Substituent effects on the electrophilic activity of nitroarenes in reactions with carbanions

Article abstract of DOI:10.1002/chem.200800821

The effect on electrophilic activity of substituents located para, ortho, and meta to the nitro group of nitrobenzenes was determined by using vicarious nucleophilic substitution of hydrogen (VNS) with the carbanion of chloromethyl phenyl sulfone (1) as the model process. Values for the relative activities of substituted nitroarenes are given relative to nitrobenzene, which was taken as the standard. This process was chosen as a model reaction because it meets key criteria, such as the wide range of substituents that can be present on the nitrobenzene ring, a low sensitivity to steric hindrance, and in particular the possibility of ensuring conditions in which the overall relative rates of reaction in competitive experiments are equal to the relative rates of nucleophilic addition. The values of relative rates of addition, which were taken to be a measure of electrophilic activity, were determined by competitive experiments in which pairs of nitroarenes competed for the VNS reaction with carbanion of 1. A comprehensive set of data for effects of substituents on the electrophilic activity of nitroarenes is presented for the first time.

Full text of DOI:10.1002/chem.200800821

FULL PAPER
DOI: 10.1002/chem.200800821
Substituent Effects on the Electrophilic Activity of Nitroarenes in Reactions
with Carbanions
Sylwia Błazej and Mieczysław Ma˛kosza*[a]
˙
Abstract: The effect on electrophilic
activity of substituents located para,
ortho, and meta to the nitro group of
nitrobenzenes was determined by using
vicarious nucleophilic substitution of
hydrogen (VNS) with the carbanion of
chloromethyl phenyl sulfone (1) as the
model process. Values for the relative
activities of substituted nitroarenes are
given relative to nitrobenzene, which
was taken as the standard. This process
was chosen as a model reaction be-
cause it meets key criteria, such as the
wide range of substituents that can be
present on the nitrobenzene ring, a low
sensitivity to steric hindrance, and in
particular the possibility of ensuring
conditions in which the overall relative
rates of reaction in competitive experi-
ments are equal to the relative rates of
nucleophilic addition. The values of
relative rates of addition, which were
taken to be a measure of electrophilic
activity, were determined by competi-
tive experiments in which pairs of ni-
troarenes competed for the VNS reac-
tion with carbanion of 1. A compre-
hensive set of data for effects of sub-
stituents on the electrophilic activity of
nitroarenes is presented for the first
time.
Keywords: carbanions
tive experiments
·
competi-
·
electrophilic
activity · nitroarenes · nucleophilic
substitution
Introduction
In recent years, the most general and successful approach to
quantitative characterization of electrophilicity and nucleo-
philicity was elaborated by Mayr et al.,[5] who constructed a
general scale of such activities.
The introduction of substituents into aromatic rings by elec-
trophilic substitution is one of the most important processes
in organic synthesis. Reactions such as nitration, halogena-
tion, sulfonation, and Friedel–Crafts-type reactions of
arenes are widely used for the manufacture of commercially
important compounds and can be considered to be primary
processes for the functionalization of aromatic rings.[1]
Early studies into the effects of substituents on the rates
and orientation of electrophilic substitution in benzene,
using mainly nitration, laid the foundations for the formula-
tion of the concept of electronic effects of substituents and
the general rules that govern the reactivity of organic com-
pounds.[1–3] Furthermore, the effects of substituents on reac-
tion rates were quantified by development of the linear free
energy relationship represented by the Hammett equation.[4]
On the other hand, much less is known about the effects
of substituents on reactions between nucleophilic agents and
arenes. First, only electron-deficient aromatic rings, such as
those in nitroarenes,[6] transition-metal complexes of
arenes,[7] azulenes,[8] and azines,[9] can add nucleophilic
agents, a process paralleling the first, rate-limiting step of
electrophilic substitution. Second, to form substitution prod-
ucts, the adducts of nucleophiles to electron-deficient arenes
should lose substituents with an electron pair that, for obvi-
ous reasons, cannot be hydride anions.
Thus, contrary to reactions of electrophiles that replace
hydrogen that departs from the intermediate adduct as a
proton, the main reaction of nucleophilic agents with nitro-
arenes was considered to be the replacement of a leaving
group, such as F, Cl, or MeO, ortho or para to the nitro
group, which proceeds by an SNAr addition–elimination
mechanism.
[a] Dr. S. Błaz˙ej, Prof. Dr. M. Ma˛kosza
Institute of Organic Chemistry
Polish Academy of Sciences
Kasprzaka 44/52
The kinetic characteristics of this process appear to be
suitable for determination of the effects of substituents on
electrophilic activity because, as a rule, the addition is the
rate-limiting step.[6,10] There are numerous papers reporting
the effects of substituents on the rate of SNAr reactions,
01-224 Warsaw (Poland)
Fax : (+48)22-632-6681
E-mail: icho-s@icho.edu.pl
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200800821.
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which are collected in the monographs of Miller[11] and Ter-
rier,[6] but the reported results are of limited value as a mea-
sure of the electrophilic activity of nitroarenes for several
reasons: 1) the rate of SNAr depends strongly on the nature
of the leaving group, thus the substituent effect can be com-
pared only for replacement of the same leaving group,
2) leaving groups should be located ortho or para to the
nitro group, which limits the possibility of varying the posi-
tions of the substituents studied, and 3) the most important
limitation is due to the fact that formation of the key inter-
mediates, sX adducts (X=halogen or other leaving group),
is a secondary process that proceeds more slowly than the
formation of sH adducts. In spite of many early observations
that nucleophiles add to nitroarenes in positions occupied
by hydrogen faster than in similarly activated positions oc-
cupied by halogens,[12] this general rule was recognized only
about 30 years ago. On this basis, a new reaction, called the
vicarious nucleophilic substitution of hydrogen (VNS),[13]
and a few other variants of nucleophilic substitution of hy-
drogen were found.[14]
The VNS is a reaction between nucleophiles that contain
a leaving group X at the nucleophilic center, for instance a-
halocarbanions, and electron-deficient arenes, mainly nitro-
arenes. It proceeds by the addition of such nucleophiles to
nitroaromatic rings in positions occupied by hydrogen to
give sH adducts that, upon base-induced b-elimination of
HX followed by acidic treatment, give products in which hy-
drogen is replaced with the nucleophile moiety. The reaction
is exemplified in Scheme 1.The VNS reaction is quite gener-
ducts by the base-induced b-elimination of HX, as shown in
Scheme 2.[19]
Scheme 2. Mechanistic picture of the VNS reaction with a-X-carbanions
(X=nucleofugal group).
Experiments with a fast radical clock suggest that forma-
tion of the sH adducts proceeds as a one-step nucleophilic
addition, not a two-step single-electron transfer and anion
radical radical coupling.[20] The overall mechanistic picture
of the VNS reaction with carbanions is shown in Scheme 2.
According to this mechanism, the rate of formation of the
s
H adduct is expressed in Equation (1):
VsH ¼ k1½ArNO2ꢁ½Cꢀꢁꢀkꢀ1½sHꢁ
ð1Þ
whereas the rate of formation of the product (P) is:
VP ¼ k2½sHꢁ½Bꢀꢁ
ð2Þ
and the rate of dissociation of the s adduct to the starting
material:
VD ¼ kꢀ1½sHꢁ
ð3Þ
Depending on the conditions and the kind of carbanion
and nitroarene used, the relative rates of these processes,
that is, nucleophilic addition, dissociation of the s adducts
into starting reagents, and the b-elimination of HX (i.e., the
relationship between k1, kꢀ1, and k2), can vary greatly, and
the relative rates obviously also depend on the position in
the nitroaromatic ring at which the addition takes place. Be-
cause VNS can proceed in two or even three positions in
many nitroarenes, the ratio of isomers depends on the rela-
tionship between these rate constants and the conditions.
Herein, we can consider two borderline cases. The first case
occurs when the rate of conversion of the s adduct into
product P is much higher than the rate of its dissociation
(i.e., k2[sH][Bꢀ]@kꢀ1[sH]), all sH adducts are converted into
products once produced, regardless of the rates of their for-
mation. In this case, the orientation of substitution is deter-
mined by the relation of rates of addition in different posi-
tions, and the process is kinetically controlled. The second
borderline case occurs when k2[sH][Bꢀ]!kꢀ1[sH]; in this
case, the sH adducts are in equilibrium with the starting ma-
Scheme 1. The VNS of 4-chloronitrobenzene with the carbanion of
chloroACHTUNGTRENNUNGmethyl phenyl sulfone.
al with respect to carbanions and electron-deficient arenes.
All carbanions containing nucleofugal groups X (X=Cl, Br,
OR, SPh, N+R3, and so on) at the carbanionic center that
can be eliminated from the sH adducts by base-induced b-
elimination of HX can react with sufficiently electrophilic
arenes along the VNS pathway.[15] In addition, O and N nu-
cleophiles that contain leaving groups, such as alkylhydro-
peroxide anions,[16] anions of hydrazine, hydroxylamine,[17]
and sulfenamide[18] derivatives, can be used in this reaction
to give nucleophilic hydroxylation and amination processes.
Mechanistic studies confirmed that VNS proceeds by two
distinct steps: formation of the sH adducts of nucleophiles
ꢀ
H
ꢀ
(Nu X ) to arenes, followed by conversion of these s ad-
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Substituent Effects
FULL PAPER
terials and the orientation is governed by the relative con-
centrations of isomeric sH adducts, the value of k1i /kꢀi 1 =Ki
(Ki denotes equilibrium constants), and the relation of the
rate constants ki2 (Curtin–Hammett principle), so this pro-
cess is thermodynamically controlled.[21]
These characteristics of VNS make this process an appro-
priate tool for estimating the effects of substituents on the
electrophilic activity of arenes. Indeed, becuase VNS pro-
ceeds by the addition of nucleophiles in positions occupied
by hydrogen ortho or para to the nitro group and this addi-
tion is the primary process, the nitroarene ring may contain
a variety of substituents located ortho, meta, or para to the
nitro group, and therefore, meta, ortho, and/or para to the
reaction sites. Consequently, there are wide possibilities to
study effects of these substituents on the rate of nucleophilic
addition and therefore, the electrophilic activity of the nitro-
arenes.
verse reaction. According to the VNS mechanism shown in
Scheme 2 and the kinetic equations [Eqs. (1), (2), and (3)],
the value of k2[Bꢀ] should be much higher than that of kꢀ1
so all sH adducts are converted into VNS products once
formed. The second requirement is that the concentrations
of the competing nitroarenes should be in excess relative to
1ꢀ during the reaction.
Under conditions that assure kinetic control (i.e., k2[Bꢀ]@
kꢀ1), there is a high possibility that k1[Cꢀ]>k2[Bꢀ], which
means the rate of addition exceeds that of elimination, and
thus the rate of formation of the VNS products does not re-
flect the rate of addition. In this situation, sH adducts accu-
mulate in the reaction mixture and the rate of VNS deter-
mined in kinetic experiments cannot be used as a measure
of the rate of addition. The accumulation of sH adducts was
observed experimentally and used to execute the cine substi-
tution of the nitro group.[23] On the other hand, in this situa-
tion the ratio of the VNS products determined in competi-
tive experiments precisely reflects the ratio of the rates of
addition because sH adducts, once formed, are converted
into the VNS products.
Results and Discussion
Herein, we present the results of our studies on the effects
of substituent on the electrophilic activity of nitroarenes in
reactions with nucleophiles by using VNS as a model pro-
cess. For these studies, a proper model nucleophile was
needed, that is, one with sufficient stablity to be handled
without decomposition, sufficient nucleophilicity to react
with moderately active nitroarenes, low steric bulk, and a
leaving group X that can assure rapid elimination of HX
from the intermediate sH adducts. Taking these criteria into
account, we chose the carbanion of chloromethyl phenyl sul-
fone (1) because, contrary to other a-halocarbanions, it is
relatively stable in the absence of air and humidity at low
temperatures. Thus, the K+ salt of this carbanion decom-
posed only to a low extent at ꢀ408C in DMF (less than 5%
after 0.5 h; DMF=N,N-dimethylformamide). Although
SO2Ph is rather a bulky group, 1ꢀ does not experience steri-
cal difficulties during addition to nitroarenes; for example, it
reacts readily in the 2-position of 3-halonitrobenzenes.[22] We
have already observed that tBuOK is a sufficiently strong
base to deprotonate 1 and to promote rapid elimination of
HCl from the sH adducts, and DMF is a good solvent for
this reaction.[19]
For technical reasons we have chosen to determine the
relative rate constants of addition of this carbanion to nitro-
arenes by performing competitive experiments relative to ni-
trobenzene, which was used as the standard. Competitive
experiments consist of treatment of a mixture of two differ-
ent nitroarenes with a small quantity of 1ꢀ and excess base,
followed by GLC analysis of the mixture of VNS products.
The composition of the mixture reflects the relationship be-
tween the rates of VNS of the two competing nitroarenes,
and consequently the relationship between the rate con-
stants of the addition reaction, provided that the reaction
proceeds under kinetic control, namely, that the conditions
assure that the rate of conversion of the intermediate sH ad-
ducts into products of the VNS reaction is faster than the re-
Competitive experiments provide a convenient way to de-
termine relative rate constants. The experimental technique
is simple, does not require advanced spectral instrumenta-
tion for recording the kinetics of fast reactions, and can be
used for nitroarenes that form more than one isomeric prod-
uct and differ substantially in activity. Moreover, competi-
tive experiments, unlike spectral measurements, can be car-
ried out in concentrations similar to those used in prepara-
tive procedures.
It should be noted that in one of our preceding papers we
have already presented an application of this method for de-
termining the effects of halogens on the electrophilic activity
of a narrow range of halonitrobenzenes.[24]
For identification of the VNS products and quantitative
analysis of the mixtures produced in the competitive experi-
ments, samples of all expected products were synthesized in
advance by preparative-scale VNS reaction of 1 with indi-
vidual nitroarenes. Most of these VNS products have been
described in our earlier papers.[25,26] Details of the analytical
and spectral data of new compounds are given in the Exper-
imental Section and Supporting Information. These com-
pounds were used for the calibration necessary for quantita-
tive GLC analyses of the reaction mixtures produced in the
competitive experiments.
After some preliminary experiments, we found conditions
that assured kinetic control and gave reproducible results.
These conditions are essentially the same as reported earli-
er.[24] The procedure for the competitive experiments is
shown in simplified way in Scheme 3.
Scheme 3. Schematic procedure of the competitive experiments.
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M. Ma˛kosza and S. Błaz˙ej
A solution of tBuOK (4 mol per mole of 1) in DMF was
added to a solution of 1, a mixture of two competing nitroar-
enes A and B (2–6 m excess w.r.t. 1), and diphenyl sulfone
(internal standard) in DMF at ꢀ408C. The mixture was
stirred at ꢀ408C for 15 s, quenched with aqueous HCl, ex-
tracted with methylene chloride, and analyzed by GLC. The
experiments were repeated 3 or 4 times and the results were
averaged. Under these conditions, the reaction of 1 with ni-
trobenzene gave two isomeric products of VNS in positions
2 and 4 in a ratio of ꢂ2.9. It should be stressed that addition
of carbanion 1ꢀ to nitrobenzene preferentially proceeds
ortho to the nitro group. Because the rates of reaction of
substituted nitroarenes differ substantially, to keep the con-
centrations of the competing arenes constant and maintain
comparable concentrations of products, the starting concen-
trations of the competing arenes were chosen according to
their relative activity. The methods of calculation of relative
rates of addition based on GLC analysis of the mixture of
products are presented in Supporting Information. More-
over, because quantitative GLC analysis of the products
mixtures is unfeasible when the activities of competing ni-
troarenes differ substantially, in the majority of cases the
relative activities of substituted nitrobenzenes were deter-
mined not in direct competition with nitrobenzene, but with
other nitrobenzenes with less different activities. To verify
the results, the relative activities of particular nitroarenes
were determined in competing experiments with two differ-
ent nitroarenes. The results of competing experiments be-
tween particular pairs of substituted nitrobenzenes are given
in the Supporting Information. The relative activities deter-
mined by competition between two different nitroarenes
differ slightly, thus two values are listed in the Supporting
Information, whereas the averaged values are given in the
main body of this paper. In the case of nitrobenzene and 2-
and 3-substituted nitrobenzenes, two or even three isomeric
VNS products are formed, therefore in further discussions
of the substituent effects we will use values for the partial
activity of a given position in substituted nitrobenzenes rela-
tive to the ortho position in nitrobenzene and also values for
the overall activity. These numbers represent the rates of ad-
dition of 1ꢀ to all active positions in substituted nitroben-
zenes relative to the combined rates of addition of 1ꢀ in the
para and both ortho positions of nitrobenzene. In further
discussion we will consider that the nitro group always occu-
pies position 1, and the positions of substituents will be
numbered accordingly.
for the b-elimination step, which thus allows equilibration of
the addition step. For this purpose, the potassium salt of 1ꢀ
in DMSO (dimethyl sulfoxide) was slowly added to solu-
tions of nitroarenes in DMSO at room temperature
(Scheme 4). Under these conditions, b-elimination is in-
Scheme 4. The VNS reaction of 1ꢀ with nitroarenes under thermodynam-
ic control.
duced by the carbanion being a much weaker base than
tBuOK, thus the value of k2 is low and, moreover, the carb-
anion is in low concentration, so the kꢀ1 @k2[Bꢀ] condition
is assured. The results are given in Table 1 for comparison
with orientation under kinetic control.
Table 1. Orientation of the VNS of some substituted nitrobenzenes with
1 under kinetic and thermodynamic control (Scheme 4).
Entry Nitroarene, Z
Kinetic products
position [%]
Thermodynamic products
position
[%]
1
2
3
4
H
4-F
2, 4
2
2, 6
2
74, 26[a]
100
4
100
100
4[b]
4
3-Cl
85, 15[a]
100
100
1-nn[c]
2, 4
85, 15[a]
[a] Ratio of isomers. [b] SNAr of F. [c] 1-Nitronaphthalene.
Under thermodynamic control, reaction of 1ꢀ with nitro-
benzene proceeds only in position 4, whereas the 2-isomer
dominates under kinetic control (Table 1, entry 1). In 4-fluo-
ronitrobenzene, only an SNAr reaction of fluorine took
place instead of VNS in position 2 (Table 1, entry 2) and in
3-Cl-nitrobenzene only the 4-isomer was formed, whereas
under kinetic control only 2- and 6-isomers were produced
(Table 1, entry 3). Similar dramatic differences in the reac-
tion course under kinetically and thermodynamically con-
trolled conditions have already been observed in the VNS
hydroxylation of 1-nitronaphthalene with tert-butyl hydro-
peroxide, that is, substitution in position 2 under kinetically
controlled conditions and in position 4 under thermodynam-
ically controlled conditions.[16]
Comparison of results of VNS under kinetic and thermody-
namic control: The values of relative rate constants deter-
mined in competitive experiments can reflect electrophilic
activities of nitroarenes only when they are carried out
under conditions that assure kinetic control of the reaction;
k2[Bꢀ]@kꢀ1 [Eqs. (2) and (3)]. To show the importance of
these conditions and the differences in the reaction course
under conditions that assure the reversibility of sH adduct
formation (i.e., thermodynamically controlled), we reacted
1ꢀ with nitroarenes under conditions that assure a low rate
Effects of substituents in 4-substituted nitrobenzenes on the
relative rate of nucleophilic addition of 1ꢀ: The results of
competitive experiments with 4-substituted nitrobenzenes
are given in Scheme 5. These data show, for instance, that 4-
tBu-nitrobenzene reacts with 1ꢀ three times more slowly
than nitrobenzene, whereas 4-chloronitrobenzene reacts 130
times faster. Halogens in 4-halonitrobenzenes affect the
electrophilicity of the reaction site (position 2) by inductive
effects that should increase in the order I<Br<Cl<F; how-
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Substituent Effects
FULL PAPER
active than the methyl analogues and nitrobenzene itself be-
cause of competing conjugation of the p electrons of oxygen
and sulfur with the phenyl group.
As expected, strongly electron-accepting substituents CN
and CF3 show a large activating effect, whereas COOiPr
(isopropyl ester was used to avoid transesterification) is
only moderately activating, six times weaker than chlorine!
A similar observation was made for the SNAr reaction of 2-
chloro-4-COOEt-nitrobenzene with piperidine, the ratio of
rates for 4-Cl/4-COOEt was 6.1. No explanation has been
proposed for this unexpected observation.[27] Speculative ra-
tionalization of this surprising result can be based on as-
sumption of two electron-accepting effects of COOR, that
is, moderate inductive and strong conjugative effects. In 4-
COOR-nitrobenzene, this substituent is located meta to the
reaction site so the addition is accelerated by only the mod-
erate inductive effect. This assumption is supported by the
high activity observed for 3-COOR-nitrobenzene, which is
much higher than 3-Cl-nitrobenzene (vide infra). In 3-
COOR-nitrobenzene, this group is located para and ortho to
the reaction site so the addition is accelerated by the strong
conjugative effect.
Scheme 5. Partial and overall (italic) relative activities of 4-substituted ni-
trobenzenes in the VNS reaction with 1.
ever, the determined order of activity is IꢂF<Cl<Br. This
is because the free p-electron pairs of the halogens in 4-hal-
onitrobenzenes are conjugated with the strongly electron-ac-
cepting nitro group, as can be
1-Nitronaphthalene exhibits higher activity than any of
the 4-substituted nitroarenes. This high activity is due to the
aromaticity of the naphthalene ring system being lower than
that of benzene, so addition to the ring of 1-nitronaphtha-
lene which destroys the aromatic system is more facile (less
energy demanding) than to nitrobenzene derivatives.
pictured by using resonance
structures.
This effect does decrease the
electron-withdrawing action of
the nitro group and thus, the ac-
tivity of the ring towards nucle-
Effects of substituents in 2-substituted nitrobenzenes on rel-
ative rates of nucleophilic addition of 1ꢀ: Scheme 6 shows
the relative activities of 2-substitued nitrobenzenes. The ac-
ophilic addition. This neat observed result is an interplay be-
tween the electron-withdrawing inductive and electron-do-
nating conjugative effects of the halogens. Although the in-
ductive effect of fluorine is the strongest, the conjugation of
fluorine with the nitro group is also the most efficient be-
cause of smaller differences between the orbital sizes of flu-
orine and carbon. Similarly, the inductive effect of chlorine
is stronger than bromine, but due to a smaller difference be-
tween the orbital sizes of chlorine and carbon, conjugation
of chlorine with the nitro group is more efficient and 4-
chloronitrobenzene is somewhat less active than 4-bromoni-
trobenzene. A similar but less clear-cut effect was observed
earlier in the SNAr reaction of 2-chloro-4-Z-nitrobenzenes
with piperidine. Halogens Z accelerated substitution in a
similar order kH/kZ =34.5 (Br), 32.3 (Cl), 24.9 (I), although
the differences in the effects are much smaller. The rate for
Z=F could not be measured because fluorine was substitut-
ed.[27]
Similar reasoning can be applied for 4-MeO-, 4-PhO-, 4-
MeS-, and 4-PhS-nitrobenzenes. Although oxygen shows a
stronger inductive accepting effect than sulfur, due to the ef-
ficient conjugation between the methoxy and nitro groups,
its electron-withdrawing effect becomes weak and 4-MeO-
nitrobenzene is less active, whereas because of its less effi-
cient conjugation, 4-MeS-nitrobenzene is more active than
nitrobenzene. 4-PhO- and 4-PhS-nitrobenzenes are more
Scheme 6. Partial and overall (italic) relative activities of 2-substituted ni-
trobenzenes in the VNS reaction with 1.
tivating effect of electron-withdrawing substituents in posi-
tion 2 relative to the nitro group is, as a rule, much weaker
than in position 4. This is due to the secondary steric effect
of these substituents, which hinders the coplanarity of the
nitro group with the ring necessary for the formation and
stabilization of the sH adducts. This is particularly evident
when the effects of halogens in the 4- and 2-positions are
compared. The secondary steric effects of a large iodine
atom ortho to the nitro group dominates over other effects,
so the rate of VNS in 2-iodonitrobenzene is too small to be
measured by competitive experiments, even against the least
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M. Ma˛kosza and S. Błaz˙ej
active 4-tert-butylnitrobenzene. Nevertheless, in spite of the
slow rate of nucleophilic addition, 2-iodonitrobenzene un-
dergoes VNS in a preparative experiment to give both iso-
mers of the VNS product (in positions 4 and 6) in reasona-
ble yields (see the Experimental Section). Similarly, the
rates of the VNS reaction of 1ꢀ with 2-MeO- and 2-tBuO-ni-
trobenzenes are too low to be measured by competitive ex-
periments, although the VNS reaction of 1 with these nitro-
arenes does proceed.[25]
of 1 with 3-halonitrobenzenes gave interesting and some-
what unexpected results, and the order of activity is F<I<
Br<Cl. Moreover, in the case of 3-iodo-, 3-bromo-, and 3-
chloronitrobenzenes, the fastest reaction occurred in the
most sterically hindered 2-position and only two isomeric
VNS products in position 2 and 6 were formed, whereas 4-
isomers were not produced. In the case of all 3-halonitro-
benzenes, the activity of position 2 was higher than position
6, and the ratios of 2/6 for F, Cl, Br, and I were 5.5, 5.5, 4.1,
and 3.1, respectively. This peculiar orientation pattern,
namely, the preference for substitution in the most sterically
hindered position 2 over 6 in the VNS reaction, was already
observed in preparative experiments.[22] A reasonable ex-
planation for this observation is that the halogens exert the
strongest accepting inductive effect on the vicinal (ortho)
positions 2 and 4 and the most efficient donating conjuga-
tion with p electrons on the para (6) position. The prefer-
ence of position 2 over position 4 is perhaps due to the
strong tendency of the kinetically controlled VNS reaction
to proceed ortho (positions 2 and 6) to the nitro group. It
should be mentioned that under conditions that assure ther-
modynamic control of the VNS reaction of 1ꢀ with 3-chloro-
nitrobenzene, only the 4-isomer was formed! (See Table 1,
entry 3.)
Because 3-halonitrobenzenes form two or even three iso-
meric products, it is reasonable to compare their overall ac-
tivities: F 18, I 31, Br 170, and Cl 260. It is interesting to
note that 3-F activates nitrobenzene nine and fourteen times
more weakly than 3-Br and 3-Cl, respectively. 3-chloro- and
3-bromonitrobenzenes are ꢂ3 and 1.7 times more active
and 3-fluoronitrobenzene is two times less active than their
4-isomers. Perhaps most interesting is a comparison of the
overall activities of nitrobenzenes that contain a COOR
group in position 3 or 4; the 3-isomer is ꢂ160 times more
active! Relative values for other substituents are: Cl 3, Br
1.7, CN 7, CF3 4. The activating effect of the 3-COOR
group is similar to that of 3-CF3 and only three times
weaker than CN. This unexpectedly large difference in activ-
ity between 3- and 4-COOMe nitrobenzenes can be ration-
alized by taking into consideration the moderate inductive
and strong conjugative effects of COOR, as discussed earli-
er. Of particular interest are the reactions of 1ꢀ with dinitro-
benzenes. Data for para-dinitrobenzene are not included in
the appropriate place because its reaction with 1ꢀ produces
a number of sideproducts. On the other hand, the reaction
of 1ꢀ with meta-dinitrobenzene proceeds efficiently,[25,26] but
with such a high rate that it cannot be determined, even in
competition with the most active 3-cyanonitrobenzene.
Contrary to 4-halonitrobenzenes in which the order of ac-
tivity was IꢂF<Cl<Br, for 2-isomers the order of activity
is I !Br<Cl<F. The observed results originate from the in-
terplay of at least three effects: the inductive effect and the
conjugation of p electrons of halogens with the nitro group,
as discussed above, and the secondary steric effect, which is
the decisive one. The most interesting case is that of 2-fluo-
ronitrobenzene in which, as well as two isomeric VNS prod-
ucts in positions 4 and 6, a 2-F SNAr product was formed at
an equal rate. It should be mentioned that the reaction of 1ꢀ
with 4-fluoronitrobenzene under kinetically controlled con-
ditions exclusively gave the VNS product without any traces
of the SNAr reaction, as shown in Scheme 5. One can sup-
pose that formation of the sF adduct, an intermediate of the
SNAr reaction in 2-fluoronitrobenzene, is facilitated because
it eliminates steric interaction between fluorine and the
nitro group that hinders coplanarity of the latter with the
ring (an example of steric assistance). Due to the small sec-
ondary steric effects of the fluorine atom, addition of 1ꢀ in
positions 2, 4, and 6 of 2-fluoronitrobenzene is faster than in
2-chloro- and 2-bromonitrobenzenes, but slower than in 4-
halonitrobenzenes. Amongst the 2-substituted nitroben-
zenes, only 2-cyanonitrobenzene reacts in a similar rate to
the 4-isomer; due to its linear shape, the cyano group does
not create secondary steric hindrances. Interestingly, 2-
COOiPr-nitrobenzene is somewhat more active than the 2-
Cl analogue, contrary to the results for the respective 4-iso-
mers.
Effects of substituents in 3-substituted nitrobenzenes on rel-
ative rates of nucleophilic addition of 1ꢀ: 3-Z-Substituted ni-
troarenes in a VNS reaction with 1 can form three isomeric
products of substitution in positions 2, 4, and 6, so the activi-
ty of particular positions (i.e., orientation of the substitu-
tion) is of additional interest (see Scheme 7). The reactions
Effects of two substituents in nitrobenzenes on the relative
rates of nucleophilic addition: The activity of some nitroar-
enes that contain two substituents in the VNS reaction with
1 are presented in Scheme 8. In 2,6-dichloronitrobenzene, a
strong deactivating secondary steric effect is observed. This
effect is much weaker in 2,6-difluoronitrobenzene, so the
electron-withdrawing inductive effect dominates and 2,6-di-
fluoronitrobenzene is ꢂ300 times more active than its di-
Scheme 7. Partial and overall (italic) relative activities of 3-substituted ni-
trobenzenes in the VNS reaction with 1.
11118
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Chem. Eur. J. 2008, 14, 11113 – 11122

Substituent Effects
FULL PAPER
cause the main reaction course of 1ꢀ with the majority of 3-
substituted nitroarenes resulted in substitution at positions 2
and 4, there were no reasons to attempt correlation of the
log of the relative rates of these nitroarenes with the Ham-
mett sp constants, which should affect substitution in posi-
tion 6.
Verification of the values of relative electrophilic activities
of nitroarenes: To verify the values of the relative electro-
philic activities determined for the VNS reaction of substi-
tuted nitroarenes with 1 by competitive experiments, we
have determined rate constants for the addition of 1ꢀ to
some nitroarenes by direct kinetic experiments. The kinetics
of addition of 1ꢀ to selected nitroarenes were studied by
using a previously reported method.[19b] Details of these ex-
periments are reported in an earlier paper.[28] Although the
conditions for these kinetic experiment measurements were
not identical to those used in the competitive experiments,
the results obtained by these different approaches are in
good agreement (Table 2).
Scheme 8. Partial and overall (italic) relative activities of disubstituted ni-
trobenzenes in the VNS reaction with 1.
chloro analogue. The additivity of the substituent effects is
observed in 2,4-disubstituted nitrobenzenes.
Due to the deactivating effect of the methoxy group, the
activity of 3-nitro-4-methoxynitrobenzene (2,4-dinitroani-
sole) can be measured in competition with 3-cyanonitroben-
zene.
Correlation of the effects of substituents on the activity of
nitroarenes with the Hammett constants: The relative activi-
ties of nitroarenes presented in Schemes 5, 6, and 7 are of
the same character as k/k0 in the Hammett equation. Thus,
the next step in our studies involved examining the correla-
tion between the log of the activities of substituted nitroar-
enes (logkZ/k0) and the Hammett s (sm) constants of the
substituents. In 4-Z-nitrobenzenes, the substituents are lo-
cated in the meta position relative to the reaction site, thus
the relative activities should correlate with the sm constants
The correlation between logkZ/k0 and the sm constants is
presented in Figure 1. In an ideal case, the points should
form a straight line through the origin and the slope would
give the value of the reaction constant, 1. As one can see,
the points are quite dispersed, the correlation is poor (r=
0.89), and the value of 1 is about 5.0. This poor correlation
indicates that effects of substituents are not limited to the
action on the reaction site. Interactions between substituents
and the nitro group that change its activating effect un-
doubtedly contributes significantly to the overall activity
and seems to be responsible for this poor correlation. Be-
Table 2. Comparison of the relative activities determined from competi-
tive experiments and direct kinetic measurements.
Compared nitroarenes
Relative activities[a]
Relative rates[b]
4-Cl/4-MeO
2,4-Cl2/4-MeO
4-MeO/4-tBu
140
390
2.4
124
850
4.55
[a] On the basis of competitive experiments in this work. [b] On the basis
of direct kinetic measurements reported in ref. [28].
Another way of verifying the values for the relative activi-
ties of nitroarenes was by using competitive experiments
analogous to those described herein, but with other a-halo-
carbanions. For this purpose, the carbanions of chloromethyl
p-chlorophenyl sulfone and bromomethyl phenyl sulfone
were chosen. The carbanions of these sulfones exhibit simi-
lar nucleophilicity to 1ꢀ, so the relative rate constants for
the addition of these carbanions to nitroarenes should be
similar to that determined in the VNS reaction with 1ꢀ.
Indeed, experiments in which nitroarenes competed for the
VNS reaction with carbanions of chloromethyl p-chloro-
phenyl sulfone and bromomethyl phenyl sulfone under con-
ditions assuring kinetic control gave results very similar to
those reported herein. These results are reported else-
where.[29]
Effects of substituents in nitroarenes on the rates of addition
of Grignard reagents: Primary alkyl Grignard reagents add
to nitroarenes in positions ortho and para to the nitro group
to form relatively stable sH adducts that can be efficiently
oxidized with KMnO4 to give alkylated nitroarenes.[30,31]
This oxidative nucleophilic substitution of hydrogen
(ONSH) is a valuable process for introducing alkyl groups
into nitroaromatic rings. It was of interest to learn whether
the relative rates of addition of the Grignard reagents to
substituted nitrobenzenes follow a similar pattern to the rel-
Figure 1. Correlation between logkZ/k0 of 4-Z-nitrobenzenes and the
Hammett sm constants of Z; y=5.0x, r=0.89. The values of sm were
taken from reference [4].
Chem. Eur. J. 2008, 14, 11113 – 11122
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11119

M. Ma˛kosza and S. Błaz˙ej
ative rates of the addition of carbanion of 1ꢀ that results in
the VNS reaction.
The addition of these nucleophiles to nitroarenes is an ir-
reversible process because dissociation of the sH adducts to
starting nitroarenes and the Grignard reagents would pro-
tial of nitroarenes, hence some selectivity should be ob-
served. Lack of selectivity indicates that the addition of
Grignard reagents is a fast, diffussion-controlled process.
ꢀ
ceed by heterolytic C C bond splitting with the electron
Conclusion
pair taken by the alkyl group, which is highly unfeasible.
Thus, relative rates for the oxidative nucleophilic alkylation
of nitroarenes with Grignard reagents can be conveniently
studied by using competitive experiments. To complement
the results of our studies into the effects of substituents in
nitroarenes on the rates of nucleophilic addition by using
VNS as the model reaction, we have made similar studies of
the ONSH reaction with nBuMgCl. The procedure was as
follows: a small quantity of nBuMgCl in THF was added to
a mixture of equimolar quantities of two nitroarenes in THF
at ꢀ788C, followed by addition of solid KMnO4 and liquid
ammonia. The liquid ammonia was added to dissolve the
KMnO4.[31] After a few minutes, the mixture was quenched
with solid NH4Cl and the ammonia was evaporated, then
the mixture was treated with acidified water containing
Na2SO3 and products were extracted and analyzed by GLC.
The products, ortho and para n-butyl nitroarenes, were de-
scribed earlier,[31] and samples for the calibration necessary
for quantitative GLC analyses were prepared as reported.
The results of these competitive experiments are presented
in Scheme 9.
The relative rate constants of the VNS reaction of a series
of substituted nitroarenes with the carbanion of chlorometh-
yl phenyl sulfone 1 were determined by using competitive
experiments. The obtained data represent a consistent set of
effects of substituents on the electrophilic activity of nitroar-
enes on reaction with nucleophiles. It should be stressed
that the observed effects are a superposition of direct elec-
tronic and steric effects on the addition site and also indirect
(secondary) effects, that is, the electronic and steric interac-
tions of substituents with the nitro group that affect its acti-
vation power. These secondary effects are often stronger
than the direct effects, and this is particularly the case when
steric effects are concerned. For instance, the bulky iodine
atom does not hinder addition in its vicinity; in 3-iodonitro-
benzene, addition in position 2 (ortho to iodine) is 3.1 times
faster than in position 6 (para to iodine), whereas the rate
of the reaction of 2-iodonitrobenzene is too slow to be mea-
sured by competitive experiments due to a strong secondary
steric effect.
These results are not only of theoretical significance, in
that they provide new insight into factors that influence the
course of nucleophilic substitution, but they also allow the
outcome of future reactions of this type to be predicted,
which is important for planning successful experiments.
The relative rate constants can be considered as semi-
quantitative measures of the effects of substituents on elec-
trophilicity of substituted nitrobenzenes. These results
reveal that in many cases our simplified intuitive approach
to the activities of nitroarenes in reactions with nucleophiles
as based on textbook knowledge are misleading. The pre-
sented electrophilicity values can supplement the extensive
scale of electrophilic activities elaborated by Mayr et al.[5] In
fact, determination of the absolute rate constants for addi-
tion of 1ꢀ and other carbanions to some nitroarenes, as re-
ported in a separate paper,[28] allows incorporation of these
results in this scale.
Scheme 9. Partial and overall (italic) relative rates of addition of
nBuMgCl to substituted nitrobenzenes relative to nitrobenzene.
Surprisingly, the rates of addition of nBuMgCl to various
nitroarenes are negligibly different. For instance, addition to
4-MeO- and 4-CN-nitrobenzenes proceeds at the same rate,
whereas addition of 1ꢀ to 4-CN-nitrobenzene proceeds 1200
times faster than to 4-MeO-nitrobenzene. One can rational-
ize these unexpected results in two ways: 1) the addition is a
very fast, diffusion-controlled process, thus there is no ob-
served selectivity or 2) the formation of sH adducts does not
proceed by nucleophilic addition, but as a two-step process,
that is, a single-electron transfer (SET) and subsequent cou-
pling of anion radicals of nitroarenes with the alkyl radicals.
The participation of the SET mechanism in the addition of
Grignard reagents to nitroarenes was postulated and con-
firmed experimentally by Bartoli et al.[32] However, the rates
of the SET processes should correlate with the redox poten-
Experimental Section
General: 1H and 13C NMR spectra were recorded by using Varian Mercu-
ry 400 (400 MHz) or Brucker AM-500 (500 MHz) instruments. Chemical
shifts are expressed in ppm referenced to TMS and coupling constants
are in Hz. Mass spectra were recorded by using AMD 604 Inectra GmbH
(EI ionization) and Mariner (ESI ionization) spectrometers. GLC analy-
ses were performed by using a HP 6890 chromatograph equipped with a
HP-5 capillary column. Melting points are uncorrected. Silica gel
Merck 60 (230–400 mesh) was used for column chromatography. Alumi-
num foil Kieselgel 60/F254 (Merck) was used for TLC. All solvents used
for column chromatography, extraction, and recrystallization were dis-
tilled. DMF was purified by distillation over CaH2, THF was distilled
11120
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Chem. Eur. J. 2008, 14, 11113 – 11122

Substituent Effects
FULL PAPER
over benzophenone potassium, and extra-pure DMSO was used. All re-
actions were carried out under an argon atmosphere.
Reaction of 2,4-difluoronitrobenzene with 1 (2 products)
(3,5-difluoro-2-nitro)benzyl phenyl sulfone: Yield 39%; m.p. 158–1618C
(EtOH); 1H NMR (400 MHz, CDCl3): d=4.61 (s, 2H), 7.02–7.09 (m,
2H), 7.51–7.62 (m, 2H), 7.68–7.78 ppm (m, 3H); 13C NMR (100 MHz,
CDCl3): d=57.41, 106.62 (dd, J=25.86, 24.14 Hz), 115.96 (dd, J=24.14,
3.45 Hz), 125.92 (dd, J=25.00, 4.32 Hz), 126.69 (d, J=11.21 Hz), 129.09,
130.04, 134.70, 137.40, 155.64 (dd, J=263.81, 12.93 Hz), 162.80 ppm (dd,
J=258.63, 12.07 Hz); MS (EI): m/z (%): 188 (10), 172 (51), 141 (41), 77
(100), 51 (34); HRMS (ESI): m/z calcd for C13H9NO4F2NaS: 336.01126
[M+]; found: 336.01273.
Most of the reagents were commercially available (Aldrich). Isopropyl 4-
nitro- and 2-nitrobenzoates were obtained from the appropriate acids ac-
cording to a known procedure.[33] Chloromethyl phenyl sulfone was syn-
thesized according to a known procedure.[25]
General procedure for the VNS reaction of nitroarenes with sulfone 1: A
solution of chloromethyl phenyl sulfone (0.570 g, 3 mmol) and nitroarene
(3 mmol) in THF or DMF (1 mL) was added to a solution of tBuOK
(1.02 g, 9 mmol) in THF or DMF (5 mL) cooled to ꢀ788C (THF) or
ꢀ408C (DMF). After 20 min, the reaction mixture was quenched with
acetic acid (3 mL) or aqueous HCl (1:10, 5 mL), diluted with water
(100 mL), and extracted with CH2Cl2. The combined extracts were
washed with water and dried over Na2SO4. The products were isolated
and purified by column chromatography and/or recrystallization.
[(5-fluoro-2-nitro)phenyl]chloromethyl phenyl sulfone: Yield 50%; m.p.
166–1688C (EtOH); 1H NMR (400 MHz, CDCl3): d=7.19 (d, J=1.1 Hz,
1H), 7.30 (ddd, J=9.36, 6.79, 2.75 Hz, 1H), 7.58–7.63 (m, 2H), 7.29–7.70
(2H), 7.90–7.93 (m, 2H), 8.17 ppm (dd, J=9.18, 4.95 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=68.62, 118.25 (d, J=22.84 Hz), 119.27 (J=
26.29 Hz), 128.25 (d, J=9.48 Hz), 128.40 (d, J=9.06 Hz), 129.39, 129.90,
134.93, 135.15, 144.97, 164.68 ppm (d, J=257.50 Hz); MS (EI): m/z (%):
188 (100), 130 (44), 107 (28), 77 (87), 51 (43); HRMS (ESI): m/z calcd
for C13H9NO4FNaSCl: 351.98171 [M+]; found: 351.98063.
The VNS reaction under thermodynamic conditions: The carbanion of
chloromethyl phenyl sulfone was generated from a solution of sulfone 1
(1.9 g, 10 mmol) in DMSO (20 mL) passed through a layer of ground
KOH, and then added to a solution of nitroarene (1 mmol) in DMSO
(5 mL) at RT over 10 min. The mixture was acidified with aqueous HCl
(1:10) and the products were isolated in the same way as in the preceding
procedure.
General procedure for the preparative ONSH reaction of nitroarenes
with nBuMgCl: A solution of n-butylmagnesium chloride (1.5 mL, 2m) in
THF (3 mL) was added dropwise to a solution of nitroarene (2.0 mmol)
in THF (10 mL) cooled to ꢀ788C. After 5 min, powdered KMnO4 (0.4 g,
2.5 mmol) and liquid NH3 (5 mL) were added, then after 1 min the reac-
tion mixture was treated with powdered NH4Cl (0.5 g), and then the am-
monia was evaporated. The crude reaction mixture was decolorized with
water and Na2SO3, then treated with aqueous HCl (1:10), extracted with
CH2Cl2 (100 mL), and washed with water. The extracts were dried over
MgSO4 and the products were isolated and purified by column chroma-
tography.
Examples of preparative VNS reactions
Reaction of 2-fluoronitrobenzene with 1 (3 products)
(3-fluoro-2-nitro)benzyl phenyl sulfone: Yield 25%; m.p. 220–2218C
(hexane/ethyl acetate); 1H NMR (400 MHz, CDCl3): d=4.36 (s, 2H),
7.07 (brd, J=8.32 Hz, 1H), 7.12 (dd, J=11.0, 1.79 Hz, 1H), 7.52–7.57 (m,
2H), 7.67–7.74 (m, 3H), 7.98 ppm (t, J=8.32 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d=61.81, 120.76 (d, J=21.4 Hz), 126.25 (d, J=
2.6 Hz), 126.87 (d, J=4.3 Hz), 128.46, 129.42, 134.50, 136.66 (d, J=
7.8 Hz), 137.38, 155.11 ppm (d, J=265.7 Hz); MS (EI): m/z (%): 249 (6),
154 (100), 141 (15), 107 (29), 96 (61), 77 (80), 51 (46); HRMS (ESI): m/z
calcd for C13H10NO4FNaS: 318.02068 [M+]; found: 318.02052.
Procedures for the competitive experiments
VNS reaction with sulfone 1: tBuOK (0.6m) in THF (0.8 mL; stock solu-
tion kept at ꢀ408C) was rapidly added to a solution of competing nitro-
arenes A and B (0.2–0.6 mmol), chloromethyl phenyl sulfone (0.023 g,
0.12 mmol), and diphenyl sulfone (internal standard; ꢂ0.005 g,
0.02 mmol) in DMF cooled to ꢀ408C. After 15 s, the reaction mixture
was quenched at ꢀ408C with aqueous HCl (1:10, 3 mL), then diluted
with water (70 mL) and extracted with CH2Cl2 (5 mL). The extracts were
dried over Na2SO4 and analyzed by using GLC with an internal standard
and calibration procedures. The reaction was repeated 3 times for each
pair of nitroarenes and the results were averaged.
(3-fluoro-4-nitro)benzyl phenyl sulfone: Yield 30%; m.p. 217–2198C
(hexane/ethyl acetate); 1H NMR (400 MHz, CDCl3): d=4.60 (s, 2H),
7.28–7.33 (m, 2H), 7.48–7.55 (m, 3H), 7.66–7.69 (m, 1H), 7.70–7.74 ppm
(m, 2H); 13C NMR (100 MHz, CDCl3): d=57.48 (d, J=2.6 Hz), 118.29
(d, J=19.8 Hz), 123.69, 128.40, 128.57 (d, J=3.5 Hz), 129.46, 132.53 (d,
J=8.6 Hz), 134.49, 135.41, 137.57, 154.52ppm (d, J=258.9 Hz); MS (EI):
m/z (%): 295 (15) [M+], 154 (55), 141 (70), 124 (34), 107 (46), 96 (30), 77
(100), 51 (41); HRMS (EI): m/z calcd for C13H10NO4FS: 295.03146 [M+];
found: 295.03254.
ONSH reaction with nBuMgCl: A 2m solution of nBuMgCl (1 mmol) in
THF (0.5 mL) was added to a solution of competing nitroarenes A and B
(2.0–2.5 mmol) and diphenyl sulfone (internal standard; ꢂ0.05 g,
0.2 mmol) in THF (10 mL) cooled to ꢀ788C. After 5 min, powdered
KMnO4 (0.18 g, 1.1 mmol) and liquid NH3 (5 mL) were added. Oxidation
was carried out for 1 min, then powdered NH4Cl (0.5 g) was added and
the ammonia evaporated. The crude reaction mixture was decolorized
with water containing Na2SO3, treated with diluted HCl (1:10), extracted
with CH2Cl2 (50 mL), and washed with water. Extracts were dried over
Na2SO4 and analyzed by using GLC with an internal standard and cali-
bration procedures. The reaction was repeated 3 times for each pair of ni-
troarenes and the results were averaged.
(2-nitrophenyl)chloromethyl phenyl sulfone: Yield 11%; m.p. 120–1228C
(hexane/ethyl acetate); 1H NMR (400 MHz, CDCl3): d=7.12 (s, 1H),
7.35–7.40 (m, 2H), 7.63 (ddd, J=8.01, 7.61, 1.52 Hz, 1H), 7.70–7.77 (m,
4H), 8.11–8.78 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=89.01,
125.21, 129.90, 130.91, 131.42, 132.00, 132.43, 133.50, 145.95, 148.93 ppm;
MS (EI): m/z (%): 170 (100), 155 (19), 112 (62), 91 (85); HRMS (ESI):
m/z calcd for C13H10NO4ClNaS: 334.02776 [M+]; found: 334.02538.
Reaction of 2-iodonitrobenzene with 1 (2 products)
(3-iodo-2-nitro)benzyl phenyl sulfone: Yield 28%; m.p. 170–1718C
(EtOH); 1H NMR (400 MHz, CDCl3): d=4.39 (s, 2H), 7.21 (t, J=
7.90 Hz, 1H), 7.51–7.55 (m, 2H), 7.58 (dd, J=7.90, 1.10 Hz, 1H), 7.66–
7.72 (m, 3H), 7.92 (dd, J=7.90, 1.20, 1H); 13C NMR (100 MHz, CDCl3):
d=57.94, 86.21, 122.24, 128. 45, 129.37, 131.48, 132.66, 134.50, 137.50,
141.26 ppm; MS (EI): m/z (%): 403 (2) [M+], 357 (20), 262 (100), 245
(9), 204 (19), 77 (68); HRMS (EI): m/z calcd for C13H10NO4IS: 402.93753
[M+]; found: 402.93899.
Calculation of total relative activities of competing nitroarenes
Equation (4) gives the relative activities of competing nitroarenes:
ꢀ
ꢁ
ꢁ
½B0ꢁꢀ½PB
½B0
ꢁ
ln
ꢁ
kB
kA
ꢀ
¼
ð4Þ
½A0 ꢁꢀ½PA
½A0
ꢁ
ln
ꢁ
(3-iodo-4-nitro)benzyl phenyl sulfone: Yield 34%; m.p. 187–1898C
(EtOH); 1H NMR (400 MHz, CDCl3): d=4.30 (s, 2H), 7.28 (dd, J=8.35,
1.60 Hz, 1H), 7.54–7.60 (m, 2H), 7.65–7.72 (m, 3H), 7.70 (d, J=1.60 Hz,
1H), 7.77 ppm (d, J=8.35 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
61.34, 125.37, 128.56, 128.89, 129.39, 131.34, 134.16, 134.47, 136.3, 136.8,
143.98 ppm; MS (EI): m/z (%): 403 (13) [M+], 262 (60), 232 (58), 77
(49), 71 (76), 57 (100); HRMS (EI): m/z calcd for C13H10NO4IS:
402.93753 [M+]; found: 402.93838.
in which kA is the relative rate constant of the addition of the carbanion
to nitroarene A, kB is the relative rate constant of the addition of the
carbanion to nitroarene B, [A0] is the starting concentration of nitroarene
A, [B0] is the starting concentration of nitroarene B, [PA] is the final con-
centration of product(s) formed from nitroarene A, and [PB] is the final
concentration of product(s) formed from nitroarene B.
Chem. Eur. J. 2008, 14, 11113 – 11122
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11121

M. Ma˛kosza and S. Błaz˙ej
Example calculation of partial relative activities with A=o-Z1-nitroben-
zene and B=o-Z2-nitrobenzene:
[10] J. F. Bunnet, R. E. Zahler, Chem. Rev. 1951, 49, 273.
[11] J. Miller, Aromatic Nucleophilic Substitution, Elsevier, Amsterdam,
1968.
[12] V. von Richter, Ber. Dtsch. Chem. Ges. 1871, 4, 21; R. B. Davis, L. C.
Pizzini, J. Org. Chem. 1960, 25, 1884.
kðB2-isoÞ kðB4-isoÞþð2-isoÞ 1þð2-isoÞA
4-iso
¼
ð5Þ
4-iso
kðA2-isoÞ kðA4-isoÞþð2-isoÞ
1þð2-isoÞB
´
[13] J. Golinski, M. Ma˛kosza, Tetrahedron Lett. 1978, 19, 3495.
[14] O. N. Chupakhin, V. N. Charushin, H. C. van der Plas, Nucleophilic
Aromatic Substitution of Hydrogen, Academic Press, San Diego,
1994; M. Ma˛kosza, K. Wojciechowski, Chem. Rev. 2004, 104, 2631;
M. Ma˛kosza, Russ. Chem. Bull. 1996, 45, 491.
[15] M. Ma˛kosza, J. Winiarski, Acc. Chem. Res. 1987, 20, 282; M. Ma˛kos-
za, K. Wojciechowski, Liebigs Ann./Recueil 1997, 9, 1805.
[16] M. Ma˛kosza, K. Sienkiewicz, J. Org. Chem. 1990, 55, 4979; M. Ma˛-
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in which 2-iso and 4-iso indicate the 2- and 4-isomers, respectively. The
kðB4-isoÞþð2-isoÞ/kAð4-isoÞþð2-isoÞ term is equal to kB/kA calculated from Equa-
tion (4).
kBð2-isoÞ/kAð2-isoÞ can be calculated from the known ratio of the total rate con-
stants of addition to A and B and the ratio of the 4-isomer to the 2-
isomer in nitroarenes A and B.
From the simple calculation the desired relations can be determined:
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kðA4-isoÞ kðA2-isoÞ
4-iso
¼
ð2-isoÞA
ð6Þ
kðB2-isoÞ kðB2-isoÞ
Details of calculations are given in the Supporting Information.
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Acknowledgement
The authors are deeply indebted to Professor Herbert Mayr for very val-
uable discussions.
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an overall VNS reaction that proceeds in two distinct steps is some-
what incorrect. More precise would be descriptive terms irreversible
(kinetic control) and reversible (thermodynamic control) formation
of the sH adduct. However, usage of these terms could be mislead-
ing because the overall VNS is an irreversible process.
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Received: April 30, 2008
Revised: July 11, 2008
Published online: November 5, 2008
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