Quantification and Theoretical Analysis of the Electrophilicities of Michael Acceptors

Article abstract of DOI:10.1021/jacs.7b05106

In order to quantify the electrophilic reactivities of common Michael acceptors, we measured the kinetics of the reactions of monoacceptor-substituted ethylenes (H₂C=CH-Acc, 1) and styrenes (PhCH=CH-Acc, 2) with pyridinium ylides 3, sulfonium ylide 4, and sulfonyl-substituted chloromethyl anion 5. Substitution of the 57 measured second-order rate constants (log k) and the previously reported nucleophile-specific parameters N and s_N for 3-5 into the correlation log k = s_N(E + N) allowed us to calculate 15 new empirical electrophilicity parameters E for Michael acceptors 1 and 2. The use of the same parameters s_N, N, and E for these different types of reactions shows that all reactions proceed via a common rate-determining step, the nucleophilic attack of 3-5 at the Michael acceptors with formation of acyclic intermediates, which subsequently cyclize to give tetrahydroindolizines (stepwise 1,3-dipolar cycloadditions with 3) and cyclopropanes (with 4 and 5), respectively. The electrophilicity parameters E thus determined can be used to calculate the rates of the reactions of Michael acceptors 1 and 2 with any nucleophile of known N and s_N. DFT calculations were performed to confirm the suggested reaction mechanisms and to elucidate the origin of the electrophilic reactivities. While electrophilicities E correlate poorly with the LUMO energies and with Parr's electrophilicity index ω, good correlations were found between the experimentally observed electrophilic reactivities of 44 Michael acceptors and their calculated methyl anion affinities, particularly when solvation by dimethyl sulfoxide was taken into account by applying the SMD continuum solvation model. Because of the large structural variety of Michael acceptors considered for these correlations, which cover a reactivity range of 17 orders of magnitude, we consider the calculation of methyl anion affinities to be the method of choice for a rapid estimate of electrophilic reactivities.

Full text of DOI:10.1021/jacs.7b05106

Article
pubs.acs.org/JACS
Quantification and Theoretical Analysis of the Electrophilicities of
Michael Acceptors
Dominik S. Allgauer, Harish Jangra, Haruyasu Asahara, Zhen Li, Quan Chen, Hendrik Zipse,*
̈
Armin R. Ofial,* and Herbert Mayr*
Department Chemie, Ludwig-Maximilians-Universitat Munchen, Butenandtstrasse 5-13, 81377 Munchen, Germany
̈
̈
̈
S
* Supporting Information
ABSTRACT: In order to quantify the electrophilic reactivities
of common Michael acceptors, we measured the kinetics of the
reactions of monoacceptor-substituted ethylenes (H2CCH-
Acc, 1) and styrenes (PhCHCH-Acc, 2) with pyridinium
ylides 3, sulfonium ylide 4, and sulfonyl-substituted chloro-
methyl anion 5. Substitution of the 57 measured second-order
rate constants (log k) and the previously reported nucleophile-
specific parameters N and sN for 3−5 into the correlation log k
= sN(E + N) allowed us to calculate 15 new empirical
electrophilicity parameters E for Michael acceptors 1 and 2.
The use of the same parameters sN, N, and E for these different
types of reactions shows that all reactions proceed via a
common rate-determining step, the nucleophilic attack of 3−5 at the Michael acceptors with formation of acyclic intermediates,
which subsequently cyclize to give tetrahydroindolizines (stepwise 1,3-dipolar cycloadditions with 3) and cyclopropanes (with 4
and 5), respectively. The electrophilicity parameters E thus determined can be used to calculate the rates of the reactions of
Michael acceptors 1 and 2 with any nucleophile of known N and sN. DFT calculations were performed to confirm the suggested
reaction mechanisms and to elucidate the origin of the electrophilic reactivities. While electrophilicities E correlate poorly with
the LUMO energies and with Parr’s electrophilicity index ω, good correlations were found between the experimentally observed
electrophilic reactivities of 44 Michael acceptors and their calculated methyl anion affinities, particularly when solvation by
dimethyl sulfoxide was taken into account by applying the SMD continuum solvation model. Because of the large structural
variety of Michael acceptors considered for these correlations, which cover a reactivity range of 17 orders of magnitude, we
consider the calculation of methyl anion affinities to be the method of choice for a rapid estimate of electrophilic reactivities.
INTRODUCTION
log k20°C = sN(E + N)
(1)
■
Michael additions belong to the most important C−C-bond-
forming reactions in organic chemistry.1 Although kinetic
investigations of numerous Michael additions have been
reported in the past,1b,2 a general method to predict the
corresponding reactivities and selectivities is still missing.
It has been demonstrated that within narrow families of
Michael acceptors, relative reactivities correlate with the
corresponding LUMO energies.3 Parr’s electrophilicity index,
which is defined as “the square of its electronegativity divided
by its chemical hardness”,4 has also been reported to be a
measure for relative reactivities of structurally related electro-
philes.5−7 In some reaction series, correlations with the local
electrophilicity index defined as the product of the global
electrophilicity index and the Fukui function at the reaction
site8 have also been analyzed.9−12
where E is a nucleophile-independent electrophilicity parame-
ter, N is an electrophile-independent nucleophilicity parameter,
and sN is an electrophile-independent nucleophile-specific
susceptibility parameter, usually in the range 0.5 < sN < 1.2.13
In previous characterizations of electrophilicities of Michael
acceptors, we have focused on nitro- and 1,1-diacceptor-
substituted ethylenes, which give persistent anions in reactions
with stabilized carbanions (reference nucleophiles) in DMSO
solution (Scheme 1).14 The kinetics of these reactions were
usually monitored photometrically.
This method, which allowed us to characterize the
electrophilicities of a large variety of Michael acceptors, could
not be adapted to the investigation of the synthetically most
important Michael acceptors, for example, monoacceptor-
substituted ethylenes, because the nucleophilic attack of
stabilized carbanions at acrylates, acrylonitrile, vinyl ketones,
or vinyl sulfones is usually reversible due to the low stabilization
In systematic investigations, we have shown that rate
constants for the reactions of carbenium ions, Michael
acceptors, and other sp2 hybridized electrophiles with n-
(amines, alkoxides, etc.), π- (alkenes, arenes, resonance
stabilized carbanions, etc.), and σ-nucleophiles (hydride donors,
alkylzirconocenes, etc.) can be expressed by the correlation
Received: May 17, 2017
© XXXX American Chemical Society
A
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these electrophilicities E, the rate constants of the reactions of 1
and 2 with any nucleophile of known N and sN values can be
predicted with high reliability. Quantum chemical calculations
are then employed to elucidate the origin of the observed
electrophilicities.
Scheme 1. Reference Reactions for the Determination of
Electrophilic Reactivities of 1,1-Diacceptor-Substituted
Olefins
RESULTS AND DISCUSSION
General. Since the (3 + 2)-cycloadditions (Huisgen
reactions) of Michael acceptors 1 and 2 with pyridinium ylides
■
Scheme 2. Concerted and Stepwise Cycloadditions of
Pyridinium Ylides 3 with Acceptor-Substituted Olefins 1 and
2
of the resulting carbanions. Other groups have circumvented
this problem by performing the kinetic investigations in
aqueous or alcoholic solution, where the initially generated
carbanions are immediately trapped by proton transfer from the
solvent.15−24
A method to characterize Michael acceptor reactivities in
aprotic solvents (DMSO) has recently been employed for the
characterization of 1,2-diacceptor substituted ethylenes. By
employing nucleophiles which give adducts that undergo fast
subsequent intramolecular reactions, the reversibility of the C−
C-bond-forming step could be suppressed.25
We now report on the kinetics of the reactions of Michael
acceptors 1a−1i and 2a−2f with pyridinium ylides 3a−3f,
sulfonium ylide 4, and the sulfonyl-chloro-substituted methyl
anion 5 (Chart 1) and show that all reactions of these
structurally diverse nucleophiles with simple Michael acceptors
proceed with rate determining formation of one C−C-bond
followed by fast cyclization. In addition, we report that the rate
constants of all of these reactions follow eq 1, which allowed us
to determine the nucleophile-independent electrophilicity
parameters E for Michael acceptors 1a−1i and 2a−2f. With
Chart 1. Electrophilicities of Acceptor-Substituted Olefins 1
and 2 Investigated in This Work by Using Pyridinium Ylides
3a−f, Sulfonium Ylide 4, and Carbanion 5 as Structurally
Scheme 3. Mechanisms for the Reactions of Acceptor-
Substituted Olefins 1 with (a) Sulfonium Ylide 4 and (b)
Carbanion 5
a
Diverse Reference Nucleophiles
3 involve 6 electrons ([4π + 2π]), concerted (kconc; Scheme 2,
right) or stepwise (k2; Scheme 2, left) mechanisms have to be
considered.29−31 In stepwise processes, intermediate betaines
are formed (k2) which cyclize (krc) to give tetrahydroindolizines
(Scheme 2). For other 1,3-dipolar cycloaddition reactions,
stepwise mechanisms via diradical intermediates have also been
considered.32−34 A stepwise mechanism via zwitterionic
intermediates has recently been reported for the 1,3-dipolar
cycloadditions of pyridinium ylides with substituted benzyli-
dene malononitriles and chalcones.26
a
Ts = p-tosyl. Reactivity parameters N/sN in DMSO are from the
following references: for 3a−f, ref 26; for 4, ref 27; and for 5, ref 28.
B
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Scheme 4. Synthesis of the Indolizines 7
Scheme 7. Reactions of Chloro(phenylsulfonyl)-Stabilized
Carbanion 5 (Generated from 13) with Alkyl Acrylates 1a−c
Scheme 8. 2:1-Product Formation by the Reaction of
Carbanion 5 (Generated by Deprotonation of 13) with
Methyl Acrylate 1a (2 equiv)
Scheme 5. Reactions of Michael Acceptors 2 with
Pyridinium Ylides 3
Figure 1. (a) Decay of the absorbance of 3d ([3d]0 = 5 × 10−5 M) at
427 nm during the reaction with 1e ([1e]0 = 5.22 × 10−4 M) in
DMSO at 20 °C. (b) Linear correlation of kobs with the concentration
of 1e.
formation of intermediate betaines or acceptor-stabilized
carbanions, respectively (k2; Scheme 3). The subsequent ring
closures (krc) to cyclopropanes are usually fast pro-
cesses.27,28,35−37
Products. The reactions of Michael acceptors 1 with
pyridinium ylides 3, generated by deprotonation of their
conjugate acids, 3·HX, in DMSO gave tetrahydroindolizines 6
as initial products (Scheme 4). Given that tetrahydroindolizines
had been reported to be unstable at ambient temperature,31 we
did not attempt the isolation of 6 but oxidized them with
chloranil to the corresponding indolizines 7, which were
obtained in 52−98% yield after purification (Scheme 4).
The analogous (3 + 2)-cycloaddition of ethyl methacrylate 1i
with pyridinium ylide 3e (generated in situ from 3e·HBr and
NEt3) and subsequent decarboxylative oxidation with chloranil
was reported previously.38 The reaction of ethyl crotonate (2a)
with 3c·HBr under the conditions of the reactions in Scheme 4
furnished 2-methyl-substituted indolizine 8a in 84% yield.
Scheme 6. Cyclopropanations of Michael Acceptors 1 with
Sulfonium Ylide 4
a
a
For diastereomeric ratios see the Supporting Information.
Further 2-substituted indolizines were obtained by a
combination of styrene-derived Michael acceptors 2b−f with
pyridinium salts 3·HX under biphasic conditions (CH2Cl2/
aqueous NaOH). The initially formed tetrahydroindolizines 9
The reactions of sulfonium ylide 4 and carbanion 5 with
Michael acceptors proceed stepwise, with initial irreversible
C
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Table 1. Experimental and Calculated Second-Order Rate
Constants for the Reactions of Michael Acceptors 1 and 2
with Ylides 3 and 4 or Carbanion 5 in DMSO at 20 °C
Table 1. continued
d
cycloaddition (ref 25). The previously reported electrophilicity value
of E(2f) = −18.82 (ref 14g) was derived only from the rate constant
e
for the reaction of 2f with 4 and is revised in this work. Second-order
rate constant k2 from ref 14g.
Figure 2. Correlation of (log k2)/sN for the reactions of Michael
acceptors 1c−h with nucleophiles 3−5 against the nucleophilicity
parameters N of 3−5 (DMSO, 20 °C). For all correlations, a slope of
1.0 was enforced, as required by eq 1 (individual correlations for all
electrophiles investigated are shown in the Supporting Information).
were not isolated but subsequently oxidized with chloranil as
displayed in Scheme 5.26
When 1 equiv of chloranil was employed, partial oxidation of
9 furnished ester- or cyano-substituted dihydroindolizines 10c
and 10e in 89 and 90% yield, respectively. Treatment of
tetrahydroindolizines 9 with 2 equiv of chloranil resulted in the
formation of indolizines 8 (Scheme 5). The reactions of
acceptor-substituted ethylenes 1a−c and 1e−h with sulfonium
ylide 4 in DMSO at ambient temperature gave cyclopropanes
12 (42−92% yield) by Michael-initiated ring closure (MIRC)
reactions with variable diastereoselectivities (Scheme 6).
Cyclopropanes were also obtained by the reactions of
carbanion 5 (generated by deprotonation of its conjugate
acid 13) with the alkyl acrylates 1a−c in DMSO at ambient
temperature (Scheme 7).
When 13 and 1a (2 equiv) were combined at low
temperature in THF with potassium tert-butoxide as the base,
cyclic β-keto ester 16 was formed by a 2-fold Michael addition
with subsequent Dieckmann condensation (Scheme 8, for the
detailed mechanism see Supporting Information). Analogous
4,4-disubstituted cyclohexane β-keto esters were previously
obtained when phenylacetonitriles or phenylacetates were
treated with 1a (2 equiv) under basic conditions (tBuOK,
THF, rt).39
Kinetic Studies. The kinetics of the reactions of acceptor-
substituted olefins 1 and 2 with pyridinium ylides 3, sulfonium
ylide 4, and carbanion 5 in DMSO at 20 °C were monitored
photometrically by following the disappearance of the
absorbances of nucleophiles 3−5 at or close to their absorption
maxima. Due to their low stabilities, nucleophiles 3 and 4 were
generated in solution by combining freshly prepared solutions
of 3·HX or 4·HBF4 and KOtBu (typically 1.05 equiv) in
a
b
Calculated by eq 1 from N, sN (Chart 1), and E from this table. Bis-
exponential decay of the absorbance was observed and only the initial
rate was used to determine k2. Not used for the determination of E as
the reaction rate may already be enhanced by a partially concerted
c
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Figure 3. Comparison of the electrophilic reactivities of Michael acceptors 1 and 2 with those of structurally diverse Michael acceptors 17a−z13g,14,25
(Abbreviations: ani = 4-methoxyphenyl, dma = 4-(dimethylamino)phenyl, pnp = 4-nitrophenyl).
Figure 4. Correlation of log kGSH (with kGSH in a DMSO/buffer
mixture at pH 7.4 from ref 23d, converted from M−1 min−1 to M−1
s−1) with the electrophilicity parameters E for five α,β-unsaturated
a
esters and one enone. The log kGSH for pent-1-en-3-one was used.
Figure 5. Gibbs energy surface for the reaction of methyl vinyl ketone
(1g) with pyridinium ylide 3c (SMD(DMSO)/B2PLYP/cc-pVTZ//
DMSO directly before each kinetic experiment. Carbanion 5
was prepared in solution by deprotonation of the correspond-
SMD(DMSO)/B3LYP/6-31G(d,p) level, in kJ mol−1).
ing CH acid 13 with KOtBu (1.00−1.05 equiv) in dry THF at
−78 °C. Then, small amounts of the thus generated stock
before each kinetic experiment. Pseudo-first-order conditions
were achieved by using electrophiles 1 and 2 in high excess
solution were dissolved in DMSO at room temperature directly
E
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different reaction products (tetrahydroindolizines 6 and 9
(Schemes 4 and 5) and cyclopropanes 12 and 15 (Schemes 6
and 7)) all investigated reactions proceed via a common rate-
determining step: the initial C−C-bond formation to the
intermediate betaines or carbanions. It is, therefore, possible to
directly compare the electrophilicities of Michael acceptors 1
and 2 derived in this work from stepwise 1,3-dipolar
cycloadditions (Huisgen reactions) and cyclopropanations by
MIRC reactions with electrophilicities previously derived from
the kinetics of carbanion additions as illustrated in Scheme 1.
Figure 3 compares the electrophilic reactivities of Michael
acceptors determined in this work (1, 2) with previously
reported electrophilicities of bis-acceptor-substituted ethylenes
(17). With −24.7 < E < − 7.5, a reactivity range of 17 orders of
magnitude is covered for reactions with nucleophiles of sN = 1,
corresponding to relative reaction times of 1 s versus 3 billion
years. In combination with the reported N and sN parameters of
more than 1000 nucleophiles,13g eq 1 can now be used to
predict rate constants for a large variety of potential reactions of
Michael acceptors 1, 2, and 17 with nucleophiles and thus
define their synthetic potential.
Figure 6. Transition states for stepwise and concerted reaction of
methyl vinyl ketone (1g) with pyridinium ylide 3c (SMD(DMSO)/
B3LYP/6-31G(d,p) structures). Distances are in pm, and angles are in
degrees. Charge parameters were obtained by summing Mulliken
atomic charges over all centers of the two reactants.
(≥10 equiv) over nucleophiles 3−5, which resulted in
monoexponential decays of the nucleophiles’ UV−vis absor-
bances. First-order rate constants kobs (s−1) were then derived
by least-squares fitting of the exponential function At = A0·
exp(−kobst) + C to the time-dependent absorbances At (Figure
1a). Correlations of kobs with the concentrations of Michael
acceptors 1 and 2 were linear (Figure 1b). The second-order
rate constants k2 (M−1 s−1) listed in Table 1 were derived from
the slopes of the linear kobs versus [1] (or [2]) correlations (see
Supporting Information for the individual correlations of all
investigated reactions).
The rates of formation of covalent bonds between
nucleophiles and electrophiles have furthermore been discussed
to be useful parameters for identifying biological targets40 and
predicting toxicological effects.23 In this context, Schuurmann
̈
̈
If the reactions of Michael acceptors 1 and 2 with ylides 3
and 4 proceed stepwise with rate-determining formation of the
intermediate betaines, then the measured second-order rate
constants equal k2 as defined in Schemes 2 and 3a. Analogously,
the observed rate constants for the reaction of carbanion 5 with
Michael acceptors 1a−c correspond to k2 (Scheme 3b) if the
formation of the carbanionic intermediates 14 (Scheme 7) is
rate-determining. As the rates of attack of nucleophiles at
electron-deficient π-systems have previously been shown to
follow eq 1, this equation may also be suitable to correlate the
rate constants listed in Table 1. Figure 2 shows that the
correlations of (log k2)/sN for the reactions of electrophiles 1
and 2 with ylides 3 and 4 as well as with carbanion 5 versus the
corresponding nucleophilicity parameters N are indeed linear
with a slope of roughly 1.0 as required by eq 1, indicating a
common rate-determining step for these different reactions.
Though only two rate constants for the reactions with
sulfonium ylide 4 and one rate constant for the reaction with
carbanion 5 are shown in Figure 2, the matching of these k2
values with the correlation lines is quite remarkable, as the N
values of these nucleophiles (abscissa of Figure 2) have been
derived from the rates of their reactions with quinone methides
and benzhydrylium ions.
and co-workers have determined rate constants log kGSH for the
Michael additions of glutathione (GSH) to a set of 58 α,β-
unsaturated carbonyl compounds.23d The fair linear correlation
of log kGSH for the reactions with six Michael acceptors, for
which E parameters have been determined in this study (Figure
4), indicates that the electrophilicity parameters E may also be
applicable for quantitative structure−activity relationships.41−43
Santelli and co-workers reported linear relationships of
Hammett σp parameters with the reduction potentials (E1/2
)
and frontier orbital energies of a series of Michael acceptors.7 In
our study, neither log k for the reactions with pyridinium ylide
3a nor electrophilicities E of monosubstituted ethylenes 1a-1h
correlate well with Hammett’s σp and σp constants,44
−
respectively (see Supporting Information, Section 4). Whereas
SO2F was found to be the best electron-acceptor substituent in
arenes (Hammett constants) as well as in vinylic position (our
data), the high electrophilicity of benzoyl substituted ethylenes
(and also of benzoyl substituted styrenes) cannot be predicted
by Hammett substituent constants, confirming the need of a
separate Michael acceptor reactivity scale.
Quantum Chemical Calculations. In order to examine
the conclusions drawn from the kinetic investigations by an
independent method and to characterize the transition states of
these reactions more closely, we have investigated the potential
energy surfaces (PES) for the reactions of pyridinium ylide 3c
with four Michael acceptors of widely differing electrophilicities
(1d, 1f, 1g, and 2e) at the SMD(DMSO)/B2PLYP/cc-pVTZ//
SMD(DMSO)/B3LYP/6-31G(d,p)45,46 level of theory. Since
the results for all four systems were similar (Figures S25−S29),
only the reaction of 3c with methyl vinyl ketone (1g) will now
be discussed explicitly. The free energy surface in Figure 5
reveals a stepwise mechanism as the lowest energy pathway
(see also Figure S25 for ΔHsol‑opt surface and Figure S26 for
results at different levels of theory). Nucleophilic attack of 3c at
the terminal position of vinyl ketone 1g gives zwitterion ZW1
over a free energy barrier of 63.3 kJ mol−1. The barrier for the
collapse of this adduct to 5-membered ring adduct 6 is much
lower than that for the reverse reaction back to the reactants,
Electrophilicity parameters E for acceptor-substituted olefins
1 and 2 in the first column of Table 1 were determined by least-
squares minimization [minimization of Δ2 = ∑(log k2 − sN(N
+ E))2] considering the rate constants of their reactions with
pyridinium ylides 3a−e, sulfonium ylide 4, and carbanion 5.
The rate constant for the reaction of acrylonitrile 1f with
quinolinium ylide 3f (marked by footnote c in Table 1)
deviates by a factor of 18 from k2 predicted by using eq 1, which
is still within the limit of confidence of eq 1 (that is, within 2
orders of magnitude) but also might be due to a low degree of
concertedness of the reaction. Therefore, this reaction was not
considered for the determination of the electrophilicity
parameter E of acrylonitrile 1f.
All 57 measured rate constants (k2exp) in Table 1 (except
one) agree within 1 order of magnitude with the rate constants
(k2calcd) calculated by eq 1. This indicates that despite the
F
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Table 2. Quantum Chemically Calculated Frontier Orbital Energies, Global (ω), and Local (ωβ) Electrophilicities As Well As
Methyl Anion Affinities (MAAs) of Michael Acceptors
−MAA (kJ mol−1
)
a
b
b
b
b
c
d
Michael acceptor
E
εHOMO (Hartree)
εLUMO (Hartree)
global ω (eV)
local ωβ (eV)
ΔGgas
ΔGsol‑sp
1a
−18.84
−19.07
−20.22
−23.54
−18.36
−19.05
−16.76
−15.25
−22.77
−12.09
−23.59
−24.52
−24.69
−24.60
−23.01
−19.39
−16.63
−13.85
−19.49
−17.79
−15.71
−14.07
−11.31
−7.50
−20.55
−19.36
−17.33
−13.30
−12.93
−12.76
−11.32
−10.80
−10.28
−10.11
−9.42
−0.27299
−0.27018
−0.26291
−0.23432
−0.27133
−0.28955
−0.24738
−0.24946
−0.26630
−0.32333
−0.26444
−0.23332
−0.23960
−0.24292
−0.23367
−0.23235
−0.26113
−0.25556
−0.26528
−0.27664
−0.30733
−0.27143
−0.29924
−0.26834
−0.23512
−0.25831
−0.25656
−0.21263
−0.25143
−0.20434
−0.22045
−0.23815
−0.22917
−0.23995
−0.25994
−0.25084
−0.18246
−0.18808
−0.18661
−0.20491
−0.21214
−0.18767
−0.20226
−0.21015
−0.04454
−0.04291
−0.04079
−0.03058
−0.05219
−0.05700
−0.05476
−0.07147
−0.03698
−0.06439
−0.03391
−0.06275
−0.06449
−0.07488
−0.06919
−0.07737
−0.08298
−0.09700
−0.05705
−0.07861
−0.11295
−0.09656
−0.11734
−0.07201
−0.06617
−0.10948
−0.11015
−0.08495
−0.08056
−0.07478
−0.08670
−0.09709
−0.08527
−0.09406
−0.10707
−0.09360
−0.07722
−0.07918
−0.07661
−0.08668
−0.08977
−0.08470
−0.09208
−0.09719
1.50
1.47
1.41
1.17
1.62
1.76
1.61
1.97
1.36
1.97
1.31
1.75
1.80
2.04
1.90
2.11
2.26
2.67
1.70
2.17
3.09
2.63
3.25
2.01
1.83
3.09
3.12
2.36
2.19
2.05
2.40
2.71
2.34
2.60
3.00
2.57
2.18
2.23
2.14
2.45
2.53
2.45
2.67
2.84
0.62
0.61
0.58
0.49
0.37
0.82
0.60
0.44
0.52
0.98
0.51
0.39
0.36
0.47
0.43
0.42
0.56
0.59
0.60
0.55
0.92
0.59
0.77
0.81
0.46
0.24
0.28
0.70
0.62
0.63
0.65
0.81
0.73
0.70
0.88
0.78
0.54
0.55
0.53
0.61
0.62
0.62
0.68
0.70
−205.5
−203.4
−205.7
−187.1
−246.0
−205.1
−222.8
−251.9
−189.9
−295.9
−187.1
−186.9
−219.7
−190.0
−207.7
−231.4
−268.2
−264.6
−246.9
−223.1
−264.1
−260.8
−301.9
−355.3
−284.5
−266.3
−281.9
−290.2
−344.3
−311.2
−318.9
−311.1
−330.7
−331.9
−325.4
−344.7
−295.6
−297.7
−284.6
−312.1
−314.8
−329.6
−344.2
−354.2
−80.7
−75.1
−71.6
−59.6
−96.8
−109.4
−104.2
−116.7
−51.9
−160.5
−49.8
1b
1c
1d
1e
1f
1g
1h
1i
1j
2a
2b
−36.1
−51.8
−66.1
−60.4
2c
2d
2e
2f
−74.8
2g
−113.3
−123.8
−93.1
2h
17a
17b
17c
17d
17e
17f
17g
17h
17i
17j
17k
17l
17m
17n
17o
17p
17q
17r
17s
17t
17u
17v
17w
17x
17y
17z
−74.2
−132.4
−113.9
−149.8
−174.8
−104.8
−75.2
−86.8
−141.3
−155.9
−135.3
−147.1
−161.9
−154.4
−160.7
−177.4
−169.6
−120.4
−123.2
−130.7
−137.4
−141.3
−147.3
−163.6
−174.6
−9.15
−17.90
−17.29
−16.36
−16.11
−15.83
−13.39
−12.18
−11.87
a
b
c
Empirical electrophilicity parameter as defined in eq 1. Calculated at B3LYP/6-31G(d,p) level in the gas phase. Calculated at B3LYP/6-311+
d
+G(3df,2pd)//B3LYP/6-31G(d,p) level in the gas phase. Based on methyl anion affinities (ΔGgas), which were corrected for solvent effects by
adding single point solvation energies calculated at B3LYP/6-31G(d,p) using the SMD (solvent = DMSO) solvation model on gas phase optimized
geometries at the same level.
i.e., the formation of the first C−C-bond with formation of
ZW1 is rate-limiting.
stable diastereoisomer of 6 over a marginally higher barrier
(67.3 kJ mol−1).47 The side-by-side comparison of the
transition states for the stepwise and the concerted cyclo-
additions shown in Figure 6 clearly documents the large
similarity of both processes. The angle of attack, the largely
different lengths of the forming C−C bonds, and the charge
transfer from the attacking nucleophile to the electrophile (0.28
or 0.29 electrons) are almost the same for the transition state of
A second reaction pathway starting from the same
zwitterionic intermediate, ZW1, may lead to pyridine
elimination and formation of a cyclopropane. In agreement
with the much higher barrier calculated for this pathway,
cyclopropanes were not detected among the reaction products.
The stepwise formation of the 5-membered ring adduct 6
competes with a concerted process, which yields a slightly less
G
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Again, the calculated potential energy surface confirms our
interpretation of the kinetic data.
In order to elucidate methods for predicting the synthetic
potential of Michael acceptors so far not yet experimentally
characterized, we investigated correlations of experimentally
determined electrophilic reactivities with various quantum
chemically calculated properties:
Methyl anion affinities (MAA = −ΔG298) were calculated as
the Gibbs reaction energies for the methyl anion additions
shown in eq 2.
Following the methodology used in earlier studies,48 gas phase
MAA values were calculated at B3LYP/6-311++G(3df,2pd)//
B3LYP/6-31G(d,p) level45 (see Supporting Information for
details). In addition, solvent effects were probed by additional
single-point calculations with the SMD continuum solvation
model for dimethyl sulfoxide (DMSO)46 at B3LYP/6-31G(d,p)
level as well as full geometry optimization with this solvation
model.
Figure 7. Correlation between experimentally determined electro-
philicities (E) and gas phase lowest unoccupied molecular orbital
energies (εLUMO) calculated at B3LYP/6-31G(d,p) level for the 44
electrophiles listed in Figure 3.
Parr’s electrophilicity indices ω (eq 3) for 44 Michael
acceptors were calculated from the electronic chemical
potential μ (eq 4) and the chemical hardness η (eq 5).
ω = μ2/2η
(3)
1
2
μ = (εHOMO + εLUMO
)
(4)
(5)
η = (εLUMO − εHOMO
)
Values for the electronic chemical potential μ and the chemical
hardness η were derived from orbital energies for the lowest
unoccupied molecular orbital (εLUMO) and the highest occupied
molecular orbital (εHOMO) calculated at gas phase B3LYP/6-
31G(d,p) level (in Hartree). Following the practice in ref 5,
Parr’s electrophilicity index ω is then expressed in eV. Local
electrophilicity indices ωβ at the β-centers of Michael acceptors
(eq 2) were calculated using the nucleophilic Fukui function
(f+k) as defined in eq 6.
Figure 8. Change of gas phase HOMO and LUMO energies (in
Hartree) by the introduction of a β-phenyl group at ethyl acrylate (1b
→ 2b).
the stepwise pathway and the concerted, but very asynchronous
cycloaddition reaction.
Using the same theoretical approach, the potential and Gibbs
energy surfaces in DMSO have also been calculated for the
reactions of pyridinium ylide 3c with Michael acceptors 1d, 1f,
and 2e (Figures S27−S29). In all three cases, the barriers for
the stepwise and concerted cycloadditions are energetically
quite close, with a small preference for the stepwise pathway in
the reaction of 2e and an equally small preference for the
concerted pathway in the reactions of 1d and 1f. However, in
all of these reactions the structural and electronic characteristics
of the transition states for concerted pathway share the same
asynchronicity as those shown in Figures 5 and 6 for the
reaction of vinyl ketone 1g and thus confirm that all of these
(stepwise or concerted) pathways exhibit the reactivity
characteristics typical for the nucleophilic addition to Michael
acceptors, as derived from the kinetic investigations described
above.
Analogous calculations for the reaction of sulfonium ylide 4
with acrylonitrile (1f) also showed the rate-determining
formation of zwitterion 11, as suggested in Scheme 6, which
expels dimethyl sulfide over a barrier of only 5.2 kJ mol−1
(Figure S30). A slightly different approach of the two reactants
leads to a concerted process with a 2.3 kJ mol−1 higher Gibbs
activation energy, where ring closure and expulsion of dimethyl
sulfide start before the initial Michael addition is complete.
ωβ = ωf +
(6)
β
The condensed Fukui function for the nucleophilic attack at the
β-atom (f+β) in an electrophile was calculated using a procedure
from ref 8.
The most relevant calculated properties for the 44 Michael
acceptors shown in Figure 3 are listed in Table 2 (for further
quantum chemically calculated data, see the Supporting
Information).
Correlation with LUMO Energies and Parr’s electro-
philicity Index. Liu and co-workers49 as well as Yu and co-
workers3 have reported excellent correlations between electro-
philic reactivities of benzhydrylium ions and the corresponding
LUMO energies. However, Figure 5 in ref 3 shows that Michael
acceptors ArCHC(Acc)2 with different acceptor groups Acc
follow separate electrophilicity vs LUMO energy correlations.
In line with these observations, Figure 7 in this work shows that
LUMO energies are not a useful guide for predicting
electrophilic reactivities when a larger variety of Michael
acceptors are compared. Even inferior correlations are obtained
when using LUMO energies calculated with larger basis sets
(such as 6-311++G(3df,2pd), R2 = 0.362, Figure S10) or
H
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Figure 9. β-Phenyl effect on different descriptors for electrophilic reactivities of Michael acceptors (ΔGsol‑sp corresponds to the negative values of the
methyl anion affinities in DMSO solution, eq 2).
calculated in the presence of the SMD solvation model for
DMSO (R2 = 0.351, see Supporting Information).
potential μ (eq 4) is only slightly affected by the phenyl
substitution, whereas hardness η (eq 5) decreases and, as a
consequence, ω increases, in contrast to the experimentally
observed decrease of electrophilic reactivity. A certain portion
of the decrease of electrophilic reactivity by β-phenyl can
certainly be explained by a steric effect. However, whatever the
reason, it is obvious that (like LUMO energies) Parr’s
electrophilicity ω is not suitable to predict electrophilic
reactivities for a wider range of Michael acceptors, as shown
in Figure 10a. When moving from global (ω) to local
electrophilicity indices ωβ (eq 6), the correlations with
experimentally determined E parameters improve, but with R2
= 0.467 still remain unsatisfactory (Figure 10b). We note in
passing that the latter correlation does not improve with other
strategies for calculating local electrophilicity parameters (see
Supporting Information for details).
Excellent correlations between the electrophilic reactivities of
benzhydrylium ions and their Lewis acidities, represented by
pKR+ values or calculated methyl anion affinities have previously
been reported.51,52 While the high qualities of these correlations
can be assigned to the constant steric demand of these
electrophiles, a fair correlation between electrophilic reactivities
and the Lewis acidities pKR+ has also been observed for
carbocations of variable structure.53 For that reason, it appeared
promising to also examine the relationship between electro-
philicities and Lewis acidities of the Michael acceptors. Figure
11 shows the correlation between electrophilicities and
calculated gas phase methyl anion affinities. Though of
moderate quality, this correlation is already much better than
The teams of Contreras, Domingo, Perez, and Chamorro
have examined Parr’s electrophilicity index ω (eq 3) and
modifications thereof for rationalizing and predicting electro-
philic reactivities.11,50 Within the series of benzhydrylium ions,
good correlations have been found.50 They furthermore
observed good correlations between the electrophilicity
parameters of Michael acceptors and Parr’s electrophilicity
indices within families of closely related Michael acceptors, e.g.,
benzylidenemalononitriles.5,11 The good correlations obtained
within these families, however, do not allow a generalization.
While the authors explicitly predicted that introduction of a
phenyl group in β-position of methyl acrylate leads to an
increase of electrophilicity, the kinetic data reported in this
work show the opposite: Ethyl cinnamate (2b) is more than 5
orders of magnitude less electrophilic than ethyl acrylate (1b).
Figure 8 illustrates the β-phenyl effect on frontier orbital
energies.
It is a general phenomenon that conjugation raises HOMO
and lowers LUMO energy levels. For that reason, the large
reduction of electrophilicity by β-phenyl substitution is not in
line with the expectations on the basis of LUMO energies. The
same discrepancy arises with all other Michael acceptors as
shown in Figure 9. In all cases, β-phenyl substitution lowers
LUMO energies and at the same time decreases electrophilicity.
For a similar reason, Parr’s electrophilicity index ω (eq 3)
fails to predict the β-phenyl effect. Due to the simultaneous
raising of HOMO and lowering of LUMO, the electronic
I
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Figure 12. Correlation between experimentally determined electro-
philicities (E) and methyl anion affinities (−MAA = ΔGsol‑sp, in kJ
mol−1) in DMSO calculated at SMD(DMSO)/B3LYP/6-311++G-
(3df,2pd)//B3LYP/6-31G(d,p) level for the 44 electrophiles listed in
Figure 3.
those related to orbital energies (Figure 7 and Figure S3). A
good linear correlation was observed, however, when the
empirical electrophilicity parameters E (derived from kinetic
measurements) were plotted against the methyl anion affinities
calculated for DMSO solution (Figure 12).
The correlation did not improve significantly when the
methyl anion affinities calculated for DMSO-solvated gas-phase
optimized structures in Figure 12 were replaced by methyl
anion affinities derived from structures, which had been
geometrically optimized in DMSO solution (R2 = 0.8867,
Figure S19). For that reason, our discussion will focus on
correlations with the methyl anion affinities calculated for
DMSO-solvated gas-phase optimized structures. Let us first
compare the different slopes in Figures 11 and 12: The ratio of
these slopes (0.0758/0.1083 = 0.70) indicates that the
differences of the methyl anion affinities in the gas phase are
attenuated to 70% in DMSO solution. This information can
directly be derived from a plot of methyl anion affinities in
DMSO solution versus MAA in the gas phase (Figure S24).
Combination of eq 1 with the Eyring equation leads to
Figure 10. Correlation between experimentally determined electro-
philicities (E) and (a) global electrophilicity index ω and (b) local
electrophilicity index ωβ calculated at B3LYP/6-31G(d,p) level for the
44 electrophiles listed in Figure 3.
ΔG⧧ = 2.303RT[log(kBT/h) − sN(E + N)]
(7)
which can be rewritten as eq 8 for the reaction with a certain
nucleophile
ΔG⧧ = −2.303RTsNE + const
(8)
Insertion of the correlation derived in Figure 12 yields eq 9
ΔG⧧ = 0.61·sN·ΔGsol‐sp + const
′
(9)
which shows that in reactions of Michael acceptors with
nucleophiles of sN = 0.7 about 43% of the differences of the
Gibbs reaction energies are reflected in the transition states.
Figure 12 illustrates that the experimentally determined E
values deviate on average by 1.3 units from the correlated
values, while the maximum deviations are 3 units in E,
corresponding to a deviation of a factor of 100 in rate constants
for reactions with nucleophiles having a typical susceptibility
factor of sN = 0.7. We consider this as an excellent agreement in
view of the wide structural variety covered by the Michael
Figure 11. Correlation between experimentally determined electro-
philicities (E) and gas phase methyl anion affinities (−MAA = ΔGgas
,
kJ mol−1) calculated at B3LYP/6-311++G(3df,2pd)//B3LYP/6-31G-
(d,p) level for the 44 electrophiles listed in Figure 3.
J
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Article
Notes
acceptors in this investigation, which span 17 orders of
magnitude in electrophilicity E.
The authors declare no competing financial interest.
CONCLUSION
ACKNOWLEDGMENTS
■
■
Kinetic investigations show that the reactions of weakly
activated Michael acceptors with pyridinium ylides ((3 + 2)-
cycloadditions), a sulfonium ylide, and a phenylsulfonyl-
substituted chloromethyl anion (cyclopropanations) follow eq
1, indicating stepwise processes with a common rate-
determining step. This conclusion, which has been confirmed
by potential energy surface calculations, implies that a single set
of electrophilicity parameters E for Michael acceptors can be
used to calculate rate constants for ordinary Michael additions
(for example, additions of carbanions) as well as for a variety of
other reactions which proceed via rate-determining formation
of the first C−C σ-bond. By inclusion of these data in our
comprehensive electrophilicity scale, the direct comparison of
weak and strong electrophiles becomes possible. The electro-
philicities of the acceptor-substituted olefins investigated in this
work may also broaden the experimental basis for the ongoing
developments of the distortion/interaction energy model54 and
the activation strain model.55
Quantum chemical calculations show that neither LUMO
energies nor Parr’s electrophilicity index allow the prediction of
relative reactivities of structurally diverse Michael acceptors. In
contrast, a good correlation between electrophilic reactivities
and quantum chemically calculated methyl anion affinities in
DMSO solution was found, which may also be useful for
evaluating the toxicological profile of naturally occurring or
anthropogenic Michael acceptors. It is thus indicated that the
relative reactivities of different families of Michael acceptors
cannot be derived from orbital interactions of the reactants but
from the thermodynamics of the rate-determining step, as
postulated by the Bell−Evans−Polanyi principle.56
We thank the Deutsche Forschungsgemeinschaft for financial
support (SFB 749, projects B1 and C6) and the China
Scholarship Council for a fellowship to Z. L.
REFERENCES
■
(1) (a) Bergmann, E. D.; Ginsburg, D.; Pappo, R. Org. React. 1959,
10, 179−556. (b) Patai, S.; Rappoport, Z. In The Chemistry of Alkenes;
Patai, S., Rappoport, Z., Eds.; Wiley: New York, 1964; pp 469−584.
(c) Nagata, W.; Yoshioka, M. Org. React. 1977, 25, 255−476.
(d) Oare, D. A.; Heathcock, C. H. In Topics in Stereochemistry; Eliel, E.
L., Wilen, S. H., Eds.; Wiley-Interscience: New York, 1989; Vol. 18, pp
227−407. (e) Rappoport, Z. In Nucleophilicity; Harris, J. M.,
McManus, S. P., Eds.; American Chemical Society: Washington, DC,
1987; pp 399−424. (f) Oare, D. A.; Heathcock, C. H. In Topics in
Stereochemistry; Eliel, E. L., Wilen, S. H., Eds.; Wiley-Interscience:
Hoboken, NJ, 1991; Vol. 20, pp 87−170. (g) Perlmutter, P. In
Tetrahedron Organic Chemistry Series; Baldwin, J. E., Ed.; Pergamon:
Oxford, 1992; Vol. 9.
(2) (a) Bernasconi, C. F. Tetrahedron 1989, 45, 4017−4090.
(b) Rappoport, Z.; Ladkani, D. Chem. Scripta 1974, 5, 124−133.
(3) Zhuo, L.-G.; Liao, W.; Yu, Z.-X. Asian J. Org. Chem. 2012, 1,
336−345.
(4) Parr, R. G.; Szentpal
́
y, L. v.; Liu, S. J. Am. Chem. Soc. 1999, 121,
1922−1924.
(5) Domingo, L. R.; Per
́
ez, P.; Contreras, R. Tetrahedron 2004, 60,
6585−6591.
́ ́
(6) Domingo, L. R.; Ríos-Gutierrez, M.; Perez, P. Molecules 2016, 21,
748.
(7) Moraleda, D.; El Abed, D.; Pellissier, H.; Santelli, M. J. Mol.
Struct.: THEOCHEM 2006, 760, 113−119.
(8) Contreras, R. R.; Fuentealba, P.; Galvan
́ ́
, M.; Perez, P. Chem.
Phys. Lett. 1999, 304, 405−413.
(9) (a) Chattaraj, P. K.; Sarkar, U.; Roy, D. R. Chem. Rev. 2006, 106,
2065−2091. (b) Chattaraj, P. K.; Roy, D. R. Chem. Rev. 2007, 107,
PR46−PR74. (c) Chattaraj, P. K.; Giri, S.; Duley, S. Chem. Rev. 2011,
111, PR43−PR75.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b05106.
■
S
(10) Liu, S. In Chemical Reactivity Theory − A Density Functional
View; Chattaraj, P. K., Ed.; CRC Press: Boca Raton, FL, 2009; Chapter
13, pp 179−192.
Detailed experimental procedures and compound char-
acterization data, results of individual kinetic experi-
ments, and details of quantum chemical calculations
(PDF)
(11) (a) Aizman, A.; Contreras, R.; Per
889−895. (b) Per
Theoretical Aspects of Chemical Reactivity; Theoretical and Computa-
tional Chemistry series; Toro-Labbe, A., Ed.; Elsevier, Amsterdam,
́
ez, P. Tetrahedron 2005, 61,
́
ez, P.; Domingo, L. R.; Aizman, A.; Contreras, R. In
́
2007; Vol. 19, Chapter 9, pp 139−201.
(12) Wondrousch, D.; Bohme, A.; Thaens, D.; Ost, N.; Schuurmann,
̈
̈
̈
AUTHOR INFORMATION
■
G. J. Phys. Chem. Lett. 2010, 1, 1605−1610.
Corresponding Authors
*zipse@cup.uni-muenchen.de
*ofial@lmu.de
*herbert.mayr@cup.uni-muenchen.de
ORCID
Haruyasu Asahara: 0000-0002-1808-7373
Hendrik Zipse: 0000-0002-0534-3585
Armin R. Ofial: 0000-0002-9600-2793
Herbert Mayr: 0000-0003-0768-5199
Present Addresses
D.S.A.: Clariant Produkte (Deutschland) GmbH, 84504
Burgkirchen, Germany.
(13) (a) Mayr, H.; Patz, M. Angew. Chem., Int. Ed. Engl. 1994, 33,
938−957. (b) Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.;
Janker, B.; Kempf, B.; Loos, R.; Ofial, A. R.; Remennikov, G.;
Schimmel, H. J. Am. Chem. Soc. 2001, 123, 9500−9512. (c) Mayr, H.;
Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66−77. (d) Mayr, H.;
Ofial, A. R. Pure Appl. Chem. 2005, 77, 1807−1821. (e) Mayr, H.;
Ofial, A. R. J. Phys. Org. Chem. 2008, 21, 584−595. (f) Mayr, H.;
Lakhdar, S.; Maji, B.; Ofial, A. R. Beilstein J. Org. Chem. 2012, 8, 1458−
1478. (g) For a comprehensive database of nucleophilicity parameters
N, sN, and electrophilicity parameters E, see http://www.cup.lmu.de/
oc/mayr/DBintro.html.
(14) (a) Lucius, R.; Loos, R.; Mayr, H. Angew. Chem., Int. Ed. 2002,
41, 91−95. (b) Lemek, T.; Mayr, H. J. Org. Chem. 2003, 68, 6880−
6886. (c) Berger, S. T. A.; Seeliger, F. H.; Hofbauer, F.; Mayr, H. Org.
Biomol. Chem. 2007, 5, 3020−3026. (d) Kaumanns, O.; Lucius, R.;
Mayr, H. Chem. - Eur. J. 2008, 14, 9675−9682. (e) Lakhdar, S.;
Tokuyasu, T.; Mayr, H. Angew. Chem., Int. Ed. 2008, 47, 8723−8726.
(f) Kanzian, T.; Nicolini, S.; De Crescentini, L.; Attanasi, O. A.; Ofial,
H.A.: Department of Applied Chemistry, Faculty of Engineer-
ing, Osaka University, Osaka 565-0871, Japan.
Q.C.: Institut fur Anorganische and Angewandte Chemie,
̈
Universitat Hamburg, 20148 Hamburg, Germany.
̈
K
DOI: 10.1021/jacs.7b05106
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
A. R.; Mayr, H. Chem. - Eur. J. 2010, 16, 12008−12016. (g) Appel, R.;
Mayr, H. J. Am. Chem. Soc. 2011, 133, 8240−8251. (h) Zenz, I.; Mayr,
H. J. Org. Chem. 2011, 76, 9370−9378. (i) Asahara, H.; Mayr, H.
Chem. - Asian J. 2012, 7, 1401−1407.
(37) Riches, S. L.; Saha, C.; Filgueira, N. F.; Grange, E.; McGarrigle,
E. M.; Aggarwal, V. K. J. Am. Chem. Soc. 2010, 132, 7626−7630.
(38) Allgauer, D. S.; Mayr, H. Eur. J. Org. Chem. 2013, 6379−6388.
̈
(39) DeGraffenreid, M. R.; Bennett, S.; Caille, S.; Gonzalez-Lopez de
Turiso, F.; Hungate, R. W.; Julian, L. D.; Kaizerman, J. A.; McMinn, D.
L.; Rew, Y.; Sun, D.; Yan, X.; Powers, J. P. J. Org. Chem. 2007, 72,
7455−7458.
(15) (a) Ogata, Y.; Okano, M.; Furuya, Y.; Tabushi, I. J. Am. Chem.
Soc. 1956, 78, 5426−5428. (b) Finley, K. T.; Call, D. R.; Sovocool, G.
W.; Hayles, W. J. Can. J. Chem. 1967, 45, 571−573.
(40) Gersch, M.; Kreuzer, J.; Sieber, S. A. Nat. Prod. Rep. 2012, 29,
659−682.
(41) Mayr, H.; Ofial, A. R. SAR QSAR Environ. Res. 2015, 26, 619−
646.
(42) At pH 7.4, glutathione (GSH) was shown to react with enones
to give S-alkylation, terminal N-alkylation, and adducts of two-fold (S
(16) (a) Ogata, N.; Asahara, T. Bull. Chem. Soc. Jpn. 1966, 39, 1486−
̌
́ ́ ́
1490. (b) Sestakova, I.; Horak, V.; Zuman, P. Collect. Czech. Chem.
Commun. 1966, 31, 3889−3902. (c) Dienys, G. J.; Kunskaite, L. J. J.;
Vaitkevicius, A. K.; Klimavicius, A. V. Org. React. (Tartu), Engl. Ed.
1975, 12, 275−282. (d) Adomeniene, O.; Dienys, G.; Stumbreviciute,
Z. Org. React. (Tartu), Engl. Ed. 1978, 15, 38−44.
and N) alkylation: Slawik, C.; Rickmeyer, C.; Brehm, M.; Bohme, A.;
̈
(17) (a) Mallik, K. L.; Das, M. N. Z. Phys. Chem. 1960, 25, 205−216.
(b) Sanui, K.; Ogata, N. Bull. Chem. Soc. Jpn. 1967, 40, 1727.
(c) Shenhav, H.; Rappoport, Z.; Patai, S. J. Chem. Soc. B 1970, 469−
476. (d) Szczesna, J.; Kostecki, M.; Kinastowski, S. Rocz. Akad. Roln.
Poznaniu 1988, 192, 99−104. (e) Kostecki, M.; Szczesna, J.;
Kinastowski, S. Rocz. Akad. Roln. Poznaniu 1993, 256, 25−32.
(18) (a) Bunting, J. W.; Toth, A.; Heo, C. K. M.; Moors, R. G. J. Am.
Chem. Soc. 1990, 112, 8878−8885. (b) Heo, C. K. M.; Bunting, J. W. J.
Org. Chem. 1992, 57, 3570−3578.
Schuurmann, G. Environ. Sci. Technol. 2017, 51, 4018−4026.
̈
̈
(43) Mulliner, D.; Wondrousch, D.; Schuurmann, G. Org. Biomol.
̈
̈
Chem. 2011, 9, 8400−8412.
(44) Hansch, C.; Leo, A.; Hoekman, D. Exploring QSAR −
Hydrophobic, Electronic and Steric Constants; American Chemical
Society: Washington, DC, 1995.
(45) (a) Ditchfield, R.; Hehre, W. J.; Pople, J. A. J. Chem. Phys. 1971,
54, 724−728. (b) Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A. J.
Chem. Phys. 1980, 72, 650−654. (c) Clark, T.; Chandrasekhar, J.;
Spitznagel, G. W.; Schleyer, P. v. R. J. Comput. Chem. 1983, 4, 294−
301. (d) Dunning, T. H., Jr. J. Chem. Phys. 1989, 90, 1007−1023.
(e) Becke, A. D. J. Chem. Phys. 1993, 98, 5648−5652. (f) Grimme, S. J.
Chem. Phys. 2006, 124, 034108.
(46) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B
2009, 113, 6378−6396.
(47) As compounds 6 were not isolated but oxidized to give isolated
indolizines 7, the stereochemical course was not investigated.
(19) (a) Friedman, M.; Wall, J. S. J. Am. Chem. Soc. 1964, 86, 3735−
3741. (b) Friedman, M.; Cavins, J. F.; Wall, J. S. J. Am. Chem. Soc.
1965, 87, 3672−3682. (c) Friedman, M.; Wall, J. S. J. Org. Chem. 1966,
31, 2888−2894. (d) Friedman, M.; Romersberger, J. A. J. Org. Chem.
1968, 33, 154−157.
́ ́
(20) (a) Carsky, P.; Zuman, P.; Horak, V. Collect. Czech. Chem.
Commun. 1965, 30, 4316−4336. (b) Feit, B. A.; Pazhenchevsky, R.;
Pazhenchevsky, B. J. Org. Chem. 1976, 41, 3246−3250.
(21) (a) Ferry, N.; McQuillin, F. J. J. Chem. Soc. 1962, 103−113.
(b) Feit, B.-A.; Zilkha, A. J. Org. Chem. 1963, 28, 406−410. (c) Ring,
R. N.; Tesoro, G. C.; Moore, D. R. J. Org. Chem. 1967, 32, 1091−
1094.
(48) Byrne, P. A.; Kobayashi, S.; Wurthwein, E.-U.; Ammer, J.; Mayr,
̈
H. J. Am. Chem. Soc. 2017, 139, 1499−1511.
(49) Wang, C.; Fu, Y.; Guo, Q.-X.; Liu, L. Chem. - Eur. J. 2010, 16,
2586−2598.
(22) (a) Morton, M.; Landfield, H. J. Am. Chem. Soc. 1952, 74,
3523−3526. (b) Davies, W. G.; Hardisty, E. W.; Nevell, T. P.; Peters,
R. H. J. Chem. Soc. B 1970, 998−1004.
́
(50) (a) Chamorro, E.; Duque-Norena, M.; Perez, P. J. Mol. Struct.:
̃
THEOCHEM 2009, 896, 73−79. (b) Chamorro, E.; Duque-Norena,
̃
M.; Perez, P. J. Mol. Struct.: THEOCHEM 2009, 901, 145−152.
(51) Schindele, C.; Houk, K. N.; Mayr, H. J. Am. Chem. Soc. 2002,
124, 11208−11214.
́
(23) (a) Roberts, D. W.; Natsch, A. Chem. Res. Toxicol. 2009, 22,
592−603. (b) Schwobel, J. A. H.; Wondrousch, D.; Koleva, Y. K.;
̈
(52) (a) Mayr, H.; Ammer, J.; Baidya, M.; Maji, B.; Nigst, T. A.;
Ofial, A. R.; Singer, T. J. Am. Chem. Soc. 2015, 137, 2580−2599.
(b) Mayr, H.; Ofial, A. R. Acc. Chem. Res. 2016, 49, 952−965.
(53) Mayr, H.; Patz, M.; Gotta, M. F.; Ofial, A. R. Pure Appl. Chem.
1998, 70, 1993−2000.
Madden, J. C.; Cronin, M. T. D.; Schuurmann, G. Chem. Res. Toxicol.
̈
̈
2010, 23, 1576−1585. (c) Amslinger, S.; Al-Rifai, N.; Winter, K.;
Wormann, K.; Scholz, R.; Baumeister, P.; Wild, M. Org. Biomol. Chem.
̈
2013, 11, 549−554. (d) Bohme, A.; Laqua, A.; Schuurmann, G. Chem.
̈
̈
̈
Res. Toxicol. 2016, 29, 952−962.
(54) (a) Ess, D. H.; Houk, K. N. J. Am. Chem. Soc. 2008, 130,
10187−10198. (b) Bickelhaupt, F. M.; Houk, K. N. Angew. Chem., Int.
Ed. 2017, 56, 10070−10086.
́ ́
(24) Petnehazy, I.; Clementis, G.; Jaszay, Z. M.; Toke, L.; Hall, C. D.
̈
J. Chem. Soc., Perkin Trans. 2 1996, 2279−2284.
(25) Allgauer, D. S.; Mayr, H. Eur. J. Org. Chem. 2014, 2956−2963.
̈
(55) (a) van Zeist, W.-J.; Bickelhaupt, F. M. Org. Biomol. Chem. 2010,
(26) Allgauer, D. S.; Mayer, P.; Mayr, H. J. Am. Chem. Soc. 2013, 135,
̈
́
8, 3118−3127. (b) Fernandez, I.; Bickelhaupt, F. M. Chem. Soc. Rev.
15216−15224.
2014, 43, 4953−4967.
(27) Appel, R.; Hartmann, N.; Mayr, H. J. Am. Chem. Soc. 2010, 132,
17894−17900.
(56) (a) Bell, R. P. Proc. R. Soc. London, Ser. A 1936, 154 (882), 414−
429. (b) Evans, M. G.; Polanyi, M. Trans. Faraday Soc. 1938, 34, 11−
(28) Li, Z.; Chen, Q.; Mayer, P.; Mayr, H. J. Org. Chem. 2017, 82,
2011−2017.
24.
(29) Zugravescu, I.; Petrovanu, M. N-Ylid Chemistry; McGraw-Hill:
New York, 1976.
(30) (a) Mikhailovskii, A. G.; Shklyaev, V. S. Chem. Heterocycl.
Compd. 1997, 33, 243−265. (b) Jacobs, J.; Van Hende, E.; Claessens,
S.; De Kimpe, N. Curr. Org. Chem. 2011, 15, 1340−1362. (c) Kakehi,
A. Heterocycles 2012, 85, 1529−1577.
(31) Tsuge, O.; Kanemasa, S.; Takenaka, S. Bull. Chem. Soc. Jpn.
1985, 58, 3137−3157.
(32) Huisgen, R. J. Org. Chem. 1976, 41, 403−419.
(33) (a) Firestone, R. A. J. Org. Chem. 1968, 33, 2285−2290.
(b) Firestone, R. A. J. Org. Chem. 1972, 37, 2181−2191.
(34) Huisgen, R. J. Org. Chem. 1968, 33, 2291−2297.
(35) Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. Rev. 1997, 97,
2341−2372.
(36) Appel, R.; Mayr, H. Chem. - Eur. J. 2010, 16, 8610−8614.
L
DOI: 10.1021/jacs.7b05106
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX