Elucidation of the vicarious nucleophilic substitution of hydrogen mechanism via studies of competition between substitution of hydrogen, deuterium, and fluorine

Article abstract of DOI:10.1021/jo010590z

Relations of rates of the vicarious nucleophilic substitution of hydrogen (VNS) and S_NAr substitution of fluorine in 2-fluoronitrobenzenes with chloroalkyl aryl sulfone carbanions were determined from competitive experiments carried out at various concentrations of base. The observed dependence of the VNS/S_NAr rate ratio on the base concentration confirmed the two-step mechanism of the VNS, which consists of reversible formation of σ^H adducts of the α-chlorocarbanion to nitroarene, followed by base-induced β-elimination of HCl. It was also evidenced that both of these processes can be the rate-limiting steps: the β-elimination at low base concentration and the nucleophilic addition at high base concentration. Consistent with that conclusion is the finding that the kinetic isotope effect in the VNS reaction decreases from 4.2 (a value typical of a primary KIE) to 0.8 (a value typical of a secondary KIE) with increasing base concentration. Also reported is our discovery that the S_NAr substitution of the 2-fluoronitrobenzenes studied in this work was subject to base catalysis under some of the experimental conditions employed in our competitive experiments.

Full text of DOI:10.1021/jo010590z

394
J . Org. Chem. 2002, 67, 394-400
Elu cid a tion of th e Vica r iou s Nu cleop h ilic Su bstitu tion of
Hyd r ogen Mech a n ism via Stu d ies of Com p etition betw een
Su bstitu tion of Hyd r ogen , Deu ter iu m , a n d F lu or in e
Mieczysław Ma¸kosza,*,† Tadeusz Lemek,† Andrzej Kwast,† and Franc¸ois Terrier‡
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/ 52, 01-224 Warsaw, Poland,
and Universite´ de Versailles Saint-Quentin-en-Yvelines, 45 avenue des Etats-Unis,
78035 Versailles Cedex, France
icho-s@icho.edu.pl
Received J une 12, 2001
Relations of rates of the vicarious nucleophilic substitution of hydrogen (VNS) and SNAr substitution
of fluorine in 2-fluoronitrobenzenes with chloroalkyl aryl sulfone carbanions were determined from
competitive experiments carried out at various concentrations of base. The observed dependence
of the VNS/SNAr rate ratio on the base concentration confirmed the two-step mechanism of the
VNS, which consists of reversible formation of σH adducts of the R-chlorocarbanion to nitroarene,
followed by base-induced â-elimination of HCl. It was also evidenced that both of these processes
can be the rate-limiting steps: the â-elimination at low base concentration and the nucleophilic
addition at high base concentration. Consistent with that conclusion is the finding that the kinetic
isotope effect in the VNS reaction decreases from 4.2 (a value typical of a primary KIE) to 0.8 (a
value typical of a secondary KIE) with increasing base concentration. Also reported is our discovery
that the SNAr substitution of the 2-fluoronitrobenzenes studied in this work was subject to base
catalysis under some of the experimental conditions employed in our competitive experiments.
Sch em e 1
In tr od u ction
Nucleophiles possessing leaving groups at the nucleo-
philic center react with nitroarenes and some other elec-
tron-deficient arenes replacing hydrogen with the nu-
cleophile moiety. The reaction, known as vicarious nu-
cleophilic substitution of hydrogen VNS,1 proceeds with
a variety of nucleophiles such as carbanions containing
halogen, alkoxy, thioalkoxy, etc. leaving groups, alkyl
hydroperoxide anions,2 and many amination reagents.3,4
Thus, VNS is a general method for introduction of C, O,
and N substituents via direct replacement of hydrogen
in electron-deficient aromatic rings. A large body of
investigations has been devoted to clarify the essential
features of the reaction and its applications in organic
synthesis.5 Much less comprehensive remains our knowl-
edge of the reaction mechanism,6 mainly because of the
experimental complexity of kinetic investigations. The
generally accepted mechanistic pathway of VNS is shown
in Scheme 1.
The reaction proceeds via addition of the nucleophile
-NuX to an ortho or para position of the nitroarene and
subsequent base-promoted â-elimination of HX from the
intermediate σH-adduct. Since direct kinetic data have
not yet been accumulated, this mechanistic picture is
based on the results obtained in competitive experiments
where changes in the product ratio of the VNS and a
reference reaction were examined.2a,3,7,8 In particular, nice
information has been derived from a competition between
VNS and SNAr substitution of a halogen atom (F, Cl)
located in similarly activated positions of the same
nitroarene molecule.7 Thus, it was found that the VNS/
SNAr product ratio increases when a strong soluble base,
e.g., t-BuOK, was used in high concentrations. Should
the base concentration not affect the rate of the SNAr
processsa reasonable assumption in many casessthe
results imply that the base must play an important role
in determining the rate of the VNS reaction. On this
ground, it was concluded that the base-promoted â-elim-
ination of HX is the rate-limiting step of the reaction,
whereas the nucleophilic addition is a fast and reversible
* To whom correspondence should be addressed. Fax: +22-632 66
81.
† Polish Academy of Sciences.
‡ Universite´ de Versailles Saint-Quentin-en-Yvelines.
(1) Golin´ski, J .; Ma¸kosza, M. Tetrahedron Lett. 1978, 37, 3495.
Ma¸kosza, M.; Winiarski, J . Acc. Chem. Res. 1987, 20, 282. Ma¸kosza,
M. Pol. J . Chem. 1992, 66, 3.
(2) (a) Ma¸kosza, M.; Sienkiewicz, K. J . Org. Chem. 1998, 63, 4199.
(b) Ma¸kosza, M.; Sienkiewicz, K. J . Org. Chem. 1990, 55, 4979. (c)
Brose, T.; Holtzscheiter, F.; Mattersteig, G.; Pritzkow, W.; Voerckel,
V. J . Pract. Chem. 1992, 334, 497-504.
(3) Ma¸kosza, M.; Białecki, M. J . Org. Chem. 1992, 57, 4784.
Ma¸kosza, M.; Białecki, M. J . Org. Chem. 1998, 63, 4878.
(4) Katritzky, A. R.; Laurenzo, K. L. J . Org. Chem. 1988, 53, 3978-
3982. Katritzky, A. R.; Laurenzo, K. L. J . Org. Chem. 1986, 51, 5039.
Pagoria, P. F.; Mitchell, R.; Schmidt, R. D. J . Org. Chem. 1996, 61,
2934-2935. Seko, S.; Kawamura, N. J . Org. Chem. 1996, 61, 442.
(5) (a) Ma¸kosza, M. Synthesis 1991, 103. (b) Ma¸kosza, M.; Wojcie-
chowski, K. Liebigs Ann./ Recueil 1997, 1805. (c) Ma¸kosza, M.; Dani-
kiewicz, W.; Wojciechowski, K. Phosphorus, Sulfur Silicon 1990, 53,
457. (d) Terrier, F. Nucleophilic Aromatic Displacement: The Infuence
of the Nitro Group; VCH: New York, 1991. (e) Chupakin, O. N.;
Charushin, V. N.; van der Plas, H. C. Nucleophilic Aromatic Substitu-
tion of Hydrogen; Academic Press: San Diego, 1994.
(6) Ma¸kosza, M.; Kwast, A. J . Phys. Org. Chem. 1998, 11, 341.
(7) Glinka, T.; Ma¸kosza, M. J . Org. Chem. 1983, 48, 3860.
(8) Ostrowski, S.; Ma¸kosza, M. Tetrahedron 1988, 44, 1721.
10.1021/jo010590z CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/29/2001

Nucleophilic Substitution of Hydrogen Mechanism
J . Org. Chem., Vol. 67, No. 2, 2002 395
of kinetic situations predicted by eq 1. This should also
help in clarifying the role that kinetic isotope effects
(KIE) can possibly play as a diagnostic tool for the un-
derstanding of the mechanism of VNS reactions.
We have succeeded in delineating all the reactivity
facets of Scheme 1 by carrying out a detailed study of
the reactions of the fluoronitroarenes 1a -d with the
halocarbanion C-2 to afford competitively the SNAr and
VNS substitution products 3a -d and 4a -d (or 5a -d ),
respectively. Following a communication of preliminary
promising results,10 we report here a full and compre-
hensive account of this work that, for clarity, we will
discuss in a point-to-point approach.
Resu lts a n d Discu ssion
Scheme 2 describes our competitive strategy with the
observed rates of the VNS and SNAr reactions being given
F igu r e 1. Value of kVNS as a function of base concentration
calculated according eq 1.
by eqs 4 and 5 where the various rate constants k1, k-1
,
k2, and k′ , k′ , k′ refer to the depicted individual steps.
That the steady-state approximation also applies with
1
-1
2
process. Support for this reasonable conclusion has also
come from the determination of notable kinetic isotope
effects for the VNS reactions of some carbanions9 and
k′ .k′ for the SNAr pathway is an assumption that
2
-1
reflects the most commonly reported situation for mono-
nitroactivated arenes.11 In eqs 4 and 5, 1 and C-2 refer
to the fluoronitroaromatic and the carbanion at hand,
respectively, while PH and PF represent the products of
the hydrogen and fluorine substitutions, respectively; i.e.,
we will express the product distribution as [PH] ) [3] and
[PF] ) [4] + [5].
oxygen nucleophiles2a with 1,3-dinitrobenzene (kH/kD
)
3.9 and 7.0, respectively). In contrast with this mecha-
nistic picture, KIE values close to unity were observed
in other systems.7 Also, numerous examples of competi-
tion experiments in which the VNS/SNAr ratio does not
depend appreciably on the strength and concentration
of the base have been found. This situation clearly called
for further experiments in mechanistic studies.
d[PH]
dt
k1k2[B]
)
[1][C-2]
(4)
(5)
Assuming that the steady-state approximation applies,
the observed rate constant kVNS for formation of the VNS
product according to Scheme 1 is given by eq 1. As shown
in Figure 1, this equation predicts a curvilinear depen-
dence of kVNS upon the base concentration with the
possible observation of two limiting situations corre-
sponding to the reduced equations (2) and (3) at low and
high base concentrations, respectively:
k-1 + k2[B]
d[PF]
k′ k′
1
2
)
[1][C-2] ) k′ [1][C-2]
1
dt
k′ + k′
-1 2
For experiments conducted at a constant base concen-
tration ([B]t ) [B]o), a standard treatment of eqs 4 and 5
affords eq 6, which shows that the [PH]/[PF] ratio must
depend curvilinearly on [B]o, as does the rate of the VNS
substitution alone (Figure 1). However, the plateau will
k1k2[B]
Rate
[ArH][Nu]
) kVNS
)
(1)
k-1 + k2[B]
now correspond to the ratio k1/k′ and not to k1.
1
kVNS ) K1k2[B]
kVNS ) k1
(2)
(3)
[PH]
[PF]
k1k2[B]0
)
(6)
k′ (k-1 + k2[B]0)
1
Mod el Rea gen ts a n d Rea ction Con d ition s. The
4-X-substituted 2-fluoronitrobenzenes 1a -d and the car-
banion of chloromethyl p-tolyl sulfone C-2 have been
selected as the most appropriate model reagents to study
Scheme 2. Apart from a similar activation by the o-nitro
group, the C2-F and C6-H positions of 1a -d are
symmetrically located with respect to the X substituent.
Changing the nature of X should therefore equally affect
the two electrophilic centers, allowing us to disclose how
a variation in the overall electron-deficiency of the
benzene ring affects the competition between the SNAr
and VNS processes.
Equation 2 relates to a thermodynamically controlled
process that prevails when the intermediate σ-adduct is
formed in a fast preequilibrium step (k-1 . k2[B]). In this
instance, the â-elimination step is rate-limiting and the
rate of the overall VNS reaction will depends linearly on
the strength and concentration of the base B.
Conversely, eq 3 describes a kinetically controlled
process that is operating when the nucleophilic addition
step is rate limiting (k2[B] . k-1). Then, the â-elimination
step is so fast that the formation of the intermediate σH
adduct can be considered as an irreversible process.
Each of these limiting situations is believed to have
been observed in individual instances of VNS reactions.
For a full confirmation of Scheme 1, it was important,
however, to design suitable model reagents and reaction
conditions that would allow coverage of the entire range
On the above grounds, Scheme 2 was investigated by
mixing DMF solutions of the two reagents at -40 °C. The
reacting concentration of the nitroarene 1 was 3 × 10-3
(10) Ma¸kosza, M.; Lemek, T.; Kwast, A. Tetrahedron Lett. 1999, 40,
7541.
(9) Stahly, P. G.; Stahly, B. C.; Maloney, J . R. J . Org. Chem. 1988,
53, 690.
(11) (a) Miller, J . Aromatic Nucleophilic Substitution; Elsevier:
London, 1968; Vol. 8. (b) Bernasconi, C. F. Chimia 1980, 34, 1; ref 5d.

396 J . Org. Chem., Vol. 67, No. 2, 2002
Ma¸kosza et al.
Sch em e 2
Th e Rea ction s of 1a -c. As can be seen, the shape of
the product profiles obtained for 1b and 1c fits well the
curvilinear behavior predicted by eqs 1 and 6 with the
observation of the two limiting situations expected for a
thermodynamically controlled VNS process at low base
concentrations and a kinetically controlled process at
high base concentrations. Interestingly, the [PH]/[PF] ratio
levels off close to unity in the case of the bromonitroarene
1c. This implies that the addition of C-2 occurs at
essentially similar rates at the C6-H and C2-F positions
ortho to the NO2 group of 1c. Carrying out the reactions
under different experimental conditions, e.g., mixing
equimolar amounts of 1c and C-2 in the presence of a
large excess of a strong base like t-BuOK (in the
concentration range 0.05-0.3 mol L-1), did not change
the product distribution, thereby confirming the conclu-
sion that k1 ∼ k′ for the 1c system. The situation is not
1
actually very different for the 1b system with a k1/k′
ratio of about 0.8.
1
F igu r e 2. VNS/SNAr product ratio vs concentration of car-
banion C-2 in the reactions of 4-substituted 2-fluoronitroben-
zenes: 1a (4), 1b (0), 1c (9), 1d (O).
The somewhat different shape of the product profile
in the case of 1a can be explained in terms of the electron-
donating +M effect of the OCH3 group to the ring.15 This
will reduce the stability of the intermediate σ-adduct by
increasing k-1 appreciably while making at the same time
the â-elimination pathway more difficult (k2 decreases).
Accordingly, the k2[B]0/k-1 ratio should be smaller for 1a
(X ) OCH3) than for 1b (X ) F) or 1c (X ) Br), accounting
for the greater difficulty to reach the kinetic control
region. On the other hand, the possible conjugation of
the 4-OCH3 group with the NO2 group in 1a must also
reduce the electron-withdrawing effect of this substit-
uent and, hence the overall electrophilic reactivity of
the nitroarene. This will in turn reinforce the ipso effect
of the fluorine atom, leading to a relatively faster
nucleophilic addition of the carbanion C-2 at the fluoro-
bearing carbon C2 than at the unsubstituted carbon C6,
mol L-1 while that of the carbanion C-2 varied in the
range 2 × 10-2 to 0.6 mol L-1, being therefore in a
sufficient excess to consider [B]o as essentially constant
during the course of a given experiment. After 10 s, the
reaction mixtures were quenched with strong acid and
analyzed by using a reversed-phase HPLC or GC tech-
nique. This analysis confirmed the complete disappear-
ance of the starting nitroarene and the formation of
products arising from the expected VNS and SNAr
processes.
Formation of some amounts of nitrobenzyl sulfones
5a -d indicates that some decomposition of the chloro-
methyl moiety of the SNAr products 4a -d has occurred
under the experimental conditions; however, no differ-
ence in the product distribution was observed when the
reaction mixtures were quenched after longer times, e.g.,
60 s.12 The sum of the concentrations of 4a -d and 5a -d
was therefore taken as representative of the efficiency
of the SNAr pathway.
i.e., k′ > k1.16
1
(12) This indicates that the initially formed neutral SNAr product
4 is transformed into the stable anionic form of 4 and 5 via action of
C-2 on a proton or a “positive” chlorine at the position R, promoting
proton- or halogen-exchange reactions, respectively. Halogen exchange
between carbanions and their chlorinated analogues is a common
process, observed most frequently when carbanions of halogenated
sulfones are concerned.13,14
(13) Ma¸kosza, M.; Kwast, A. Bull. Soc. Chim. Belg. 1994, 103, 445.
(14) Galvagni, M.; Kelleher, F.; Paradisi, C.; Scorrano, G. J . Org.
Chem. 1990, 55, 4454-4459.
(15) (a) Terrier, F. Chem. Rev. 1982, 82, 77. (b) Exner, O. In
Correlation Analysis in Chemistry. Recent Advances; Chapman, N. B.,
Shorter, J ., Eds.; Plenum Press: New York, 1978; Chapter 10.
In the case of the difluoronitroarene 1b, some competi-
tive SNAr substitution of the p-fluorine atom also oc-
curred to a measurable extent. Figure 2 expresses the
results obtained, showing how the ratio [PH]/[PF] of the
VNS and SNAr productssonly the SNArortho product was
considered for 1bsdepends for each of the nitroarenes
studied on the sulfone anion concentration.

Nucleophilic Substitution of Hydrogen Mechanism
J . Org. Chem., Vol. 67, No. 2, 2002 397
F igu r e 4. [PH]/[PF] as a function of [B0] (eq 8) for a given
F igu r e 3. Product ratios: VNS/SNArpara ([), VNS/SNArortho
(0), and SNArortho/SNArpara (O) versus concentration of carbanion
C-2 in the reaction with 1b.
A
B
C
k-1/k-′ 1 ratio and k2 > k2 > k2
.
accepted for most SNAr systems. In fact, the above
findings can only be understood if the departure of F-
from our substrates 1a -d is assisted by the base reagent.
In the case of 1b, this assistance seems to be more
effective for the displacement of the para than the ortho
fluorine atom, accounting for the observed regular de-
Th e Rea ction of 1d . Ba se Ca ta lysis of th e SNAr
Rea ction s. The product profile obtained for 1d (X )
COO-t-Bu) is rather unexpected. Following a rapid
increase at low base concentrations, the [PH]/[PF] ratio
is seen to decrease with increasing [B]0, reaching a
crease of the SNArortho/SNArpara ratio at [B]o< 0.4 mol L-1
.
plateau corresponding to a k1/k′ value of about 1.5 at
1
[B]0 ) 0.3 mol L-1. A similar product profile with a more
pronounced maximum was obtained when the effect of
the concentration of C-2 on the reactivity of 1d studied
at 0 °C.
Assuming that such a base catalysis is actually opera-
tive to some extent in the reactions of C-2 with 1a -d ,
the results obtained should fit Scheme 3 rather than
Scheme 2 with the rate of the SNAr substitution being
in this instance given by eq 7.
Keeping with the model, the observed decrease in the
[PH]/[PF] ratio for 1d in the intermediate [B]o range can
be viewed as the result of a decrease in the rate of the
VNS substitution and/or an increase in that of the SNAr
substitution. Obviously, it is difficult to visualize how an
increase in [B]0 can have an inhibiting effect on the VNS
substitution since the base is necessarily a partner of the
â-elimination step. It follows that the decrease observed
in the [PH]/[PF] ratio must reflect an acceleration of the
SNAr process. This conclusion means that, contrary to
the assumption made in deriving eq 5, the substitution
of the fluorine atom by carbanion C-2 may be a base-
catalyzed reaction. A reconsideration of the results
obtained for 1b supports this proposal.
d[PF]
dt
k′ k′ + k′ k′ [B]
1
2
1 3
)
[1][C-2]
(7)
k′ + k′ + k′ [B]
-1
2
3
2
[PH]
k1k2k′ [B]0 + (k1k2k′ + k1k2k′ )[B]0
3
-1
2
)
[PF] k′ k′ k2[B]0 + (k′ k′ k-1 + k′ k′ k2)[B]0 + k′ k′ k-1
2
1
3
1
3
1
2
1 2
(8)
k′
k2
3
<
(9)
k′
k-1
-1
As mentioned earlier, the reaction of C-2 with difluo-
ronitroarene 1b afforded not only the VNS and SNArortho
products related to Scheme 2 but also some amount of
the product of the SNArpara substitution of the p-nitro-
activated fluorine atom (4b′ and dechlorinated 5b′).
Taking account of this latter reaction, the base depen-
Combining eqs 7 and 4 affords eq 8 for the [PH]/[PF]
ratio. As a matter of fact, a mathematical analysis of this
complicated equation predicts that the [PH]/[PF] ratio can
exhibit a maximum value provided that the inequality
expressed in eq 9 is obeyed. Working out eq 8 with in-
dence of the VNS/SNArortho, VNS/SNArpara, and SNArortho
/
A
B
C
creasing k2 at a given k-1/k′ ratio, i.e., k2 > k2 > k2
,
-1
SNArpara product ratios can be compared (Figure 3).
Contrary to the VNS/SNArortho ) [PH]/[PF] ratio which fits
well the overall behavior depicted in Figure 1, the VNS/
SNArpara ratio is subject to a base dependence that closely
resembles that observed for the VNS/SNAr ratio for 1d .
This is really an unexpected behavior if the SNAr reac-
tions proceed through a rate-limiting nucleophilic addi-
tion step, as we had originally assumed and is commonly
thus afforded the family of curves drawn in Figure 4,
which shows that a maximum is present only when eq 9
is fulfilled. Similar changes in the shape of the [PH]/[PF]
function from C to A are induced when decreasing the
k-1/k′ ratio at a given k2 value. Interestingly, these
-1
trends appear to be consistent with the expected influ-
ence of the X-substituent on the rate parameters.
Obviously, the above results point to the occurrence of
base-catalyzed fluoride anion departure in the SNAr
pathways involved in the reactions of C-2 with 1a -d , as
depicted in Scheme 3. While such a situation has been
described for the reactions of fluoronitroarenes with
(16) In as much as a fluorine atom has a much greater -I effect
but a much smaller +M effect than a OCH3 group, the similarly
possible through-the-ring conjugation of the NO2 group with the
p-fluoro atom in 1b is not expected to affect the k1/k′ ratio at a major
1
extent.17

398 J . Org. Chem., Vol. 67, No. 2, 2002
Ma¸kosza et al.
Sch em e 3
was produced via dechlorination of the initial SNAr
product 8. A separate experiment using an authentic
sample of 8 confirmed that the decomposition of this
product readily occurs in basic medium to give 9.
In the absence of a CR-H bond in the σF adduct, no
base catalysis of the SNAr pathway was expected to affect
the VNS/SNAr competition of Scheme 4. As shown in
Figure 5, the VNS/SNAr profile (open circles) fits very
well the simple curvilinear base dependence predicted
by eq 6 with a rapid access to the plateau associated
with the occurrence of a kinetically controlled VNS
process. A most noteworthy feature, however, is that this
plateau corresponds to a much larger predominance of
the VNS reaction, i.e., [PH]/[PF] ∼ 25, than that found in
the reactions of 1d with the secondary carbanion C-2
under the same conditions where [PH]/[PF] ∼ 1.1 was
observed (solid circles).
In this regard, the available evidence is that the
reactivity of C-6 is commonly 3-4 times greater than that
of C-2 in covalent addition processes at C-H ring
positions.21 Since the ring C-H and C-F positions of
1a -d are rather similar in terms of steric demand,22
there is no reason why this relative reactivity should be
modified on going from σH to σF adducts. It follows that
the quite different [PH]/[PF] ratios observed here in the
systems involving C-2 and C-6 must be a consequence
of different rates of the fluoride ion departure, which
appears to be the rate-limiting step in the reaction of C-6.
The possible acceleration of the SNAr reaction of 1d with
C-2 but not that with C-6 by the base reagent is a
reasonable explanation of this observation, although
steric hindrances caused in this step by tertiary C-6 may
also contribute to this effect.
Althought the occurrence of base catalysis in the
SNAr reactions of Schemes 2 and 3 can only be taken into
account within the complicated mathematical formalism
of eq 8, the competitive VNS/SNAr strategysdeveloped
in this work to get a better understanding of the VNS
reactionsremains actually useful for the two following
reasons:
(1) Notwithstanding the fact that it is difficult to
differentiate between the parameters responsible for the
observed variations of the [PH]/[PF] ratio in the low base
region, the initial increase of this ratio with increasing
[B]0 implies necessarily that the rate of the VNS reaction
is accelerated by the base reagent. Thus, the VNS
reaction proceeds with formation of the σH adduct in a
fast equilibrium step that is followed by a rate-limiting
base-catalyzed â-elimination step.
neutral nucleophiles such as secondary amines,18 we are
not aware of works reporting a similar behavior in SNAr
reactions involving anionic nucleophiles, especially car-
banions. Only to be noted is a report by Leffek and
Tremaine that the rate of reaction of 2,4-dinitrofluo-
robenzene with diethyl malonate anion increases regu-
larly with increasing the carbanion concentration.19
However, this phenomenon was not recognized as arising
from base catalysis of the departure of F-.
Why the SNAr reactions of Scheme 3 are subject to
base-catalysis is therefore an interesting question. This
behavior requires two major conditions: (1) ability of the
σF adduct to return to the starting materials, thus some
reversibility of the addition step, i.e., k′ being at least
of the same order of magnitude as k′ ; (2) the hydrogen
-1
2
atom bonded at the CR carbon of σF must be sufficiently
acidic to allow base-promoted elimination of HF. Regard-
ing the first condition, a key point is that we are here
dealing with reactions carried out in DMF, a dipolar
aprotic solvent where the solvation of small ions with a
localized negative charge like F- is rather poor20 while
that of highly delocalized anionic species such as σ-ad-
ducts is very much favored. As a result, fluoride anion
departure of σF may be rather difficult, accounting for k′
comparable to k′ . The fact that the reaction must
2
-1
proceed with replacement of a small fluorine atom by a
bulky nucleophile may also contribute to this inequality.
On the other hand, it seems reasonable to anticipate that
having a base-catalyzed concerted E-2-type breaking of
the CR-HR and C2-F bonds in σF should not be very
different from having the base-catalyzed E-2 elimination
of HCl in the σH adduct.
Th e Rea ction of 1d w ith a Ter tia r y Ca r ba n ion .
Definitive evidence that our reasoning regarding the
course of the SNAr reactions expressed in Scheme 3 is
actually correct was obtained by studying of the reaction
of 1d with the tertiary carbanion C-6 derived from the
deprotonation of 1-chloroethyl phenyl sulfone 6. Since the
low stability of C-6 precluded its use as the excess base
reagent, Scheme 4 was investigated by mixing equimolar
amounts of 1d and 6 in the presence of t-BuOK in a large
excess, a procedure shown to afford reliable results in
the reaction of 1c with C-2 (vide supra). In this reaction,
the VNS products 7 and 9 were formed, and the latter
(2) The plateau at high [B]0 strongly suggests that the
two VNS and SNAr processes are both occurring with
rates independent from the base concentration. In regard
to the VNS, it means that this process is under kinetic
control with a rate-limiting formation of the σH adduct.
Less definite conclusions can be made for the SNAr
reaction. It is also kinetically controlled, the overall
kinetic behavior being identical to the one predicted by
the simple competitive model of Scheme 2, i.e., [PH]/[PF]
) k1/k′ , or it is controlled by the k′ /k′ ratio and the
1
1
-1
(17) Chambers, R. D.; Close, D.; Williams, D. L. H. J . Chem. Soc.,
Perkin Trans. 1980, 778. Chambers, R. D.; Musgrave, W. K. R.;
Waterhous, J . S.; Williams, D. L. H.; Burdon, J .; Hollyhead, W. B.;
Tatlow, J . C. J . Chem. Soc., Chem. Commun. 1974, 239. Brooke, G.
M. J . Fluorine Chem. 1997, 86, 1.
(18) (a) Reference 5d, pp 46-58. (b) Nudelman, N. S. In The
Chemistry of Amino, Nitroso, Nitro and Related Groups Part 2.
Supplement F2; Patai, S., Ed.; Wiley: New York, 1996; p 1215.
(19) Leffek, K. T.; Tremaine, P. H. Can. J . Chem. 1973, 51, 1659.
(20) Vlasov, V. M. J . Fluorine. Chem. 1993, 61, 193.
rate of F- departure k′ . The latter case seems to be
2
working in the reaction of Scheme 4.
Isotop e Effects. The two major conclusions presented
above have been further consolidated by a study of the
(21) Mudryk, B.; Ma¸kosza, M. Tetrahedron 1988, 44, 209.
(22) Manderville, R. A.; Durst, J . M.; Buncel, E. J . Phys. Org. Chem.
1996, 9, 515.

Nucleophilic Substitution of Hydrogen Mechanism
J . Org. Chem., Vol. 67, No. 2, 2002 399
Sch em e 4
DCl
â-elimination step (k2 < k2HCl) and possible secondary
effects on the rate constants for formation and dissocia-
D
D
H
tion of the σH adduct (k1H/k1 e 1; k-1H/k-1 g 1; K1
<
K1D). As can be seen, Figure 6 reflects a reasonable
reverse secondary isotope effect of k1H/k1 ∼ 0.8 and
D
shows that the VNS reaction of 1e proceeds at a much
lower rate than that of 1c in the low to moderate [B]0
region. The situation is fully consistent with the idea that
the VNS reaction is now controlled by the â-elimination
step and that the relative values of the [PH]/[PF] ratios
for 1c and 1e are governed by a primary kinetic effect:
kH/kD ∼ 4.2 at [B]0 ∼ 0.08 mol L-1, the higher value of
which should be expected at lower [B]0, being in agree-
ment with the following estimation made for a pure
thermodynamically controlled VNS reaction: kH/kD
)
k1Hk2 k-1D/k1Dk2 k-1 ∼ 8 with k1H/k1 ∼ 0.8, k-1H/k-1
H
D
H
D
D
F igu r e 5. VNS/SNAr ratio in the reactions of secondary and
tertiary carbanions C-2 (b) and C-6 (O) with 1d versus
concentration of t-BuOK.
∼ 1.2, and k2H/k2 ∼ 12 at -40 °C.23 This suggests the
D
view that the base-induced â-elimination step of the VNS
reaction of 1c with C-2 proceeds via an E2-like transition
state. More importantly, this suggests that measuring
KIE effects may be particularly valuable tool for the
mechanistic analysis of VNS substitutions.
As a test for this approach, the reaction of 4-bromo-2-
deuterionitrobenzene 10 with carbanion C-2 to afford a
mixture of the protio and deuterio VNS products 11 and
11-d has been studied (eq 10). In this instance, the KIE
values were calculated as the product ratios [11-d]/[11]
which were measured at different base concentrations
using mass spectroscopy.
F igu r e 6. VNS/SNAr product ratio vs concentration of car-
banions C-2 in the reaction of 1c (O) and its deuterated
analogue 1e (b).
Because of the absence of fluorine in the nitroarene
molecule, the reactions were very clean, allowing mea-
surements over a wider base concentration range. Also,
as the H/D competition in 10 is of intramolecular nature,
the results of the KIE measurements are much more
reliable than those derived from a comparison of the two
compounds 1c and 1e. As can be seen in Figure 7, the
KIE profile for 10 resembles that drawn for the 1c/1e
kinetic isotope effects associated with the reaction of C-2
with 4-bromo-6-deuterio-2-fluoronitrobenzene 1e. The
kinetic behavior of this compound was studied under the
same experimental conditions as those used for its protio
analogue 1c. The related [PH]/[PF] profiles are compared
in Figure 6.
Contrary to those for the fluorine SNAr process, all the
parameters of the VNS reaction may be affected by the
replacement of H by D with a primary effect on the
(23) Melander, L.; Saunders, W. H. J r. Reaction Rates of Isotopic
Molecules; J . Willey & Sons: New York, 1980.

400 J . Org. Chem., Vol. 67, No. 2, 2002
Ma¸kosza et al.
excess of concentrated HClaq. The mixture was subjected to
HPLC, orsafter neutralization with solid sodium bicarbonates
to GLC analyses. The reactions were repeated two to five times
for each base concentration [B]0. The chromatographic analy-
ses were repeated three times for each reaction and the results
were averaged.
Rea ction s P er for m ed w ith a n Excess of C-2 (Sch em e
2, F igu r es 2, 3, a n d 6). According to the general procedure,
0.30-7.0 mmol of t-BuOK, 1.01 equiv in respect to t-BuOK of
2, and 0.03 mmol of nitroarene 1a -e were used. The calculated
concentration of t-BuOK was employed as a concentration of
C-2 ([B]0).
Rea ction s P er for m ed in th e P r esen ce of a n Excess of
t-Bu OK (Sch em e 4, F igu r e 5). According to the general
procedure, 0.41-2.95 mmol of t-BuOK was used. Amounts of
the other reagents used (0.05-0.1 mmol of sulfone 2 or 0.04-
0.05 mmol of 6, and 0.02-0.04 mmol of 1d ) were appropriate
to provide a sufficient excess of t-BuOK in all experiments.
The [B]0 values (Figure 5) were calculated from the initial
amount of t-BuOK used, diminished by that, consumed for
deprotonation of the sulfone.
Kin etic Isotop e Effect in th e Rea ction of 10 w ith C-2
(Eq 10, F igu r e 7). According to the general procedure, 0.11-
6.0 mmol of t-BuOK, 1.01 molar equiv with respect to t-BuOK
of 2, and 0.01 mmol of 10 were used. After the reaction was
quenched, the mixture was diluted with water and extracted
three times with CH2Cl2. The extract was washed with water
and dried with Na2SO4, and the solvent was evaporated. The
reactions were repeated three times for each base concentra-
tion. The crude products were subjected to GCMS analysis.
The isotope-ratio measurements were made for fragment ions
214/215 (M+ - Ts) and 323/324 (M+ - NO2) as the parent ion
of the product was too small. Both ions gave very similar
isotope ratios; thus an isotope effect of fragmentation was
assumed to be negligible if any, and the KIE values on Figure
7 are for 323/324 ions. The calculated concentration of t-BuOK
was employed as B0 of C-2.
F igu r e 7. Dependence of the observed kinetic isotope effects
(KIE) in the VNS reaction of C-2 on concentration of base.
pair with a strong dependence of [B]0 in the low concen-
D
tration range and a plateau corresponding to a k1H/k1
value of about 0.9 at high [B]0 values.
These results leave no doubt that the VNS reactions
of mononitrobenzene derivatives with the secondary
carbanion of chloromethyl tolyl sulfone occur according
to the mechanism shown in Scheme 1. Base-promoted
E2-type elimination of HCl from the intermediate
σH-adduct is rate-limiting at low base concentrations.
Nucleophilic addition of 2 at the nitro-activated unsub-
stituted position becomes rate-limiting at high base
concentrations.
Identification of the products and calibrations for HPLC and
GC analyses were performed using authentic samples of
compounds synthesized independently.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e Rea ction s of Ca r ba n ion s
C-2 or C-6 w ith Nitr oa r en es 1a -e or 10 u n d er th e
Con d ition s of Sp ecified Ba se Con cen tr a tion s (Sch em es
2 a n d 4, Eq 10). The reactions were performed in a 10 mL
round-bottom flask, dried at 100 °C prior to use, equipped with
a magnetic bar and a septum with an inlet and an outlet
needle for dry argon. The appropriate amount of freshly
sublimed t-BuOK was placed in the flask and then dissolved
by addition of dry DMF (8.0 mL) while in a thermostatic bath.
The mixture was stirred for 5 min at -40 ( 0.2 °C, and then
a solution of the carbanion precursor (2 or 6) in DMF (1.0 mL)
was added. The mixture was stirred for 1 min, and then a
solution of the nitroarene (1a -e) in DMF (1.0 mL) was added
at once. After 10 s (or 1 min for reactions of 6) of a vigorous
stirring the reaction was quenched by quick addition of a small
Ack n ow led gm en t. This work was supported by the
State Committee for Scientific Research (KBN) (Grant
No. PBZ 6.01). M.M. thanks the Foundation of Polish
Sciences for a Professorial Subsidy. This work was a
product of collaboration between PAN (Polish Academy
of Sciences) and CNRS.
Su p p or tin g In for m a tion Ava ila ble: Procedures for the
preparation of starting materials and samples of the products
including characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O010590Z