Reactions of nitroheteroarenes with carbanions: Bridging aromatic, heteroaromatic and vinylic electrophilicity

Article abstract of DOI:10.1002/chem.200800329

The relative rate constants for the vicarious nucleophilic substitution (VNS) of the anion of chloromethyl phenyl sulfone (1^-) with a variety of nitroheteroarenes, for example, nitropyridines, nitropyrroles, nitroimidazoles, 2-nitrothiophene, and 4-nitropyrazole, have been determined by competition experiments. It was shown that nitropyridines are approximately four orders of magnitude more reactive than nitrobenzene. Among the five-membered heterocycles 2-nitrothiophene is the most active followed by nitroimidazoles and 4-nitropyrazole. Nitropyrroles are the least electrophilic nitroheteroarenes with reactivities comparable to nitrobenzene. Quantum chemically calculated methyl anion affinities (B3LYP/6-311 G(d,p)//B3LYP/ 6-31G(d)) of the nitroarenes correlated only moderately with the partial relative rate constants. The correlation of these activities with the LUMO energies of nitroarenes is even worse. By measuring the second-order rate constants of the addition of 1" to nitroarenes and to diethyl arylidenemalonates 10, it was possible to link the electrophilic reactivities of nitroheteroarenes with the comprehensive electrophilicity scale based on the linear-free-energyrelationship log k(20°C) = s(N + E).

Full text of DOI:10.1002/chem.200800329

DOI: 10.1002/chem.200800329
Reactions of Nitroheteroarenes with Carbanions: Bridging Aromatic,
Heteroaromatic, and Vinylic Electrophilicity
Florian Seeliger,[a] Sylwia Błazej,[b] Sebastian Bernhardt,[a] Mieczysław Ma˛kosza,*[b] and
˙
Herbert Mayr*[a]
Dedicated to Professor Helmut Schwarz on the occasion of his 65th birthday
Abstract: The relative rate constants
for the vicarious nucleophilic substitu-
tion (VNS) of the anion of chlorometh-
yl phenyl sulfone (1ꢀ) with a variety of
nitroheteroarenes, for example, nitro-
pyridines, nitropyrroles, nitroimida-
zoles, 2-nitrothiophene, and 4-nitropyr-
azole, have been determined by com-
petition experiments. It was shown that
nitropyridines are approximately four
orders of magnitude more reactive
than nitrobenzene. Among the five-
membered heterocycles 2-nitrothio-
phene is the most active followed by
nitroimidazoles and 4-nitropyrazole.
Nitropyrroles are the least electrophilic
nitroheteroarenes with reactivities
comparable to nitrobenzene. Quantum
chemically calculated methyl anion af-
only moderately with the partial rela-
tive rate constants. The correlation of
these activities with the LUMO ener-
gies of nitroarenes is even worse. By
measuring the second-order rate con-
stants of the addition of 1ꢀ to nitroar-
enes and to diethyl arylidenemalonates
10, it was possible to link the electro-
philic reactivities of nitroheteroarenes
with the comprehensive electrophilicity
scale based on the linear-free-energy-
finities (B3LYP/6–311G(d,p)//B3LYP/
A
6–31G(d)) of the nitroarenes correlated
Keywords: aromatic vicarious nu-
cleophilic substitution
·
density
functional calculations · heterocy-
cles · kinetics · linear free energy
relationships
relationship log k
A
N
Introduction
In general, the reaction proceeds by fast and reversible
addition of a carbanion, bearing a leaving group X (e.g. hal-
ogen) at the carbanion center, to a nitroarene, followed by
The concept of vicarious nucleophilic substitution (VNS) of
hydrogen in electron-deficient arenes was developed three
decades ago.[1,2] Since then this method has been thoroughly
studied and has become a versatile tool for the introduction
of a variety of substituents into aromatic or heteroaromatic
nitro compounds.[3–6]
ꢀ
base-induced b-elimination of H X from the resultant sH-
adduct. At least two equivalents of base are necessary for
the reaction to proceed, one for the deprotonation of the
CH-acid to form the carbanion and the second for inducing
ꢀ
the b-elimination of H X. After final protonation, the sub-
stituted
nitroarene
or
-heteroarene
is
obtained
(Scheme 1).[7–10]
It has been reported that the solvent, the nature and con-
centration of the base, and the steric demand of the carban-
ion have a considerable influence on the ratio of isomeric
[a] Dr. F. Seeliger, S. Bernhardt, Prof. Dr. H. Mayr
Department Chemie und Biochemie
Ludwig-Maximilians Universität München
Butenandtstrasse 5–13, 81377 München (Germany)
Fax : (+49)89-2180-77717
products.[11] When there is a high excess of the base, H X
ꢀ
elimination is faster than the retroaddition of the sH-adduct,
and the formation of the sH-adducts becomes irreversible.
Nitro-substituted heteroarenes, similar to their carbocyclic
analogues, readily enter the VNS reaction giving products
that are important building blocks in organic synthesis.[12]
Therefore, it is of interest to determine their electrophilic
activities and compare them with those of typical aliphatic
electrophiles.
E-mail: Herbert.Mayr@cup.uni-muenchen.de
[b] Dr. S. Błaz˙ej, Prof. Dr. M. Ma˛kosza
Institute of Organic Chemistry
Polish Academy of Sciences
ul. Kasprzaka 44/52, 01–224 Warsaw, POB 58 (Poland)
E-mail: Icho-s@icho.edu.pl
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
6108
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 6108 – 6118

FULL PAPER
Scheme 1. Mechanism of the vicarious nucleophilic substitution in nitro-
arenes with the anion of chloromethyl phenyl sulfone (1ꢀ).
Understanding and predicting the influence of substitu-
ents will help to control regioselectivity in nucleophilic aro-
matic displacement reactions. Analogous substituent effects
on the electrophilic activities of nitro-substituted benzenoid
arenes have already been studied earlier.[13,14]
Scheme 2. VNS reactions of 3-nitropyridines 4a–d with the anion of
chloromethyl phenyl sulfone (1ꢀ).[17] i) 1. DMF, KOtBu, ꢀ408C, 5 min; 2.
HCl(aq). [a] Ref. [18]. [b] Ref. [19,20]
Results and Discussion
Product studies: As shown previously, the anion of chloro-
methyl phenyl sulfone (1ꢀ) undergoes VNS reactions with a
broad variety of electron-deficient arenes[15,16] and was used
as a substrate in earlier mechanistic studies.[7–10,13,14] Accord-
ingly, it was chosen as the reference nucleophile also in this
work. For the determination of relative electrophilic reactiv-
ities of various heteroarenes toward 1ꢀ by competition ex-
periments, it was necessary to have samples of all VNS
products, which were synthesized as described in Schemes 2
and 3. Some of these products were described earlier, as
specified in the schemes.
The ratios of isomeric products obtained by VNS reac-
tions of 3-nitropyridine (4a),[18] 2-chloro-3-nitropyridine
(4b),[18] and 2-methoxy-5-nitropyridine (4d)[20] with the sul-
fonyl carbanion 1ꢀ agree with those reported in the litera-
ture (Scheme 2). Compound 4c is predominately attacked
by 1ꢀ at position 6 to yield 4cp as the major product
(Scheme 2) in accordance with the quantitative competition
experiments discussed below. In contrast, the reaction of 1ꢀ
with 4-methoxy-3-nitropyridine was reported to yield only
the corresponding 2-substitution product.[20]
The VNS reactions of 1ꢀ with N-methyl-2-nitropyrrole
(5a) and N-methyl-3-nitropyrrole (5b) gave only single re-
gioisomers (Scheme 3).[21,22]
While Crozet and co-workers[24–26] reported the exclusive
formation of 6ao, when 6a was treated with 1 and potassium
hydroxide in DMSO at room temperature, we isolated a
mixture of 4-benzenesulfonylmethyl-1-methyl-5-nitroimida-
zole (6ao, 42%) and 15% of the corresponding 2-isomer
(6ap, Scheme 3) in accordance with earlier reports.[23] Only
one regioisomer was obtained in the reaction of 1-methyl-4-
nitroimidazole (6b, Scheme 3) with 1ꢀ.
1-Methyl-4-nitropyrazole (7) was exclusively attacked at
position
5 to give 5-benzenesulfonylmethyl)-1-methyl-4-
nitro-1H-pyrazole (7o) in 86% yield (Scheme 3), in analogy
to previously reported reactions of 7 with other carban-
ions.[27,28] In contrast to the regioselectivity of the reaction of
5a with 1ꢀ (see above), 2-nitrothiophene (8) is selectively at-
tacked at the 3-position by 1ꢀ (Scheme 3).[22,29]
In the presence of strong bases, 1-unsubstituted nitropyr-
roles, nitroimidazoles, and nitropyrazoles are converted into
the corresponding anions, which do not react with nucleo-
philes. Therefore we used the non-acidic 1-methylated deriv-
atives 5–7 for our competition experiments.
Competition experiments: For the determination of the rela-
tive electrophilic reactivities of the electron-deficient arenes
3–8, a mixture of two nitroheteroarenes was treated with
chloromethyl phenyl sulfone (1) and KOtBu. The products,
obtained after treatment of the reaction mixtures with dilut-
Chem. Eur. J. 2008, 14, 6108 – 6118
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6109

H. Mayr, M. Ma˛kosza et al.
A low reaction temperature (ꢀ408C) and a high concen-
tration of potassium tert-butoxide (four equivalents) guaran-
teed the reaction to proceed under kinetic control with irre-
versible formation of the sH-adduct (Scheme 1). Because b-
elimination of HCl from the sH-adducts is much faster than
the reverse reaction (k2[B]@kꢀ1),[13,14] the ratio of the isolat-
ed products reflects the ratio of the addition rate constants
k1. As competitors for the nitroheteroarenes we used the
para-substituted nitrobenzenes 3b–d (formula see Figure 1)
and 1-nitronaphthalene (3e), which allowed us to combine
the relative reactivities of this work with those of earlier
studies.[13,14] A summary of all relative reactivities deter-
mined in this investigation is shown in Table 1. If there is
Table 1. Reactivity ratios derived from competition experiments.
A
B
Analysis
k[a,b]
Regioselectivity
[4ao]:
[4ap]=12ꢁ2
[4ao]:
[4ap]=12ꢁ2
4a
3e
GC
17ꢁ1
G
ACHTREUNG
HPLC[c]
GC
13ꢁ1
U
ACHTREUNG
4b
4c
3e
3d
19ꢁ1
HPLC[c]
GC
21ꢁ0.1
4.5ꢁ0.4
4.2ꢁ0.3
4.8ꢁ0.1
3.7ꢁ0.2
3.7ꢁ0.5
2.2ꢁ0.1
5.0ꢁ0.3
2.8ꢁ0.3
3.1ꢁ0.4
11ꢁ1
A
ACHTREUNG
HPLC[c]
GC[d]
GC
A
ACHTREUNG
3e
4d
4c
3e
HPLC[c]
GC
3b
5b
5b
5a
5a
3b
GC
GC
HPLC[c]
GC
6a
3b
A
ACHTREUNG
HPLC[e]
GC
9.9ꢁ1.4
7.0ꢁ0.3
5.7ꢁ0.4
6.2ꢁ 0.5
1.8ꢁ0.1
1.0ꢁ0.1
1.1ꢁ0.02
2.7ꢁ0.3
3.9ꢁ0.5
4.1ꢁ0.7
A
ACHTREUNG
3c
6b
6a
3c
A
ACHTREUNG
GC
HPLC[c]
GC
6b
7
3d
3c
GC
HPLC[c]
GC
3d
8
7
3e
GC
HPLC[c]
[a] k=kA/kB (ratio of the overall reactivity of A and B). [b] The indicated
errors refer to the reproducibility of the chromatographic analysis, devia-
tions between the results obtained by different methods show that the ab-
solute errors are bigger. [c] Analysis at 264 nm. [d] Amount of ortho
Scheme 3. VNS reactions of five-membered heterocycles 5–8 with the
anion of chloromethyl phenyl sulfone (1ꢀ). i) 1. DMF, KOtBu, ꢀ408C,
5 min; 2. HCl(aq). [a] Ref. [21]. [b] Ref. [22]. [c] Ref. [23].
product of 4c is estimated on the basis of [4cp]:
[e] Analysis at 280 nm.
A
ed hydrochloric acid, were extracted with chloroform and
analyzed by GC and/or HPLC (Scheme 4).
more than one reaction center in the nitroheteroarenes, also
the chromatographically determined product ratios are
given. The results obtained by HPLC analysis are in good
agreement with those from GC measurements. Whereas the
results of the two methods differ by 25% for the first entry
of Table 1, the deviation for all other systems is less than
10%. For further evaluation only the results obtained by
GC are considered.
Equation (1) represents the logarithm of the competition
constants kA/kB =k. By expressing all available competition
constants (GC) in this way, an overdetermined set of linear
equations [Eq. (1)] was obtained, which is solved by least
squares minimization[30] to give the krel values listed in
Figure 1. The activity of one ortho-position in nitrobenzene
Scheme 4. Competition experiment for determining the relative electro-
philic reactivities of two nitroarenes A and B.
6110
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 6108 – 6118

Reactions of Nitroheteroarenes with Carbanions
FULL PAPER
(3a) was defined as 1.0,[13] and the previously reported over-
all activities of 4-chloronitrobenzene (3d, krel =250),[13] 4-
methoxynitrobenzene (3b, krel =1.8),[14] 4-fluoronitrobenzene
(3c, krel =100),[14] and 1-nitronaphthalene (3e, krel =4600)[14]
were treated as invariable.
log kA ꢀ log kB ¼ log k
ð1Þ
The reactions of 5-nitrofuran-2-carbonitrile, 2-bromo-5-ni-
trothiophene, and 5-nitrothiazole with 1ꢀ gave complex mix-
tures of products, which could not be analyzed quantitative-
ly by GC and HPLC. Their electrophilic reactivities could,
therefore, not be determined by analogous competition ex-
periments. In line with these observations, nitrothiazoles
have previously been reported to decompose in the presence
of alkoxides.[31–33]
Direct rate measurements: In 2003, Lemek et al. showed
that the reactions of a-halocarbanions with 4-methoxynitro-
benzene (3b) yield persistent sH-adducts in DMF at
ꢀ408C.[8] The second-order rate constants for these addi-
tions were determined by UV/Vis spectroscopy. Analogous-
ly, we determined the rate constants for the additions of 1ꢀ
to 3b, 3d, and 2,4-dichloronitrobenzene (3 f, studied in refs.
[13] and [14]) by following the absorbance of the sH-adduct
at 425 nm (Table 2). To inhibit the elimination of HCl from
Table 2. Second-order rate constants k2 of the reactions of carbanion 1ꢀ
with vinylic and aromatic electrophiles in DMF at ꢀ408C.
[b]
Entry
A[a]
B
k2 (ꢀ408C) [mꢀ1 sꢀ1
]
1[c]
2[c]
3[c]
4[c]
5[c]
6[e]
7[e]
8[e]
1ꢀ
3b
1ꢀ
(2.26ꢁ0.12)”10ꢀ1
(2.34ꢁ0.17)”10ꢀ1
(2.95ꢁ0.11)”101
(2.77ꢁ0.08)”101
(1.95ꢁ0.11)”102
(1.01ꢁ0.03)”101
4.65ꢁ0.31[f]
3b
1ꢀ
3d
3d
3 f[d]
1ꢀ
1ꢀ
1ꢀ
10a
10b
10c
1ꢀ
1ꢀ
2.64ꢁ0.12
[a] Compound used in excess to ensure pseudo-first-order kinetics.
[b] Bold values are considered to be more reliable and are used for fur-
ther calculations. [c] Exponential increase of the sH-adduct (425 nm) is
followed. [d] 3 f: 2,4-dichloro-nitrobenzene. [e] Exponential decrease of
the electrophile band is followed. [f] DHꢀ =(28.3ꢁ1.1) kJmolꢀ1 and
DSꢀ =(ꢀ111ꢁ5) Jmolꢀ1 Kꢀ1
.
the sH-adducts, chloromethyl phenyl sulfone (1) was used in
slight excess over KOtBu. Entries 1/2and 3/4 of Table 2
show that the second-order rate constants determined for
these additions do not depend on the reaction conditions,
that is, which of the two reagents is used as the major com-
Figure 1. Overall relative reactivities krel (ꢀ408C) of nitroheteroarenes
toward the anion of chloromethyl phenyl sulfone (1ꢀ) based on k values
(Table 1) in relation to nitrobenzene (3a, krel =2.7).[13] The numbers in
the formula give the relative reactivities of the corresponding positions
with respect to one ortho-position of nitrobenzene. The numbers in pa-
rentheses indicate HPLC results, all other numbers result from GC analy-
sis. [a] Ref. [13]. [b] Ref. [14].
Chem. Eur. J. 2008, 14, 6108 – 6118
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6111

H. Mayr, M. Ma˛kosza et al.
ponent under pseudo-first-order conditions. The ratio of the
directly measured rate constants (k3d/k3b =123, from Table 2)
is in good agreement with the relative reactivities deter-
mined by competition experiments (k3d/k3b =139, from
Figure 1). Thus, the consistency of the two independent
methods of reactivity studies is confirmed.
To compare the reactivities of aliphatic and aromatic elec-
trophiles, the kinetics of the additions of 1ꢀ to diethyl benzy-
lidenemalonates 10a–c (Scheme 5) were studied analogously
Scheme 6. Reaction of the nitroethyl anion (9ꢀ) with the quinone me-
thides 12a–c.
Table 3. Second-order rate constants k2 and Eyring activation parameters
of the reactions of the nitroethyl anion (9ꢀ) with quinone methides 12a–c
and diethyl benzylidenemalonates 10a–c in DMF. The exponential de-
crease of UV/Vis absorbances of the electrophile was followed.
[a]
k2 (208C)
[mꢀ1 sꢀ1
DHꢀ
[kJmolꢀ1
DSꢀ
k2 (ꢀ408C) [mꢀ1 sꢀ1
]
G
]
A
]
[Jmolꢀ1 Kꢀ1
]
10a (4.52ꢁ0.18)”10ꢀ1 44.4ꢁ1.7 ꢀ101ꢁ6
(3.01ꢁ0.57)”10ꢀ3
(1.56ꢁ0.15)”10ꢀ3
(1.01ꢁ0.05)”10ꢀ3
ꢁ0.23)”101
10b (2.46ꢁ0.02)”10ꢀ1 45.4ꢁ0.8 ꢀ102ꢁ3
10c 1.76”10ꢀ1
46.1ꢁ0.4 ꢀ102ꢁ1
Scheme 5. Reactions of carbanion 1ꢀ with Michael acceptors 10a–c.
12a (1.15ꢁ0.04)”103 33.3ꢁ0.5 ꢀ7.355ꢁ2(2
12b (1.94ꢁ0.10)”102 30.2ꢁ1.9 ꢀ98ꢁ6
12c (8.97ꢁ0.46)”101 31.1ꢁ1.5 ꢀ101ꢁ5
6.15ꢁ1.52
2.62ꢁ0.53
[a] Calculated from Eyring parameters.
(Table 2, entries 6–8). The electrophiles 10a–c show strong
absorption bands in the UV/Vis spectra at lmax =400–
420 nm. When treated with an excess of 1ꢀ, complete decol-
orization of the solutions was observed, indicating quantita-
tive reactions. From the exponential decay of the absorban-
ces of 10a–c, the pseudo-first-order rate constants were de-
rived and plotted against the variable concentrations of 1ꢀ
to give the second-order rate constants listed in Table 2(en-
tries 6–8).[34]
about 29000 times more reactive than nitrobenzene (3a,
Figure 1) and the 2-position of 4d is 19000 times more reac-
tive than one of the corresponding positions of 3b.
The overall reactivity of 4-ethoxy-3-nitropyridine (4c,
k
rel =1000) towards 1ꢀ is approximately 17 times lower than
the activity of 2-methoxy-5-nitropyridine (4d). With the as-
sumption that the electronic effects of methoxy and ethoxy
are similar (Hammett s), the comparison of compounds 4c
and 4d shows that the activating effect of a nitro group is
more reduced by alkoxy groups in the ortho-position than
by alkoxy groups in the para-position. Similar effects were
observed for 2- and 4-methoxynitrobenzenes.[14]
The reaction course proposed in Scheme 5 was confirmed
by the isolation of 11a, which was obtained by protonation
of the adduct of 1ꢀ and benzylidenemalonate 10a.
Kinetic studies of the reaction of 1ꢀ with diethyl benzyli-
denemalonate 10b at various temperatures yielded the
Eyring activation parameters DHꢀ =(28.3ꢁ1.1) kJmolꢀ1
and DSꢀ =(ꢀ111ꢁ5) Jmolꢀ1 Kꢀ1.
2-Chloro-3-nitropyridine (4b,
krel =87000) is only 1.1
To link the kinetic data in Figure 1 and Table 2to our
comprehensive reactivity scales,[35] we also studied the kinet-
ics of the additions of nitroethyl anion (9ꢀ) to 10a–c and the
quinone methides 12a–c in DMF (Scheme 6) at various tem-
peratures. From the second-order rate constants, the Eyring
activation parameters and the second-order rate constants at
ꢀ408C were derived (Table 3).
times more reactive than 3-nitropyridine (4a), indicating a
neglible activating effect by chlorine. On the other hand,
chlorine has a noticeable activating effect in the benzene
series, and 2-chloro-nitrobenzene is 6.4 times more reactive
towards 1ꢀ than nitrobenzene (3a).[13,14] The preferred
attack of 1ꢀ at position 4 in 3-nitropyridine (4a) is in good
agreement with the relative reactivities of different chloro-
substituted 3-nitropyridines in nucleophilic aromatic substi-
tutions of chloride.[39] 4-Chloro-3-nitropyridine reacts 16
times faster with pyridine than 2-chloro-5-nitropyridine and
31 times faster than 2-chloro-3-nitropyridine.
Relative reactivities of heteroarenes: As pyridine is well
known to be p-electron deficient compared to benzene, it is
not surprising that the nitropyridines 4a–d are more electro-
philic than analogously substituted nitrobenzenes.[36–38] The
introduction of a ring nitrogen into nitrobenzene (3a) and
4-methoxynitrobenzene (3b) increases the electrophilic re-
activity by four orders of magnitude: 3-Nitropyridine (4a) is
Pyrrole is around 1010 times more nucleophilic than ben-
zene,[40] due to its higher p-electron density and lower aro-
maticity. Remarkably, in the case of vicarious nucleophilic
substitution the electrophilicities of the nitropyrroles 5a and
6112
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 6108 – 6118

Reactions of Nitroheteroarenes with Carbanions
FULL PAPER
5b are comparable to that of nitrobenzene (3a), indicating
that the increased electron density in pyrroles is compensat-
ed by the reduced aromaticity. Thereby, 1-methyl-3-nitropyr-
role (5b, krel =5.0) is five times more reactive than its 2-
nitro isomer 5a (krel =1.0).
The same ranking of reactivity was found for the two iso-
mers of 1-methyl-nitroimidazole (6a and 6b, Scheme 1).
The 4-nitro compound 6b, which is structurally related to
5b, reacts 31 times faster with 1ꢀ than 1-methyl-5-nitroimi-
dazole (6a, krel =18).
gies have then been calculated at the B3LYP/6–311+G(d,p)
A
level. Combination of these energies with thermochemical
corrections derived from a harmonic vibrational frequency
analysis at the B3LYP/6–31G(d) level yield the enthalpies
H298 at 298 K. For detailed information, see the Supporting
Information.
A plot of the logarithms of the partial rate constants
versus the calculated methyl anion affinities shows a moder-
ate correlation (Figure 3). Multiplication of log krel with
Figure 2illustrates that replacement of a CH group by ni-
trogen generally increases the electrophilicity of the aromat-
ic ring towards 1ꢀ. This effect is much larger in the six-mem-
Figure 2. Effect of an additional nitrogen atom in the ring on the overall
activity towards 1ꢀ.
bered than in the five-membered rings. Whereas 3-nitropyri-
dine (4a) is 29000 times more active than nitrobenzene
(3a), nitroimidazole 6a is only activated by a factor of 18 in
relation to nitropyrrole 5a. Important is also the position at
which the additional nitrogen atom is located in the ring: 1-
Methyl-4-nitroimidazole (6b) is activated by a factor of 110,
whereas the isomeric nitropyrazole 7 is only 19 times more
reactive than 5b.
Figure 3. Correlation of logarithmic relative partial reactivities (ꢀ408C)
of nitroheteroarenes versus their methyl anion affinities (B3LYP/6–311+
G(d,p)//B3LYP/6–31G(d)).
N
2.303 RT converts the y axis of Figure 3 into relative activa-
tion free energies DDGꢀ. The resulting slope DDGꢀ/DDHrxn
-
ꢀ
(CH3 )=0.29 indicates that approximately 30% of the cal-
Although thiophene is considerably more nucleophilic
than benzene, acceptor-substituted thiophene derivatives are
also known to be more active in SNAr reactions than analo-
gously substituted benzene derivatives.[41–43] The activity of
2-nitrothiophene (8) in the VNS reaction with 1ꢀ follows
this pattern. With krel =18000, compound 8 is the most
active five-membered heterocycle of Figure 1, comparable
to the nitropyridines 4a–d. Possibly the low aromaticity of
thiophene and the ability of sulfur to expand its electron
octet facilitates the accommodation of the negative charge
in the sH-adduct and therefore enhances the activity in nu-
cleophilic addition reactions.
culated differences in gas-phase methyl anion affinities are
reflected by the relative activation energies in solution. A
quantitative interpretation of this ratio is problematic, be-
cause it is well-known that the differences of ion stabiliza-
tion in the gas phase are generally attenuated in solution.[45]
From the small size of this ratio and the significant scatter
shown in Figure 3 one can conclude, however, that the elec-
trophilicities of the nitroarenes depend on the relative sta-
bilities of the s-adducts but that other, transition-state spe-
cific, properties contribute.
The correlation between the relative reactivities and the
LUMO energies of the nitroarenes is even worse (R2 =0.31,
Figure 4). Nitrobenzene (3a), one of the least reactive elec-
trophiles, and 2-methoxy-5-nitropyridine (4d), one of the
most reactive electrophiles, have almost the same LUMO
energies. Thus, LUMO energies by themselves are also not
suitable for predicting the relative reactivities of nitrohetero-
Quantum chemical calculations: The nitroheteroarenes 3–8
and the corresponding methyl anion adducts have been cal-
culated with Gaussian03.[44] Structures were optimized at the
B3LYP level using the 6–31G(d) basis set. Single-point ener-
Chem. Eur. J. 2008, 14, 6108 – 6118
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6113

H. Mayr, M. Ma˛kosza et al.
Figure 5. Second-order rate constants (Lmolꢀ1 sꢀ1) for the additions of 1ꢀ
to aromatic and vinylic electrophiles (DMF, ꢀ408C).
Figure 4. Correlation of logarithmic relative partial reactivities (ꢀ408C)
of nitroheteroarenes versus the corresponding LUMO energy (B3LYP/6–
31G(d)).
where s=nucleophile-specific slope parameter, N=nucleo-
philicity parameter, E=electrophilicity parameter.
arenes. Despite the poor correlations, one observation might
be significant: Systems, which strongly deviate in a positive
or negative direction from the correlation in Figure 3 usually
deviate in the same direction in the (log krel)/ELUMO correla-
tion (Figure 4). One, therefore, might argue that systems
where the DG8 and frontier orbital term enforce each other,
give rise to the deviations in one or the other direction. We
hesitate to interpret these data more quantitatively, because
neither the relative stabilities of the adducts (Figure 3) nor
the relative magnitudes of the LUMO coefficients (see Sup-
porting Information) can correctly predict the regioselectivi-
ty of the nucleophilic attack at compounds 3a, 4a, 4b, and
6a. A special effect directing into the ortho-position of the
nitro group seems to be operating. Though one might con-
sider the positive counter ions being responsible for this
orientation, the independence of the rate constants of the
nature of the counter ion argues against this interpreta-
tion.
For that purpose, the relative rate constants at ꢀ408C
given in Figure 1 have to be converted into second-order
rate constants (Lmolꢀ1 sꢀ1) at 2 80C. From the ratio k2
(Table 2)/krel (Figure 1) for the reaction of 1ꢀ with 3b
(0.126) and 3d (0.111) one can derive that multiplication of
krel from Figure 1 with the average value 0.119 yields the
second-order rate constants (ꢀ408C, DMF) for the reactions
of 1ꢀ with the nitroarenes 3–8.
From the temperature dependence of the reaction of 1ꢀ
with 10b in DMF an activation entropy of DSꢀ =
ꢀ111 Jmolꢀ1 Kꢀ1 was determined (see footnote [f] of
Table 2). As expected, this value is of the same order of
magnitude as those for other combinations of carbanions
with neutral electrophiles in DMF (Table 3) and was, there-
fore, used to transform the second-order rate constants at
ꢀ408C into values at 208C (for details see the Supporting
Information p. S76).
Figure 6 shows a linear correlation between the rate con-
stants (log k2) of the reactions of 1ꢀ with 10a–c at 208C
(from Table 4, last column) versus the E parameters of these
electrophiles. According to Equation (2), the slope yields s=
0.64, and the intercept on the abscissa gives N=26.64 for
the carbanion 1ꢀ in DMF.
Comparison of aromatic and aliphatic electrophiles: From
the second-order rate constants k2 of the reactions of 1ꢀ
with 10a–c and 3b,d at ꢀ408C in DMF (Table 2), one can
derive that the electrophilicities of the benzylidenemalo-
nates 10a–c are in between those of 3b and 3d (Figure 5).
Because electrophilicity parameters E for compounds
10a–c have recently been determined,[46] we can now include
the nitroarenes 3–8 (Figure 1) into the comprehensive elec-
trophilicity scale based on the correlation Equation (2):[35]
Substitution of N and s for 1ꢀ and the value of log k2, calcd
(208C) from Table 4 into Equation (2) allows one to calcu-
late the electrophilicity parameters E for the nitroheteroar-
enes 3–8, which are depicted in Figure 7 along with several
previously characterized electrophiles.
It should be noted that the slope parameter s for the carb-
anion 1ꢀ was derived from only three rate constants with
electrophiles in a relatively narrow range of reactivity. For
log k2 ð20 ꢂCÞ ¼ s ðN þ EÞ
ð2Þ
6114
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 6108 – 6118

Reactions of Nitroheteroarenes with Carbanions
FULL PAPER
Figure 6. Plot of log k2 for the reactions of 1ꢀ with 10a–c (208C, DMF,
Table 4) versus the electrophilicity parameters E of the benzylidenemalo-
nates 10a–c.
Table 4. Calculation of second-order rate constants k2 (DMF, 208C) for
the reactions of the carbanion 1ꢀ with the nitroarenes 3–8 and benzylide-
nemalonattes 10 from the corresponding relative rate constants at
ꢀ408C.
krel
k2
k2 , calcd
k2, calcd (208C)[d]
(ꢀ408C)[a]
(ꢀ408C)[b]
(ꢀ408C)[c]
[mꢀ1 sꢀ1
]
[mꢀ1 sꢀ1
]
A
4b 8.7”104
4a 7.8”104
–
–
–
–
–
1.0”104
9.3”103
2.1”103
2.0”103
5.5”102
2.0”102
1.2”102
6.6”101
3.0”101
1.2”101
1.1”101
1.0”101
4.7
5”104
5”104
1”104
1”104
5”103
2”103
2”103
9”102
5”102
2”102
2”102
2”102
1”102
7”101
6”101
2”101
1”101
1”101
6
8
1.8”104
4d 1.7”104
3e 4.6”103
3 f
–
1.95”102
4c 1.0”103
6b 5.5”102
3d 2.5”102
3c 1.0”102
–
–
2.77”101
–
–
10.1
4.65
2.64
–
–
–
7
9.3”101
10a
10b
10c
–
–
–
Figure 7. Electrophilicity scale according to Equation (2). [a] Ref. [47].
[b] Ref. [40]. [c] Ref. [34a]. [d] Ref. [48]. [e] Ref. [34b]. [f] Ref. [49].
[g] Ref. [50]. [h] Ref. [46].
2.6
2.1
6a 1.8”101
5b 5.0
6.0”10ꢀ1
3.2”10ꢀ1
2.1”10ꢀ1
1.2”10ꢀ1
3a 2.7
3b 1.8
5a 1.0
2.26”10ꢀ1
–
electrophilic reactivities of nitroheteroarenes in VNS reac-
tions, which were determined by competition experiments,
with the comprehensive electrophilicity scale based on
Equation (2). Because of the uncertainty in the nucleophilic-
ity parameters N and s for carbanion 1ꢀ in DMF, the E pa-
rameters given in Figure 7 should be considered preliminary.
However, the comparison of aromatic and nonaromatic
electrophiles shown in Figure 7 provides a reliable orienta-
tion, which can be used to guide synthetic studies until more
reliable electrophilicity parameters E for these compounds
become available.
[a] From competition experiments (Figure 1). [b] From direct rate meas-
urements (Table 2). [c] Calculated by multiplication of krel with the aver-
age factor 0.119. [d] Calculated with DSꢀ =ꢀ111 Jmolꢀ1 Kꢀ1 (for details
see the Supporting Information).
that reason, the E values for electrophiles, which differ by
several orders of magnitude from those of compounds 10a–
c, should be treated with caution.
Conclusion
The UV/Vis spectroscopically determined second-order rate
constants for the reactions of the sulfonyl-stabilized carban-
ion 1ꢀ with the aromatic (3b, 3d) and nonaromatic electro-
philes (10a–c) can be used to link the manifold of relative
Experimental Section
General: 1H and 13C NMR chemical shifts are expressed in ppm and
refer to TMS. DEPT and HSQC experiments were employed to assign
Chem. Eur. J. 2008, 14, 6108 – 6118
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6115

H. Mayr, M. Ma˛kosza et al.
the signals. Syringes used to transfer reagents were purged with dry nitro-
gen prior to use. All competitive and preparative VNS reactions were
carried out with magnetic stirring in flame-dried glassware under an at-
mosphere of dry nitrogen. Dry DMF was purchased (< 50 ppm H2O).
Cooling of the reaction vessels was performed by the use of a cryostat
unit. The yields of the products in competitive experiments were deter-
mined either by gas chromatography or HPLC using diphenyl sulfone as
an internal standard. GC was performed with nitrogen as mobile phase
and FID detector on a Thermo Electron Focus apparatus equipped with
an MN 25 m”0.25 mm stainless column packed with fused-silica and an
automatic injection unit (temperature gradient: 1508C [2min]–8 8C/min–
2808C [10 min]). For HPLC a CC 250/4 Nucleosil 120–3 normal-phase
column and n-heptane and ethyl acetate as mobile phase (gradient: 0–
100% ethyl acetate or 0–50% ethyl acetate in 45 min, detector: UV/Vis)
were used. The following starting materials were prepared according to
the published procedures: Chloromethyl phenyl sulfone (1),[15] 1-methyl-
2-nitropyrrole (4a),[51] 1-methyl-3-nitropyrrole (4b),[51] 1-methyl-5-nitroi-
midazole (6a),[52] 1-methyl-4-nitroimidazole (6b),[53] 1-methyl-4-nitropyr-
azole (7),[54] 2-nitrothiophene (8),[55] 2-bromo-5-nitrothiophene,[56] 5-nitro-
thiazole.[57,58]
Figure 9. HPLC analysis of the product mixture obtained in an experi-
ment in which 1-methoxy-4-nitrobenzene (3b) and 1-methyl-3-nitropyr-
role (5b) competed for 1ꢀ (diphenyl sulfone (2) as internal standard).
The product mixtures were analyzed by gas chromatography and high-
performance liquid chromatography. The product ratios were determined
relative to diphenyl sulfone (2) as an internal standard. To guarantee the
reproducibility of the obtained results, all examined VNS products were
first isolated on a preparative scale and characterized. Figure 8 and
Figure 9 show typical GC and HPLC chromatograms obtained for a VNS
experiment, in which 1-methoxy-4-nitrobenzene (3b) was competing with
N-methyl-3-nitropyrrole (5b) for 1ꢀ.
General procedure for preparative VNS reactions: A solution of KOtBu
(452mg, 2.50 mmol) in DMF (6 mL) was added to a solution of
1
(307 mg, 1.61 mmol) in DMF (5 mL) cooled to ꢀ408C and the mixture
was stirred for 30 s. A solution of the appropriate arene or heteroarene
in DMF (2mL) was added and the mixture was stirred for a further
5 min at ꢀ408C, then 1m HCl (15 mL) was added. The mixture was then
extracted with CH2Cl2 (3”40 mL). The combined organic layers were
dried over MgSO4, and the solvent was evaporated. The pure products
were isolated by column chromatography over silica gel or recrystalliza-
tion from EtOH.
General procedure for competitive VNS reactions: Chloromethyl phenyl
sulfone (95.3 mg, 0.500 mmol), diphenyl sulfone (43.7 mg, 0.200 mmol),
and the appropriate competing arenes/heteroarenes were dissolved in
DMF (4 mL) in a 10 mL round-bottomed Schlenk flask. A 1 mL portion
of this mixture was transferred to another 10 mL round-bottomed
Schlenk flask and cooled to ꢀ408C. Then a 0.6m KOtBu solution in THF
(0.84 mL, 0.50 mmol) was added and the mixture was stirred for 15 s at
ꢀ408C. 1m HCl (5 mL) and water (5 mL) were added and the mixture
was extracted with CH2Cl2 (4 mL). The organic layer was dried over
MgSO4 and then subjected to GC (injection volume: 1 mL) or HPLC (in-
jection volume: 10 mL). The reaction was repeated three times for every
pair.
2-Benzenesulfonylmethyl-4-ethoxy-3-nitropyridine (4co): Colorless crys-
tals, 23% yield, m.p. 146–1478C (EtOH); 1H NMR (400 MHz, CDCl3):
3
d=1.45 (t, 3J=7.2Hz, 3H; CH 2CH3), 4.21 (q, J=7.2Hz, 2H; C H2CH3),
4.73 (s, 2H; CH2), 6.96 (d, 3J=5.7 Hz, 1H; 5-H), 7.52–7.80 (m, 5H;
C6H5), 8.42ppm (d, 3J=5.9 Hz, 1H; 6-H); 13C NMR (100.6 MHz,
CDCl3): d=14.1 (CH3), 60.2(CH 2-S), 66.0 (CH2CH3), 108.9 (C-5), 128.4
(CAr-H), 129.2 (CAr-H), 134.1 (CAr-H), 138.5 (CAr), 139.5 (CAr), 142.5
(CAr), 151.9 (C-6), 157.5 ppm (CAr); MS (ESI): 667.4 [2M+Na]+, 345.3
[M+Na]+, 323.3 [MH]+; MS (EI): m/z (%): 323 (3) [MH]+, 257 (11), 241
(23), 213 (21), 171 (10), 165 (30), 154 (12), 153 (32), 141 (11), 125 (12),
110 (17), 107 (11), 95 (32), 83 (20), 77 (100), 55 (18), 54 (11), 52 (18), 51
(37); elemental analysis calcd (%) for C14H14N2O5S (322.3): C 52.17, H
4.38, N 8.69, S 9.95; found: C 52.08, H 4.40, N 8.68, S 10.14.
Figure 8. GC analysis of the product mixture obtained in an experiment
in which 1-methoxy-4-nitrobenzene (3b) and 1-methyl-3-nitropyrrole
(5b) competed for 1ꢀ (diphenyl sulfone (2) as internal standard).
The relative activities determined for particular pairs of nitroheteroar-
enes were calculated from the observed product ratios with Equation (3).
ꢀ
ꢀ
ꢁ
ꢁ
P
2-Benzenesulfonylmethyl-4-ethoxy-5-nitropyridine (4cp): Pale yellow
crystals, 57% yield, m.p. 150–1518C (EtOH); 1H NMR (400 MHz,
CDCl3): d=1.53 (t, 3J=7.2Hz, 3H; CH 2CH3), 4.30 (q, 3J=7.0 Hz, 2H;
CH2CH3), 4.57 (s, 2H; CH2-S), 7.23 (s, 1H; 6-H), 7.53–7.74 (m, 5H;
C6H5), 8.74 (s, 1H; 3-H); 13C NMR (100.6 MHz, CDCl3): d=14.1 (CH3),
64.3 (CH2-S), 66.2( CH2CH3), 111.1 (C-3), 128.3 (CAr-H), 129.3 (CAr-H),
134.2(C Ar-H), 136.1 (CAr), 137.9 (CAr), 146.5 (C-6), 154.6 (CAr),
158.5 ppm (CAr); MS (ESI): 667.4 [2M+Na]+, 345.3 [M+Na]+, 323.4
[MH]+; MS (EI): m/z (%): 258 (52), 257 (100), 230 (11), 229 (63), 183
½Aꢃ0
½Bꢃ0
ꢀ
½PA
½PB
ꢃ
ln
½Aꢃ0
kA
kB
¼
ð3Þ
P
ꢀ
ꢃ
ln
½Bꢃ0
[A]0 and [B]0 are starting concentrations of the nitroheteroarenes; [PA]
and [PB] are the concentrations of reaction products of nitroarenes A
and B, respectively.
6116
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 6108 – 6118

Reactions of Nitroheteroarenes with Carbanions
FULL PAPER
(16), 107 (17), 78 (11), 77 (66), 51 (29), 39 (14); elemental analysis calcd
(%) for C14H14N2O5S (322.3): C 52.17, H 4.38, N 8.69, S 9.95; found: C
52.04, H 4.41, N 8.79, S 10.03.
[14] a) S. Blazej, Dissertation 2007, Institute of Organic Chemistry, Polish
Academy of Sciences, Warsaw; b) S. Blazej, M. Makosza, unpublish-
ed results.
[15] M. Makosza, J. Golinski, J. Baran, J. Org. Chem. 1984, 49, 1488–
1494.
5-Benzenesulfonylmethyl-1-methyl-4-nitro-1H-pyrazole (7o): Pale green
crystals, 86% yield, m.p. 193–1958C (EtOH); 1H NMR (300 MHz,
[16] M. Makosza, S. Ludwiczak, J. Org. Chem. 1984, 49, 4562–4563.
[17] Following notations are used throughout this paper: 3a, 3b, 3c, ..,
CDCl3): d=4.10 (s, 3H; CH3), 4.95 (s, 2H; CH2), 7.49–7.72(m, 5H; C
-
Ar
H), 8.01 ppm (s, 1H; 3-H); 13C NMR (75.5 MHz, CDCl3): d=38.8 (CH3),
51.4 (CH2), 128.5 (2 CAr-H), 129.4 (2 CAr-H), 129.7 (2 CAr), 134.9 (CAr-H),
136.0 (CAr-H), 136.9 ppm (CAr); elemental analysis (%) calcd for
C11H11N3O4S: C 46.97, H 3.94, N 14.94, S 11.40; found: C 47.04, H 3.95,
N 14.92, S 11.76.
4a, 4b, .., 7, etc. denote the nitro(hetero)arene. The additional
A
letter (o=ortho, p=para, or pseudo-para) indicates the position of
the CH2SO2Ph substituent in relation to the nitro group.
[18] M. Makosza, B. Chylinska, B. Mudryk, Liebigs Ann. Chem. 1984, 8–
14.
[19] M. Makosza, A. Tyrala, Synthesis 1987, 1142–1144.
[20] M. Makosza, S. Ludwiczak, Pol. J. Chem. 1998, 72, 1168–1172.
[21] E. Kwast, M. Makosza, Tetrahedron Lett. 1990, 31, 121–122.
[22] M. Makosza, E. Slomka, Bull. Pol. Acad. Sci. Chem. 1984, 32, 69–
74.
[23] M. Makosza, E. Kwast, Bull. Pol. Acad. Sci. Chem. 1987, 35, 287–
292.
[24] M. D. Crozet, V. Remusat, C. Curti, P. Vanelle, Synth. Commun.
2006, 36, 3639–3646.
[25] M. D. Crozet, P. Perfetti, M. Kaafarani, M. P. Crozet, P. Vanelle,
Lett. Org. Chem. 2004, 1, 326–330.
[26] M. D. Crozet, P. Perfetti, M. Kaafarani, P. Vanelle, M. P. Crozet, Tet-
rahedron Lett. 2002, 43, 4127–4129.
[27] M. K. Bernard, M. Makosza, B. Szafran, U. Wrzeciono, Liebigs Ann.
Chem. 1989, 545–549.
[28] M. K. Bernard, Tetrahedron 2000, 56, 7273–7284.
[29] M. Makosza, E. Kwast, Tetrahedron 1995, 51, 8339–8354.
[30] Calculated with WhatꢁsBest! 7.0 nonlinear solver, Lindo systems.
[31] G. Bartoli, O. Sciacovelli, M. Bosco, L. Forlani, P. E. Todesco, J.
Org. Chem. 1975, 40, 1275–1278.
[32] G. Bartoli, M. Fiorentino, F. Ciminale, P. E. Todesco, J. Chem. Soc.
Chem. Commun. 1974, 732.
[33] J. Liebscher, Methoden Org. Chem. (Houben-Weyl), 4th ed. 1952-,
Vol. E8b, 1994, pp. 1–398.
2-[2-Benzenesulfonyl-2-chloro-1-(4-dimethylaminophenyl)ethyl]malonic
acid diethyl ester (11a): A 0.52m solution of KOtBu in DMF (0.96 mL,
0.50 mmol) was added slowly to a solution of 1 (0.50 mmol) in DMF
(5 mL) at ꢀ408C. The mixture was stirred for 2min before a solution of
10a (0.50 mmol) in DMF (2.5 mL) was added dropwise within 1 min.
After 20 min the mixture was allowed to warm up to 08C, poured into
cooled 3% aqueous HCl (100 mL), and then extracted with ethyl acetate
(3”20 mL). After drying over MgSO4 and removal of the solvent in
vacuo at room temperature, purification of the residue by column chro-
matography (SiO2, hexane/ethyl acetate 3:1) gave a yellow oil in 69%
1
3
yield. H NMR (300 MHz, CDCl3): d=1.04 (t, J=7.2Hz, 3H; CH 2CH3),
1.24 (t, 3J=7.2Hz, 3H; CH 2CH3), 2.91 (s, 6H; N(CH3)2), 3.97 (q, 3J=
AHCTREUNG
7.2Hz, 2H; C H2CH3), 4.18 (q, 3J=7.2Hz, 2H; C H2CH3), 4.20 (dd, 3J=
9.2Hz, 3J=6.2Hz, 1H; CH), 4.53 (d, 3J=9.0 Hz, 1H; CH), 5.59 (d, 3J=
6.3 Hz, 1H; CH), 6.56 (d, 3J=8.7 Hz, 2H; CArH), 7.24 (d, 3J=9.0 Hz,
2H; CArH), 7.43–7.60 (m, 3H; CAr-H), 7.74–7.77 ppm (m, 2H; CArH);
13C NMR (75.5 MHz, CDCl3): d=13.9 (CH2CH3), 14.1 (CH2CH3), 40.5
(N
A
ACHTREUNG
(CHCl), 112.0 (2”CAr-H), 121.9 (CAr), 129.1
AHCTREUNG
(2”CAr-H), 134.1 (CAr-H), 137.9 (CAr-S), 150.4 (CAr-N), 167.6 (CO2Et),
168.2ppm ( CO2Et); MS (EI): m/z (%): 481.1 (22) [M+], 341.1 (21), 340.1
(17), 339.1 (77), 293.2 (16), 292.2 (100), 219.1 (28), 183.1 (25), 182.1 (14),
181.1 (97), 180.1 (20), 174.1 (31), 158.1 (25), 146.1 (12), 145.1 (18), 144.1
(15), 77.0 (15): HR-MS (EI): calcd for C23H28ClNO6S: 481.1326, found:
481.1313.
[34] For further details on kinetics of carbanions with Michael acceptors
see: a) S. T. A. Berger, F. H. Seeliger, F. Hofbauer, H. Mayr Org.
Biomol. Chem. 2007, 5, 3020–3026; b) F. Seeliger, S. T. A. Berger,
G. Y. Remennikov, K. Polborn, H. Mayr J. Org. Chem. 2007, 72,
9170–9180; c) O. Kaumanns, H. Mayr, J. Org. Chem. 2008, 73,
2738–2745.
Acknowledgements
[35] H. Mayr, A. R. Ofial, Pure Appl. Chem. 2005, 77, 1807–1821.
[36] G. Illuminati, F. Stegel, Adv. Heterocycl. Chem. 1983, 34, 305–444.
[37] J. Murto, L. Nummela, M. L. Hyvçnen, M. L. Murto, Acta Chem.
Scand. 1972, 26, 1351–1357.
[38] M. R. Crampton, T. A. Emokpae, C. Isanbor, Eur. J. Org. Chem.
2007, 1378–1383.
Financial support by the Deutsche Forschungsgemeinschaft (SFB 749)
and the Fonds der Chemischen Industrie is gratefully acknowledged. We
thank Prof. Dr. H. Zipse for the help with the quantum chemical calcula-
tions, P. Gramlich for support with HPLC analysis, O. Kaumanns for syn-
thesis of the diethyl benzylidenemalonates, and the Foundation for Polish
Science for a Humboldt Research Fellowship to H. M.
[39] R. R. Bishop, E. A. S. Cavell, N. B. Chapman, J. Chem. Soc. 1952,
437–446.
[40] H. Mayr, T. Bug, M. F. Gotta, N. Hering, B. Irrgang, B. Janker, B.
Kempf, R. Loos, A. R. Ofial, G. Remennikov, H. Schimmel, J. Am.
Chem. Soc. 2001, 123, 9500–9512.
[41] D. Spinelli, G. Consiglio, R. Noto, V. Frenna, J. Org. Chem. 1976,
41, 968–971.
[42] D. Spinelli, G. Consiglio, J. Chem. Soc. Perkin Trans. 2 1975, 1388–
1391.
[43] G. Doddi, G. Illuminati, P. Mencarelli, F. Stegel, J. Org. Chem. 1976,
41, 2824–2826.
[44] Gaussian 03, Revision D.03, M. J. Frisch, G. W. Trucks, H. B. Schle-
gel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgomer-
y, Jr., T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyen-
gar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N.
Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda,
O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian,
J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E.
Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W.
Ochterski, P. Y. Ayala, K. Morokuma, G. A. Voth, P. Salvador, J. J.
[1] J. Golinski, M. Makosza, Tetrahedron Lett. 1978, 19, 3495–3498.
[2] M. Makosza, J. Winiarski, Acc. Chem. Res. 1987, 20, 282–289.
[3] O. N. Chupakhin, V. N. Charushin, H. C. v. d. Plas, Nucleophilic Aro-
matic Substitution of Hydrogen, Academic Press, San Diego, 1994.
[4] F. Terrier, Nucleophilic Aromatic Displacement: The influence of the
Nitro group, VCH, New York, 1991.
[5] M. Makosza, K. Wojciechowski, Liebigs Ann. 1997, 1805–1816.
[6] M. Makosza, K. Wojciechowski, Chem. Rev. 2004, 104, 2631–2666.
[7] M. Makosza, T. Glinka, J. Org. Chem. 1983, 48, 3860–3861.
[8] T. Lemek, M. Makosza, D. S. Stephenson, H. Mayr, Angew. Chem.
2003, 115, 2899–2901; Angew. Chem. Int. Ed. 2003, 42, 2793–2795.
[9] M. Makosza, A. Kwast, J. Phys. Org. Chem. 1998, 11, 341–349.
[10] M. Makosza, T. Lemek, A. Kwast, F. Terrier, J. Org. Chem. 2002, 67,
394–400.
[11] M. Makosza, T. Glinka, A. Kinowski, Tetrahedron 1984, 40, 1863–
1868.
[12] M. Makosza, Synthesis 1991, 103–111.
[13] M. Makosza, O. Lobanova, A. Kwast, Tetrahedron 2004, 60, 2577–
2581.
Chem. Eur. J. 2008, 14, 6108 – 6118
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6117

H. Mayr, M. Ma˛kosza et al.
Dannenberg, V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C.
Strain, O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari,
J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cio-
slowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaro-
mi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng,
A. Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W.
Chen, M. W. Wong, C. Gonzalez, and J. A. Pople, Gaussian, Inc.,
Wallingford CT, 2004.
[50] R. Lucius, R. Loos, H. Mayr, Angew. Chem. 2002, 114, 97–102;
Angew. Chem. Int. Ed. 2002, 41, 91–95.
[51] H. J. Anderson, Can. J. Chem. 1957, 35, 21–27.
[52] C. E. Hazeldine, F. L. Pyman, J. Winchester, J. Chem. Soc. Trans.
1924, 125, 1431–1441.
[53] M. Lissel, Liebigs Ann. Chem. 1987, 77–79.
[54] N. Nishiwaki, T. Ogihara, T. Takami, M. Tamura, M. Ariga, J. Org.
Chem. 2004, 69, 8382–8386.
[45] C. Schindele, K. N. Houk, H. Mayr, J. Am. Chem. Soc. 2002, 124,
11208–11214.
[55] B. ꢂstman, Acta Chem. Scand. 1968, 22, 1687–1689.
[56] V. S. Babasinian, J. Am. Chem. Soc. 1935, 57, 1763–1764.
[57] H. v. Babo, B. Prijs, Helv. Chim. Acta 1950, 33, 306–313.
[58] G. Klein, B. Prijs, H. Erlenmeyer, Helv. Chim. Acta 1955, 38, 1412–
1414.
[46] O. Kaumanns, H. Mayr, 2008, unpublished results .
[47] H. Mayr, B. Kempf, A. R. Ofial, Acc. Chem. Res. 2003, 36, 66–77.
[48] T. Lemek, H. Mayr, J. Org. Chem. 2003, 68, 6880–6886.
[49] F. Terrier, S. Lakhdar, T. Boubaker, R. Goumont, J. Org. Chem.
2005, 70, 6242–6253.
Received: February 21, 2008
Published online: May 30, 2008
6118
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 6108 – 6118