Carbon Nucleophilicities of Indoles
DNBF-Cl and DNBZ-Cl. To be noted is that compounds 5a-n,
8g, 11, 13, 16, and 18 can also be viewed as being formally the
products of SEAr substitution of the arene or hetarene moiety
of the nucleophiles by electrophilic DNBF-Cl and DNBZ-Cl,
allowing the couplings to be classified as SEAr-SNAr pro-
cesses.27,33
process.56 In our systems, the absence of a base catalyst can
explain why it is difficult to achieve the ꢀ-elimination step of
eq 7, making it more favorable to complete the overall
substitution process via the three-step sequence shown in
Scheme 2, in which the initial carbon-carbon coupling is rate-
limiting.
At this stage, the question is posed of the mechanism of the
observed substitutions, as proposed in Scheme 2. On the grounds
of analogy with previous studies of the reaction of DNBF with
a number of benzenoid and π-excessive heteroaromatic sub-
strates, including indoles (Scheme 1),12,13 there is little doubt
that the processes go through the initial formation of a
zwitterionic Wheland-Meisenheimer intermediate, i.e., 6H or
7H in Scheme 2. Forlani et al. have successfully trapped such
Consistent with a rate-limiting formation of a zwitterion in
Scheme 2 is that the rate constants k1 for DNBF addition of
3a-n, 9, and 14 to the chlorine-bearing C-7 carbon of DNBF-
Cl are notably lower, i.e., by a factor 20-90, than those for
addition of these nucleophiles to the unsubstituted C-7 carbon
of DNBF (Table 2).14 Other structural things being equal, it is
a general feature that nucleophilic addition occurs faster at an
unsubstituted than a substituted carbon in nucleophilic aromatic
substitutions and related σ-complexation processes.1,2,11,49,50,57
Also to be noted is that the rate constants k1 for coupling of
DNBZ-Cl with N-methylindole, 1,2,5-trimethylpyrrole, and
azulene are very similar to those for the DNBF-Cl reactions.
This confirms previous findings that the presence of an N-oxide
group has very little influence on the electrophilic reactivity of
mononitro- and dinitro-2,1,3-benzoxadiazoles in SNAr and
related σ-complexation processes.1,3b,5d,19
Electrophilicity of DNBF-Cl and DNBZ-Cl. A quantitative
assessment of the intrinsic electrophilicity of DNBF-Cl and
DNBZ-Cl is possible by referring to the general approach to
nucleophilicity and electrophilicity recently developed by Mayr
and co-workers.26,58-60 Using a large series of diarylcarbenium
ions and various π-excessive systems as reference sets for
electrophiles and nucleophiles, respectively, these authors have
shown that it is possible to describe the rates of a large variety
of electrophile-nucleophile combinations by the three-para-
meter eq 9. In this equation, the E parameter measures the
strength of the electrophile, while N measures the strength of
the nucleophile and s is a nucleophile-specific parameter which
describes the sensitivity of the rate constant upon variation of
the electrophile.
1
intermediates by H and 13C NMR in reactions of DNBF with
supernucleophilic carbon bases of type 19.8 Then, two different
routes can be envisioned for the conversion of the zwitterion
into the substituted products.
The first that we have favored in drawing Scheme 2 involves
the rearomatization of the hetarenium moiety of the zwitterionsa
process which is energetically assisted by the recovery of the
aromaticity of the indole or other nucleophilic structuresto give
the related anionic σ-complex (i.e., 6 or 7). Facile loss of
chloride ionsa good leaving group (pKa ) -7) in SNAr
reactions48 from the anionic adducts will then afford the
substitution products. However, there is an alternative mecha-
nism to the three-step sequence of Scheme 2. This is a direct
conversion of the zwitterion into the substitution products
through ꢀ-elimination of HCl, going along with a concomitant
rearomatization of both the nucleophilic and electrophilic
structures. Such a ꢀ-elimination step is depicted in eq 7, and it
is reminiscent of the one involved in a number of vicarious
nucleophilic aromatic substitutions of hydrogen, as exemplified
in eq 8 with reference to the reaction of nitrobenzene with the
anion of chloromethyl phenyl sulfone.1,49-55 The only difference
is that in our systems the departing chlorine group is bonded to
the electrophilic moiety while the L group (e.g., Cl) is part of
the nucleophilic moiety in common vicarious substitutions.51-55
(48) (a) Perrin, D. D. Pure Appl. Chem. 1969, 20, 133. (b) Perrin, D. D. In
Dissociation Constants of Inorganic Acids and Bases in Aqueous Solution;
Butterworths: London, 1969.
(49) (a) Makosza, M. In Current trends in organic synthesis; Nozaki, H.,
Ed.; Pergamon Press: New York, 1993; p 401. (b) Makosza, M.; Woniarski, J.
Acc. Chem. Res. 1987, 20, 282.
(50) (a) Makosza, M.; Wojciechowski, K. Liebigs Ann. Chem. 1997, 1805.
(b) Makosza, M.; Wojciechowski, K. Chem. ReV. 2004, 104, 2631.
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Makosza, M.; Kwast, A. J. Phys. Org. Chem. 1998, 11, 341.
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2002, 67, 457.
(54) Chupakhin, O. N.; Charushin, V. N.; Van der Plas, H. C. In Nucleophilic
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(55) Makosza, M.; Kwast, A. Eur. J. Org. Chem. 2004, 2125.
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(57) (a) Bunnett, J. F. ReV. Chem. Soc. 1958, 12, 1. (b) Miller, J. In Aromatic
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(58) (a) Mayr, H.; Ofial, A. R. In Carbocation Chemistry; Olah, G. A.,
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That the rates of substitution do not depend significantly upon
the nature of the isotopic labeling at the reactive carbon center
of the nucleophile is key information to discriminate between
the two mechanistic pathways. This rules out a rate-determining
step involving C-H bond breaking and therefore the vicarious
route of eq 8. Should this route be operative, significant isotope
effects should be observed as found for a number of classical
vicarious substitutions reactions.52 These proceed in general
through a rate-limiting ꢀ-elimination step, at least at low
concentrations of the base catalysts used to promote the
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