Philicity of Acetonyl and Benzoyl Radicals: A Comparative Experimental and Computational Study

Article abstract of DOI:10.1002/chem.201901439

In this work, the reactivities of acetonyl and benzoyl radicals in aromatic substitution and addition reactions have been compared in an experimental and computational study. The results show that acetonyl is more electrophilic than benzoyl, which is rath

Full text of DOI:10.1002/chem.201901439

A Journal of
Accepted Article
Title: Philicity of Acetonyl and Benzoyl Radicals: a Comparative
Experimental and Computational Study
Authors: Martin Klussmann, Rik H Verschueren, Julie Schmauck,
Michael S. Perryman, Hui-Lan Yue, Julian Riegger, Bertrand
Schweitzer-Chaput, and Martin Breugst
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Philicity of Acetonyl and Benzoyl Radicals: a Comparative
Experimental and Computational Study
Rik H. Verschueren,[a] Julie Schmauck,[b] Michael S. Perryman,[a] Hui-Lan Yue,[a] Julian Riegger,[a,b]
Bertrand Schweitzer-Chaput,[a] Martin Breugst*[b] and Martin Klussmann*[a]
Abstract: Here, the reactivity of two radicals was investigated in an
experimental and computational study. Acetonyl and benzoyl
radicals were compared in aromatic substitution reactions, showing
that acetonyl is more electrophilic than benzoyl, which is rather
nucleophilic. A Hammett plot analysis of addition reactions to
substituted styrenes clearly supported that benzoyl is nucleophilic,
but in the case of acetonyl, no satisfying linear correlation against a
single substituent-related parameter was found. Computational
calculations helped to rationalize this effect and allowed obtaining a
good linear correlation against a combination of polar parameters
(σ+) and the radical stabilization energy (RSE) of the formed
intermediates. By the calculation of philicity indices for benzoyl and
acetonyl, a quantitative comparison of these two radicals with many
other reported ones is possible, possibly helping to predict
reactivities in aromatic radical substitution reactions.
that this reaction requires nucleophilic radicals to attack the
electron-deficient heteroarenes under acidic conditions.[6-7] We
observed that no reaction occurred with ketone-derived radicals
like 2, while the successful Minisci-reaction with benzoyl or acyl
radicals has been reported.[8] This raised our interest in the
philicity of those radicals and how it would affect reactions like
those shown in Scheme 1.
[H+]
OtBu
a)
O
O
O
O
- H2O
OtBu
+
+ tBuOOH
1
2
pTsOH (10 mol%)
tBuOOH (4 equiv.)
OOtBu
O
+
R
R
CH3CN, 50 °C
ca. 12 h, 76%
3
O
(5 equiv.)
O
Introduction
FeCl2 (2.5 mol%)
tBuOOH (3 equiv.)
b)
c)
tBuOO
O
+
Recently, we have begun a detailed investigation of alkenyl
peroxides, a class of compounds that is characterized by
especially weak O-O bonds compared with most other
peroxides.[1] They can easily be generated by the acid-catalyzed
condensation of simple ketones like acetone with tert-
butylhydroperoxide (tBuOOH) and the resulting alkenyl peroxide
1 decomposes into a tert-butyloxyl and the acetonyl (propan-2-
one-1-yl) radical 2 (Scheme 1a).[2] This method constitutes a
simple means of generating α-keto radicals from non-activated
ketones.[3] Both radicals can be utilized in addition reactions to
olefins,[4] for example to synthesize the γ-peroxyketone 3.[4a] The
synthesis of homologous β-peroxyketones like 4 was recently
described by the group of Li via an iron-catalyzed formation of
acyl radicals like benzoyl (5) from aldehydes and tBuOOH
(Scheme 1b).[5] A key step in this reaction is the iron-catalyzed
decomposition of tBuOOH into oxyl- and peroxyl-radicals, which
abstract a hydrogen atom from the aldehyde.
R
H
Ph
R
Ph
CH3CN, 85 °C
1 h, 75%
4
(5 equiv.)
O
5
Ph
R
H
R'
R'
R'
R'
R
H+
+ R
- H
- H+
N
N
N
N
H
H
Scheme 1. a) Generation of alkenyl peroxides 1 by acid catalysis and addition
reaction of the resulting radicals to styrenes, forming γ-peroxyketones like 3;
b) generation of benzoyl radicals 5 by iron catalysis in the synthesis of β-
peroxyketones like 4; c) the Minisci-reaction: a nucleophilic aromatic radical
substitution with heteroarenes under acidic conditions.
Radicals show electrophilic and nucleophilic behaviour,
respectively, even though they may be neutral species.[9,10] The
concept of radical philicity is well-established, yet most of the
times less straightforward to apply, compared with electro- and
nucleophilicity of closed-shell species.[11] One reason is that a
radical’s philicity may depend on the reaction partner and that
there are cases of ambiphilic or “borderline” radicals that can
behave both weakly nucleo- and electrophilic.[9a,12] Additionally,
many studies have shown that the reaction rates of radical
addition reactions cannot be explained by the philicities of the
radicals and the electronic properties of the unsaturated
reactants alone (also called polar effects), but also by the
reaction’s exothermicity (also called enthalpy effect).[9b,12-13] Thus,
many examples of radical addition reactions exist that show a
We became interested in utilizing the method of radical
formation via alkenyl peroxides (1) in other synthetic
transformations, including the Minisci-reaction.[6] This is a widely-
used nucleophilic aromatic radical substitution reaction with N-
heteroarenes that is generally conducted in the presence of acid
to increase its regioselectivity (Scheme 1c). It has been noted
[a]
[b]
R. H. Verschueren, Dr. M. S. Perryman, Dr. H.-L. Yue, J. Riegger,
Dr. B. Schweitzer-Chaput, PD Dr. M. Klussmann, Max-Planck-
Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim
an der Ruhr, Germany; E-mail: klusi@mpi-muelheim.mpg.de
J. Schmauck, PD Dr. M. Breugst, Universität zu Köln, Department
für Chemie, Greinstraße 4, 50939 Köln (Germany),
E-mail: mbreugst@uni-koeln.de
Supporting information for this article is given via a link at the end of
the document.
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counterintuitive correlation between the electronic properties of
the olefin and the radical.[13c,14] Understanding and predicting the
rates of radical additions has long been desired, but even today,
the correlation of reaction rates with substituent effects is
considered difficult.[9b,13e,15] While some success has been
achieved, sometimes aided by extensive calculations of multiple
parameters,[13e] general and simple solutions as seen for many
non-radical reactions have not been found.
The philicity of a given radical can be estimated based on its
structure,[9a] by kinetic studies and by theoretical calculations,
respectively.[12,16] A qualitative ranking of different radicals[12] as
well as quantitative radical philicity scales have also been
published.[16] Based on the general understanding of structural
factors, the acetonyl radical 2 has to be considered as rather
electrophilic, due to the electron-withdrawing effect of the
carbonyl group, while it has been calculated as being weakly
nucleophilic.[17] In contrast, the benzoyl radical 5 should be
considered as nucleophilic.[18] Yet, no combined experimental
and computational studies to compare and determine both
radicals’ philicities are known, and so we became interested to
study this aspect in detail.
Scheme 2. a) Failure of the acetone-derived radical 2 to undergo the Minisci
reaction with isoquinoline 6 under acidic conditions; b) alternative synthesis of
the desired product 7; c) successful electrophilic aromatic substitution reaction
with radical 2. Ar = 2,4,6-trimethoxyphenyl.
Results and Discussion
Minisci had shown that the radical substitution reaction with
lepidine (12) fails when the radical 13, derived from ethyl
iodoacetate, is employed (Scheme 3a), while the homologous
radical 14 forms the substitution product (Scheme 3b).[7] This
was rationalized by the decreased nucleophilic character of 13
compared with 14.
After the successful examples of acid-catalyzed addition
reactions of ketone-derived radicals like 2 to olefins, we wanted
to utilize them in the functionalization of arenes. We employed
isoquinoline (6), a common substrate in Minisci reactions that
shows a strong preference for being attacked in the 1-
position.[6b] For the in situ generation of alkenyl peroxides from
acetone and tBuOOH, we used excess para-toluenesulfonic acid
(pTsOH) to maintain overall acidic conditions in the presence of
the basic 6. In several experiments with different amounts of
reagents and solvents, we were unable to find the desired
product 7 (Scheme 2a). To be certain of the outcome of this
reaction, we synthesized 7 by an alternative route from
methylisoquinoline 8 (Scheme 2b).[19] Using it as a reference in
the analysis of the crude reaction mixtures by 1H-NMR
a)
b)
c)
(2.7 equiv.)
I
CO2Et
O
13
BzOOBz (1.0 equiv.)
FeOH(OAc)2 (7 mol%)
OEt
O
CH3CN, CF3CO2H
reflux, 4 h
N
N
N
OEt
12
12
0%
(2.7 equiv.)
CO2Et
O
I
14
BzOOBz (1.0 equiv.)
FeOH(OAc)2 (7 mol%)
unambiguously supported that
7 was not formed in the
OEt
attempted Minisci reactions. This indicates that the radical 2 is
OEt
CH3CN, CF3CO2H
reflux, 4 h
probably too electrophilic to react with
conditions.[20]
6 under acidic
N
O
56%
CF3
15
However,
when
we
employed
electron-rich
1,3,5-
CO2Me
OMe
CO2Me
CO2Me
OMe
Zn(SO2CF3)2 (2.0 equiv.)
tBuOOH (3.0 equiv.)
trimethoxybenzene, aromatic substitution by the acetonyl radical
occurred (Scheme 2c). Although the product yields are not
particularly high, we could isolate and characterize the product 9
in 39% yield and the bis-arylated ketone 10 in 8%, which had
apparently formed via the radical derived from ketone 9.
OMe
+
CHCl3/H2O/CF3CO2H
50°C, 12 h
N
N
CF3
F3C
N
64%, 1.4 : 1
Scheme 3. Reported Minisci reactions: a) failure of product formation with
radical 13 bearing an electron-withdrawing group in α-position; b) successful
product formation with homologous nucleophilic radical 14; c) product
formation with the weakly nucleophilic or electrophilic trifluoromethyl radical 15.
In contrast to the case of α-keto radicals like 2, the Minisci-
reaction with the benzoyl radical (5) has been reported.[8a,8d,8e]
When we subjected isoquinoline to the reaction conditions for
benzoyl radical addition as developed by the group of Li (see
above, Scheme 1b) in the presence of additional acid, the
substitution product 11 was indeed formed (Scheme 2d).
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However, the Minisci reaction is also known with the
trifluoromethyl radical (15),[6c,21] that has been described as
weakly nucleophilic but also as electrophilic.[16a,16b,22] These
reactions have been conducted with and without added
(Brønsted) acid, for example as shown in Scheme 3c using a
sulfinate reagent and trifluoroacetic acid.[21c]
Our qualitative results from the reactions shown above in
Scheme 2 clearly support the notion that the acetonyl radical (2)
is rather electrophilic and that the benzoyl radical (5) is rather
nucleophilic. In comparison with the reported cases shown in
Scheme 3, acetonyl is possibly similar to the ester-derived
radical 13 and more electrophilic than trifluoromethyl (15). In
order to understand the philicity of these radicals in a more
detailed and quantifiable manner, we started kinetic and
computational studies.
We used substituted styrenes to investigate the effect of the
electronic nature of the olefin on the rate of addition of the two
representative radicals 2 and 5. In order to measure relative
rates of radical addition, we conducted competition experiments
with two different styrenes in each reaction. This strategy was
chosen because the actual rate-controlling step in the benzoyl
addition reaction is not known, and in the case of the acetonyl
addition, it is believed to be the formation of the intermediate
alkenyl peroxides.[1] By performing competition experiments, the
addition reaction of the radical becomes the product-determining
step. The ratio of the two different products being formed should
thus reflect the relative addition rates of the radical onto the two
different styrenes. The data corresponding to the substituents
was then used to construct Hammett plots.
Scheme 4. Hammett plot of the benzoyl radical addition, relative rates in the
formation of 4 versus σ−.
The positive slope of the Hammett plot clearly supports the
notion that the benzoyl radical is nucleophilic. Also, the general
assessment of Héberger et al. is supported, which predicts that
addition reactions of strongly nucleophilic radicals correlate with
Hammett σ-parameters because polar effects dominate.[13b] The
good fit versus the resonance parameter σ− could indicate that
an electron transfer from the radical to the styrene occurs in the
transition state, generating partial negative charge in the
benzylic position. Such a charge transfer is generally connected
The addition of the benzoyl radical (5) was conducted as
developed previously with substituted styrenes (16a-l),
benzaldehyde, iron(II) chloride and tBuOOH at 85°C (Scheme
4).[5a] The reactions were monitored by 1H-NMR spectroscopy
until high conversion was achieved. The relative rates for each
substituted styrene were then calculated from the ratio of
logarithmic fractional conversions,[23] also called the
Ingold−Shaw expression[24] (see chapter 3.2 in the Supporting
Information). Linear free-energy relationships were constructed
by plotting the decadic logarithms of the relative rates against
various parameters for the styrenes’ substituents. The sigma
constants σ, σ+ and σ− as commonly used for Hammett plots
were generally taken from the book by Hansch, Leo and
with radical addition reactions exhibiting a polar character.[9b,13c-
e,14b,26]
The acid-catalyzed addition reaction of the acetonyl radical (2) to
substituted styrenes 16a-l was conducted as developed
previously,[4a] and the relative rates were measured as described
above. In contrast to benzoyl, no good correlation could be
obtained for the acetonyl radical addition. Judging by the R2-
value of the linear regression, the best correlation was achieved
against σ+ (Scheme 5), closely followed by σ (for additional plots
using other parameters besides σ, see the Supporting
Information, chapter 3.4). A general trend of decreasing rates
with increasingly electron-withdrawing substituents can be
imagined. This is in line with the suspected electrophilic nature
of the radical and supported by the negative slope of the
regression analysis, but the amount of scatter prohibits making
such a statement with confidence. The experiments were
carefully checked and proved to be reproducible.
Hoekman and the overview by Brown and Okamoto.[25]
A
detailed discussion of sources can be found in the Supporting
Information.
The reaction showed a clear trend of increasing reaction rates
with increasingly electron-withdrawing substituents on styrene.
The best linear fit was achieved for a plot versus σ− values
(Scheme 4), but good correlations were also achieved with σ
and σ+ (see the Supporting Information, chapter 3.6).
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correlation might simply be coincidence (see the Supporting
Information, chapter 3.4, for all of these alternative correlations).
To evaluate combinations of parameters reflecting polar and
enthalpic effects, we calculated radical stabilization energies
(RSE) for the intermediates 17 formed after radical addition
(Scheme 6a), since none of the above-mentioned radical-
specific parameter scales included all the substituents used in
our study. To make these values useful for different radical
addition reactions as well, we determined the RSE values for
simplified model compounds 19, according to the procedure
established by Coote, Zipse, and others at the G3(MP2)-RAD
level of theory (Scheme 6b, Table 1).[30] Additional values for
several other common substituents are given in the Supporting
Information.
Scheme 5. Hammett plot of the acetonyl radical addition, relative rates in the
formation of 3 versus σ+. If not noted otherwise, all substituents are in the
para-position.
Héberger et al. stated that rates from addition reactions of
strongly electrophilic radicals correlate with the alkenes’
ionization potential and for moderately electrophilic or
nucleophilic radicals with a combination of two parameters that
reflect both polar and enthalpic effects.[12,13b] Polar effects are
described by Hammett σ parameters, the alkenes’ electron
affinities or ionization potentials, while enthalpic effects are
described by radical stabilization parameters, for example.
Scheme 6. a) Formation of intermediate benzylic radicals; b) Calculation of
radical stabilization energies (RSE) for ethylbenzene model compounds.
Table 1. Radical stabilization enthalpies (RSE) for radicals 19 in kJ mol–1
calculated using the G3(MP2)-RAD level of theory according to Scheme 6b.
Since the ionization potential of substituted styrenes has only
been published for a few cases,[27] and measurement by cyclic
voltammetry proved to be difficult for the entire range used here,
we calculated the adiabatic ionization potential (IP) at the
G3(MP2)-RAD level of theory (see the Supporting Information
for further details). However, these values did not satisfyingly
correlate with the reaction rates for acetone-addition. We,
therefore, focused on several other radical-specific substituent
Entry
System
RSE
[kJ
Entry
System
RSE
[kJ
mol−1
]
mol−1
]
1
2
3
4
p-F
−67.7
−67.8
−68.2
7
p-Me
−69.3
−69.4
−70.3
m-NO2
p-CF3
H
8
p-Br
9
p-CO2Me
p-CN
−68.4
10
−70.9
(−68.3)[a]
(−71.0)[a]
parameters
for
applications
in
linear
free
energy
relationships.[15b] For example, kinetic measurements of model
radical reactions have been used by the groups of Creary and Ji
to define the parameters σ• and σjj, both of which are interpreted
as reflecting the extent of stabilization of an intermediate
benzylic radical.[28] Bordwell and Bausch derived parameters
∆AOP from pKa-values and oxidation potentials of fluorenes and
Arnold et al. defined a σ•-scale from hyperfine coupling
constants of benzylic radicals by ESR.[29] None of these scales
gave a satisfying correlation, either, with the exception of the
∆AOP-parameters. Of these, however, only five were applicable
to our dataset from 12 substituted styrenes 16, so the good
5
6
p-OAc
p-SF5
−68.6
−68.7
11
12
p-Ph
−71.0
p-NO2
−69.6
(−73.0)[a]
[a] Values originally reported by Coote, Lin and Zipse.[30b]
All calculated RSE-values from Table 1 fall within a relatively
small energy range (–71.0 < RSE < –67.7 kJ mol–1) indicating
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that even small energy changes can have a significant effect on
the experimental observations. For most systems (e.g., Table 1,
entries 4 and 10) our calculated values perfectly match those
reported previously. However, the value for p-NO2 deviated
significantly (entry 12). As the previously published value[30b] of
−73.0 kJ mol−1 better fitted to the experimental data, we decided
to use this value for the p-NO2 derivative throughout this study
(also see chapter 6.2 in the Supporting Information for a
comparison of RSE-values with radical-specific substituent
parameters).
From the RSE-values, one can observe the trend that the least
stabilizing substituents (F, CF3, m-NO2) are those that are
electron-withdrawing by inductive effects. Substituents that exert
electron-donating inductive effects (Me) or resonance effects
independent of their electronic nature (OMe, OAc, Ph, NO2) are
generally more stabilizing.
Figure 1. Hammett plot of the radical addition with acetone, relative rates in
the formation of 3 versus a combination of σ+ and the RSE-values. If not noted
otherwise, all substituents are in the para-position.
Again, the RSE-values on their own did not give a good
correlation against the reaction rates (see the Supporting
Information, chapter 3.4), indicating that the thermodynamic
stabilities of the formed radicals alone cannot explain the kinetic
reactivities. However, they already helped realizing a trend in the
different relative rates as shown in Scheme 5 above. The linear
regression (dashed line) shows a negative slope, indicating the
polar effect of an electrophilic radical. In addition, most data
points above the line (relatively high rates) correlate to radical
This correlation further supports the interpretation that the
acetonyl radical 2 is electrophilic (a negative slope against a
parameter based on σ+), but that the rate of addition also
depends on the stability of the intermediate radical 17. The good
correlation against a combination of polar and enthalpic effects
suggests, in line with Hébergers assessment,[12,13b] that acetonyl
is moderately electrophilic. The negative slope and involvement
of σ+ also supports that a charge transfer in the transition state
occurs from the styrenes to the radical.
intermediates of type 17 that receive
a high degree of
stabilization by the substituent, while the opposite is true for data
points below the dashed line (relatively low rates). For example,
the highest rate was found for p-phenylstyrene 16b, which is
weakly electron donating (polar effect) but also corresponds to
one of the most stabilized intermediates (enthalphic effect, Table
1, entry 11). The opposite case is m-NO2, which shows the
lowest rate due to its electron-withdrawing nature (polar effect)
combined with a low degree of radical stabilization (enthalpic
effect, Table 1, entry 2). The other two substituents that also
lead to the lowest RSE-values and hence to the least stabilized
radicals, are p-F and p-CF3 (Table 1, entries 1 & 3), and the
corresponding datapoints are well below the dashed line in
Scheme 5, thus the relative rates are rather low, too.
Other combinations of parameters for polar and enthalpic effects
also gave good correlations, for example the sum of the
ionization potential of the styrenes and the RSE-values. The
second highest R2-value (0.941) could be obtained for a
combination of σ+ with the radical-specific parameter σ•,
however, only values for ten out of the twelve styrenes used in
this study are published. Applying the strategy of combined
parameters to the data obtained from the benzoyl addition
reactions only resulted in a minor improvement (R2 = 0.988 for
mixing σ− with the RSE-values, see the Supporting Information,
chapter 3.6).
Consequently, we next focused on the transition state for the
addition reaction of the radical onto the double bond.[18b] DFT
calculations indicate that both reactions are highly exothermic (–
126 < ∆H < –118 kJ mol–1) and exergonic (–68 < ∆G < –58 kJ
mol–1) (see the Supporting Information). The barrier heights
(∆G‡) for the radical addition were found to fall in a close range
of +51 < ∆G‡ < 58 kJ mol–1 (for benzoyl 5, see Table 2 below)
and +52 < ∆G‡ < 55 kJ mol–1 (for acetonyl 2, see Table 3 below).
These small values indicate very fast radical addition reactions
for all cases. This is in line with the fact that the rate-controlling
step is most likely the generation of the radical rather than the
subsequent addition reaction. In line with the expectations from
the Hammond postulate, early transition states with rather long
C–C bond lengths (TS1: 2.28 Å; TS2: 2.36 Å) have been
determined for both the benzoyl and the acetonyl radical at the
DLPNO-CCSD(T)/aug-cc-pVTZ//B3LYP-D3BJ/6-31+G(d,p) level
of theory (Scheme 7). While the acetonyl radical attacks styrene
This combination of polar and enthalpic effects can be visualized
graphically by plotting the relative rates against a sum of σ-
parameters and RSE-values. We found the best correlation (R2
= 0.962) against the sum of σ+ + 0.265•RSE (Figure 1).
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through an angle of 109°, the benzoyl radical preferentially
attacks through a smaller angle (97°) due to stabilizing π-π
interactions between the aromatic rings.
Figure 2. Determination of charge transfer in the transition states.
We, therefore, calculated the charge-transfer contribution ∆ECT1
and ∆ECT2 as well as their ratio R (R = ∆ECT1/ ∆ECT2) for the
reactions of substituted styrenes and 5. Additionally, we also
determined the degree of charge transfer in the transition state
based on the charge separation q of a natural population
analysis (Figure 2). These data are summarized in Table 2, also
showing the activation barriers ∆G‡ of the transition states.
Scheme 7. Addition of the benzoyl and acetonyl radical to styrene, showing
angles of attack (in °) and bond distances (in Å) in the transition states.
To validate the hypotheses for the investigated systems, we
calculated different parameters that characterize the charge
transfer in the transition state as reported by the group of
Allonas.[13c] For both radicals 2 and 5 as well as for the styrene
derivatives 16a-l, the adiabatic ionization potential IP (IP =
E(cation) – E(radical)), the electron affinity EA (EA = E(radical) –
E(anion)), chemical hardness η [η = 0.5(IP + EA)], and chemical
potential μ [μ = 0.5(IP – EA)] were calculated at the G3(MP2)-
RAD level of theory (see the Supporting Information for further
details).
Table 2. ∆G‡, ∆ECT1, ∆ECT2, R, and q of the benzoyl radical (5) addition to
styrene derivatives 16a-l.
Styrenes
∆G‡ (kJ
∆ECT1
∆ECT2
R
q[c]
mol-1)[a]
[eV][b]
[eV][b]
16a (p-Me)
16b (p-Ph)
16c (p-H)
56.9
54.4
56.8
57.5
55.3
54.5
55.6
52.9
53.1
6.74
6.17
6.69
6.65
6.37
5.93
6.10
5.81
5.36
7.47
7.18
7.78
7.77
7.69
7.89
8.20
8.26
8.34
0.90
0.86
0.86
0.86
0.83
0.75
0.74
0.70
0.64
−0.007
0.003
0.004
0.000
0.048
0.015
0.029
0.044
0.034
Typically, addition reactions of radicals to double bonds are
described by a state correlation diagram which helps to
understand the factors that influence the reactions.[9b] This
potential energy profile considers the reactant ground-state
configuration (R• + styrene in a singlet state), the excited
reactant configuration (R• + styrene in a triplet state), and two
polar charge-transfer configurations (CTCs) ∆ECT1 and ∆ECT2
(Equations 1 and 2, Figure 2). The former accounts for the
transfer of an electron onto the styrene, while the latter accounts
for the transfer of an electron onto the radical. If the
contributions of the CTCs in the transition state are sufficiently
high (i.e., ∆ECT values are small), this will lead to a decrease of
the energy barrier.
16d (p-F)
16e (p-Br)
16g (p-CO2Me)
16h (p-CF3)
16i (p-CN)
16l (p-NO2)
[a] calculated at DLPNO-CCSD(T)/aug-cc-pVTZ//B3LYP-D3BJ/6-31+G(d,p)
level; [b] calculated at G3(MP2)-RAD level; [c] NBO charges calculated at
B3LYP-D3BJ/def2-QZVP//B3LYP-D3BJ/6-31+G(d,p) level.
ECT1 = IP(R•) – EA(Styrene)
ECT2 = IP(Styrene) – EA(R•)
Eq. (1)
Eq. (2)
For all systems studied in Table 2, ratios R of less than unity
were determined and smaller ratios were observed for electron-
withdrawing substituents (e.g., R(p-Me) = 0.90 vs. R(p-NO2) =
0.64). This indicates that the benzoyl radical 5 should be
considered as a nucleophilic radical as the radical favors acting
as an electron donor rather than an electron acceptor.[13c] This is
also in good agreement with the degree of charge separation q
between both fragments: with the exception of p-Me-styrene, the
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calculations indicate a charge transfer in the transition state from
the benzoyl radical to the styrene derivative.
Proft and coworkers.[16a,16b] Thus, the acetonyl radical 2 has an
electrophilicity index ω of 1.939 eV (agreeing perfectly with the
previously reported value[17]) and the benzoyl radical 5 of 1.034
eV. In compliance with their classification, the acetonyl radical 2
has a weak nucleophilic character, being close to the border to
weak to moderate electrophiles, while the benzoyl radical 5 has
a strong to moderate nucleophilic character. We also calculated
the global electrophilicity and nucleophilicity indices ω° and N°
according to Domingo and Perez (see the Supporting
Information, chapter 6.5.2).[16c] The acetonyl radical 2 has ω° =
3.48 eV and N° = 0.93 eV and the benzoyl radical 5 has ω° =
1.60 eV and N° = 2.70 eV. In compliance with their classification,
acetonyl is thus a marginal nucleophile and a strong electrophile,
Analogous calculations for the acetonyl radical derived systems
are summarized in Table 3. In contrast to the data for the
benzoyl radical (5, Table 2), almost all combinations between
the radical 2 and substituted styrenes now resulted in ratios R
larger than unity (except for NO2-substituted styrenes). As a
consequence, the acetonyl radical 2 tends to favor acting as an
electron acceptor rather than an electron donor and can be
considered as an electrophilic radical. In line with this analysis,
the charge separation q based on NBO charges now shows a
negative partial charge on the radical fragment.
while benzoyl is
electrophile.
a moderate nucleophile and a strong
Table 3. ∆G‡, ∆ECT1, ∆ECT2, R, and q of the acetonyl radical (2) addition to
styrene derivatives 16a-l.
The calculated philicity values are in full agreement with the
present study, indicating clearly that the acetonyl radical 2 is
more electrophilic than benzoyl 5. The ω-values also enable to
compare both with structurally different radicals that had been
investigated before.[16b] The global electrophilicity of benzoyl, for
example, is very similar to acetyl (21, ω = 1.083) and even more
so to p-methoxybenzyl (20, ω = 1.033)[31] (Figure 3). Acetonyl is
structurally and with regard to its ω-value similar to the ester-
substituted methyl radical 22 (ω = 1.930), and both types of
radicals fail in Minisci reactions (see Scheme 2a above for the
ethyl ester derivative 13). No successful Minisci reaction with the
cyanomethyl radical 23, having a similar electrophilicity index (ω
= 2.003), has ever been reported either, to the best of our
knowledge.[32,33] In contrast, trifluoromethyl 15 is less
electrophilic (ω = 1.672) than 2 – and thus more nucleophilic –
and several successful applications in Minisci reactions are
known (for example see Scheme 2c above).[6c,21]
Styrenes
∆G‡
(kJ
∆ECT1
∆ECT2
R
q[c]
mol-1)[a]
[eV][b]
[eV][b]
16a (p-Me)
16b (p-Ph)
16c (p-H)
52.7
51.8
53.1
53.7
51.5
52.8
53.5
54.2
52.9
53.9
54.4
54.0
8.62
8.05
8.56
8.53
8.25
8.18
7.81
7.98
7.69
7.43
7.24
7.14
6.44
6.15
6.75
6.74
6.66
6.22
6.86
7.17
7.23
7.23
7.31
7.36
1.34
1.31
1.27
1.27
1.24
1.32
1.14
1.11
1.06
1.03
0.99
0.97
−0.106
−0.102
−0.097
−0.100
−0.094
−0.109
−0.098
−0.081
−0.070
−0.077
−0.071
−0.076
16d (p-F)
16e (p-Br)
16f (p-OAc)
16g (p-CO2Me)
16h (p-CF3)
16i (p-CN)
16j (p-SF5)
16k (m-NO2)
16l (p-NO2)
[a] calculated at DLPNO-CCSD(T)/aug-cc-pVTZ//B3LYP-D3BJ/6-31+G(d,p)
level; [b] calculated at G3(MP2)-RAD level; [c] NBO charges calculated at
B3LYP-D3BJ/def2-QZVP//B3LYP-D3BJ/6-31+G(d,p) level.
Figure 3. Calculated global electrophilicity indeces ω for the radicals 2 and 5
from this study, in comparison with previously reported ones;[16b] all values are
given in eV.
All these energy values calculated for the benzoyl and the
acetonyl radical did not give better correlations against the
relative rates of addition, compared with Scheme 4 and Figure 1
above (see chapters 3.4 and 3.6 in the Supporting Information).
The best case was the correlation of the benzoyl addition rates
against ∆ECT1, giving a linear fit with a R2-value of 0.932.
It thus appears as if a borderline reactivity for Minisci reactions
lies somewhere between ω = 1.7 and ω = 1.9, but that will
strongly depend on the heteroarene and the reaction conditions
as well.
Finally, in order to obtain a more quantitative measure of both
radicals’ philicities, we calculated the global electrophilicity index
ω according to the scale as reported by De Vleeschouwer, De
Conclusions
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In summary, we have investigated the philicities of two radicals,
acetonyl (propan-2-one-1-yl) and benzoyl, by experiments and
calculations. The results from aromatic substitution reactions
supported the assessment that acetonyl is a rather electrophilic
radical and benzoyl rather nucleophilic: the reaction with
electron-poor isoquinoline under acidic conditions (Minisci
reaction) proceeded well for benzoyl, but failed with the acetonyl
radical. The latter could instead be successfully utilized in an
aromatic substitution reaction with electron-rich 1,3,5-
trimethoxybenzene. In addition, competition experiments in the
radical addition to substituted styrenes clearly indicated that
benzoyl is nucleophilic, reacting faster with styrenes bearing
electron-withdrawing substituents. The Hammett plot against σ−
gave a very good linear correlation, also supporting the notion of
an electron transfer from the radical to the styrenes. For the
acetonyl radical, no satisfying correlation between the relative
rates of addition and the electronic properties of the substituents
could be made. This was only achieved by plotting the rates
against a combination of polar parameters (σ+) and enthalpic
parameters, that is, the radical stabilization energies (RSE)
corresponding to the radical intermediates formed after addition.
The RSE parameters, derived from quantum-mechanical
calculations, also helped to rationalize the failed correlation of
the Hammett plot against σ-parameters alone, because the
relative rates are not only influenced by the philicity and
electronic properties of the radical and styrene, resp., but also
by the relative stability of the radical intermediates that are
formed. The substituents on the styrenes influence these two
aspects not in the same ways, thus any linear free energy
relationship against a single parameter will fail. Exactly why the
two radicals, benzoyl and acetonyl, behave so differently with
regard to linear free energy relationships is unknown to us.
these two radicals can be compared with the philicities of many
other ones for which those values have been reported. The
calculated values support the findings made by experiment, and
allow to classify the acetonyl radical as weakly nucleophilic,
close to being weakly electrophilic, and the benzoyl radical as
strongly to moderately nucleophilic.
The results from the present study could be helpful for future
investigations of radical addition reactions by providing a large
set of calculated parameters to evaluate the influence of
substituents. Additionally, they could also contribute to an
improved understanding of the relationship between the philicity
of radicals and their reactivity in aromatic substitution reactions
like the Minisci reaction.
Experimental Section
Experimental Details.
For
a detailed description of aromatic substitution reactions, the
synthesis of reference compound 7 and the measurement and evaluation
of kinetic data, see the Supporting Information, Experimental Part.
Benzoyl addition, general procedure for the competition
experiments: In an oven-dried Schlenk flask charged with a magnetic
stirring bar, FeCl2 (0.025 mmol, 2.5 mol%), styrenes (in total: 1 mmol, 1
equiv.; 0.5 mmol each of two differently substituted styrenes), internal
standard (dibromomethane and dimethyl sulfone, resp., ca. 0.5 equiv.)
and benzaldehyde (5 mmol, 5 equiv.) were dissolved in dry acetonitrile
(6.0 mL) under argon at room temperature. The resulting mixture was
then degassed by freezing it in liquid nitrogen, replacing the atmosphere
with argon and allowing it to warm to room temperature (repeated for a
total of three cycles). t-BuOOH (5.5 M solution in decane, 3.0 mmol, 3
equiv.) was then added under a stream of argon and the first sample was
taken for 1H NMR analysis (t = 0). Then the Schlenk tube containing the
reaction mixture was placed in a pre-heated oil bath at 85 °C.
Models to correlate rates of radical addition reactions to
parameters of the radicals and olefins have been made before,
taking both polar and enthalpic effects into account, sometimes
requiring more than two parameters. The advantage of the
present study, while not being able to predict absolute rates, is
that it relies on two relatively simple types of parameters,
Hammett-parameters and RSE values, that are neither specific
for the reactions under study nor difficult to determine or
calculate. The effect of different substituents on the stabilization
of radical intermediates is also reflected by parameters like
Creary’s σ• and others, developed for linear free energy
relationships of radical reactions. However, these have not been
developed for very many substituents, in contrast to the well-
established substituent parameters σ, σ+ and σ− for Hammett
plots. We thus have calculated more RSE values than was
necessary for the present study, both for substituted styrenes
and for many other olefins, in order to be of use in future studies,
and maybe in the teaching of radical chemistry, too. In the same
way, the ionization potential (IP) and the electron affinities (Ea)
for styrenes and other olefins have been calculated, too (see
chapters 6.2 and 6.3 in the Supporting Information).
Acetonyl addition: General procedure for the competition
experiments: In an oven-dried Schlenk flask charged with a magnetic
stirring bar, p-TsOH (0.05 mmol, 5 mol%), styrenes (in total: 1 mmol, 1
equiv.; 0.5 mmol each of two differently substituted styrenes), internal
standard (dibromomethane and dimethyl sulfone, resp., ca. 0.5 equiv.)
and acetone (5 mmol, 5 equiv.) were dissolved in dry acetonitrile (4.0
mL) under argon at room temperature. The resulting mixture was then
degassed by freezing it in liquid nitrogen, replacing the atmosphere with
argon and allowing it to warm to room temperature (repeated for a total of
three cycles). t-BuOOH (5.5 M solution in decane, 4 mmol, 4 equiv.) was
then added under a stream of argon and the first sample was taken for
1H NMR analysis (t = 0). Then the Schlenk tube containing the reaction
mixture was placed in a pre-heated oil bath at 50 °C.
Sample taking and analysis of competition experiments: For both
reactions, the process was monitored in selected time intervals by taking
aliquots of the reaction mixture (150 µl) into an NMR tube containing
deuterated DMSO (350 µl), which functions as the NMR solvent but also,
at ambient temperature, quenches the reaction.
Computational Details.
Finally, we have also calculated global electrophilicity indices ω
for both radicals, following established procedures. This way,
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10.1002/chem.201901439
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For
a
detailed description of all calculations, see the Supporting
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ionization potentials (IP), electron affinities (EA), chemicals hardness (η),
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Support from the DFG (KL 2221/4-2, Heisenberg scholarship to
M. K.), the Fonds der chemischen Industrie (Liebig scholarship
to M.B. and PhD scholarship to J. S.), the Chinese Scholarship
Council (scholarship to H.-L. Y.), the University of Cologne
within the excellence initiative, and Prof. Benjamin List (support
of M. S. P.) is gratefully acknowledged. We are grateful to the
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[33] It has been suggested that α-keto radicals are generally nucleophilic
and that the presence of an acid would render them more electrophilic
by coordination to the carbonyl group, see ref. 17. While we cannot
exclude that for the system under study, the similarity of radicals 22, 2
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the presence of acid plays a significant role. In addition, the presence of
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10.1002/chem.201901439
Chemistry - A European Journal
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Rik H. Verschueren, Julie Schmauck,
Michael S. Perryman, Hui-Lan Yue,
Julian Riegger, Bertrand Schweitzer-
Chaput, Martin Breugst* and Martin
Klussmann*
Page No. – Page No.
Attraction and stability. Addition reactions with acetonyl and benzoyl radicals
were compared in an experimental and computational study, showing that acetonyl
is more electrophilic than benzoyl, which is rather nucleophilic. The relative rates of
acetonyl could only be rationalized by a combination of polar parameters (σ+) and
the radical stabilization energy (RSE) of the formed intermediates. The philicities of
the radicals also affect the outcome of aromatic substitution reactions.
Philicity of Acetonyl and Benzoyl
Radicals: a Comparative
Experimental and Computational
Study
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