybenzene as reported in the literature.31 Commercially
available 1c was recrystallized from chloroform. Silyl ketene acetals
2(a, a′, b, d, e) were prepared by silylation of the deprotonated esters
according to ref 32. Silyl enol ether 2f was prepared from
acetophenone as reported in the literature.33 Enamines 2g and 2h
were synthesized by condensation of the cycloalkanones with
morpholine according to a literature procedure.34 N-deuterated-
morpholine was synthesized by deuterium exchange of morpholine
with D4-methanol followed by evaporation of the remaining methanol
(3×) before it was dried with sodium. All other chemicals were
purchased from commercial sources and used without further
purification.
Kinetics. Most rates of reactions were determined photometrically
in dry acetonitrile or in freshly distilled dry CH2Cl2. Fast reactions
were determined by using the stopped-flow technique. Slow reactions
were measured by conventional photodiode array UV−vis spectrom-
eters or 1H NMR. The temperature was kept constant at 20 0.1 °C
by using a circulating bath thermostat.
Scheme 15. Reaction of Indole with Tetrachloro-o-quinone
1e24
ASSOCIATED CONTENT
* Supporting Information
■
S
Details of the kinetic experiments, synthetic procedures, X-ray
crystal structure determination, and quantum chemical
calculations as well as NMR spectra of all characterized
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Although we had previously reported the noncatalyzed
reaction of DDQ with trimethyl-2-methylallylsilane,5 1,4-
benzoquinone (1a), and other nonactivated quinones require
Lewis acid catalysis to react with allylsilanes.25 A similar
situation is encountered for the reactions with silylated enol
ethers. Though they undergo noncatalyzed reactions with
DDQ,5 their reactions with nonactivated quinones, as 1a, have
been achieved under catalysis of trityl perchlorate26 or lithium
perchlorate.27 The more nucleophilic enamines, on the other
hand, undergo noncatalyzed reactions also with unactivated
quinones.28 As most primary and secondary amines have N
values greater than 10, they undergo Michael additions to the
parent quinone 1a to give substituted hydroquinones by
AUTHOR INFORMATION
Corresponding Author
herbert.mayr@cup.uni-muenchen.de
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the China Scholarship Council (fellowship to X.G.)
and the Deutsche Forschungsgemeinschaft (SFB 749, Project
■
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(20) Frisch, M. J.; Trucks, G. W.; Schlegel, H.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;
Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.;
Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega,
N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;
Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas; Foresman, J.
B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, Revision A.02;
Gaussian, Inc.: Wallingford, CT, 2009.
(21) It can be assumed that the reactions of π-nucleophiles at C-Cl
positions proceed analogously but from the higher reactivities of the
C−F positions in 1d compared with the C−Cl positions in 1c one can
derive that breaking of the C−F bond in the reactions of 1d cannot be
far advanced in the transition state.
(22) (a) Fischer, H.; Treibs, A.; Zaucker, E. Chem. Ber. 1959, 92,
2026−2029. (b) N for 2-ethylpyrrole can be assumed to be in
between those for pyrrole and 2,4-dimethylpyrrole.
B1) for financial support. We are grateful to Dr. Peter Mayer
for the X-ray diffraction experiments. Furthermore, we thank
Dr. Armin R. Ofial for help during preparation of this
manuscript. Dedicated to Professor Johann Mulzer on the
occasion of his 70th birthday.
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