Direct observation of the intermediate in vicarious nucleophilic substitutions of hydrogen

Article abstract of DOI:10.1002/anie.200351352

Mononitrobenzene derivatives and 1-chloro-1-arylsulfonyl-methyl anions react with formation of stable σ^H adducts (see scheme; Ts = tosyl) which are observed by UV/Vis and NMR spectroscopy. The generally accepted energy profiles for vicarious nu

Full text of DOI:10.1002/anie.200351352

Angewandte
Chemie
Vicarious Substitutions
the most intensively studied carbanion in vicarious nucleo-
philic substitutions (Scheme 2), results in the formation of a
yellow product with lmax = 408 nm (Figure 1). Since the
intensity of the final absorbance does not depend on the
concentration of 6, the conversion of 5 into the sH adduct 7
must be complete.
Direct Observation of the Intermediate in
Vicarious Nucleophilic Substitutions of
Hydrogen**
Tadeusz Lemek,* Mieczysław Ma˛kosza,
David S. Stephenson, and Herbert Mayr*
In memory of Janusz Baran
Vicarious nucleophilic substitution has proven to be a general
method for the direct replacement of hydrogen atoms in
electron-deficient aromatic rings.[1] As shown in Scheme 1,
the reaction has been postulated to proceed through the
energetically high-lying intermediate sH adduct 3.[2] Depend-
ing on the reagents and reaction conditions, nucleophilic
addition (formation of 3) or 1,2-elimination (formation of 4)
may be the rate-determining step.[2b]
Scheme 2. Stepwise formation of 8 by vicarious nucleophilic
substitution from the chloro-4-tolylsulfonyl methyl anion 6 and
nitroanisole (5).
Scheme 1. Vicarious nucleophilic substitution of hydrogen.[1]
This mechanism is in accord with all experimental
evidence so far acquired, including substituent effects,[2a]
kinetic isotope effects,[2b,c] and leaving-group dependence.[2d,e]
However, sH adducts have generally been considered as
short-lived intermediates[2a] which have never been directly
observed.[3]
Herein we report the first UV/Vis and NMR spectro-
scopic observation of sH adducts from an a halogen-substi-
tuted carbanion and mononitro-substituted benzene deriva-
tives, which allows us to observe directly the individual steps
of vicarious nucleophilic substitutions and to determine the
rates of the addition steps.
Figure 1. Formation of the sH adduct 7 from 6 (0.01m) and 5
(2”10ꢀ4 m) in DMFat ꢀ408C.
When the reactions were run with [6]0 @ [5]0 (pseudo-first-
order conditions), linear plots of ln(A¥ꢀAt) versus t were
observed, which indicate first-order kinetics with respect to
arene. From the slopes of these plots, the pseudo-first-order
rate constants k1y were derived, which were plotted against [6]
to yield the second-order rate constant k2 (Figure 2).
To confirm the identity of the sH intermediate, the
reaction of 5 with 6 was also investigated by NMR spectros-
copy. A 0.02m solution of 7 was obtained by adding equimolar
amounts of tBuOK and of 5 dissolved in [D8]THF successively
to a solution of TsCH2Cl (Ts = tosyl) and [18]crown-6 in
[D8]THF at ꢀ788C. The 1H NMR (400 MHz) spectrum taken
at ꢀ408C indicated the presence of two diastereoisomers in a
1:3 ratio, which are tentatively assigned the molecular
structures shown in Scheme 3. The structure of the major
diastereoisomer could further be corroborated by its
13C NMR spectrum.[5]
Nucleophilic addition: Addition of 4-nitroanisole (5) to
colorless solutions of 7–50 equivalents of the carbanion 6,[4]
[*] Dr.-Ing. T. Lemek, Prof. Dr. H. Mayr, Dr. D. S. Stephenson
Department Chemie
Ludwig-Maximilians-Universität München
Butenandtstrasse 5–13 (Haus F), 81377 München (Germany)
Fax: (+49)89-2180-77717
E-mail: tadeusz.lemek@cup.uni-muenchen.de
herbert.mayr@cup.uni-muenchen.de
Prof. Dr. M. Ma˛kosza
Institute of Organic Chemistry
Polish Academy of Sciences
Kasprzaka 44, 01-224 Warszawa (Poland)
[**] We thank the Alexander von Humboldt Foundation for a fellowship
to T.L., as well as the Deutsche Forschungsgemeinschaft and the
Fonds der Chemischen Industrie for financial support.
Elimination: When the solution of 7 is produced from 5
(2” 10 ꢀ4 m) with excess of 6 (5 ” 10ꢀ3 m) in DMF at ꢀ408C, the
Angew. Chem. Int. Ed. 2003, 42, 2793 – 2795
DOI: 10.1002/anie.200351352
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2793

Communications
Figure 2. Pseudo-first-order rate constants of the addition reactions of
5 with 6 in DMFat ꢀ408C ([6]0 @[5]0).
Figure 3. Formation of the anion 8 by treatment of the sH adduct 7
(2”10ꢀ4 m) with tBuOK (2”10ꢀ2 m; DMF, ꢀ408C). The color of the
reaction mixture changes from yellow to purple.
While anti-elimination of HCl converts the minor diaster-
eoisomer of 7 directly into the E isomer of 8, the correspond-
ing Z isomer of 8 is expected to be formed by anti-elimination
from the major diastereoisomer. It is not clear whether the
exclusive formation of the E isomer of 8 is a result of
stereoisomerization at the stage of 7 (by deprotonation–
reprotonation of 7 at the CHCl position) or a result of base-
induced isomerization of the Z isomer of 8 into the thermo-
dynamically more favorable E isomer of 8. Stereomutation of
the two stereoisomers of 7 by retroaddition (!5 + 6) is
excluded because the formation of 8 from the major stereo-
isomer requires the presence of a higher concentration of
base.
Scheme 3. Chemical shift values from 1H NMR spectroscopy of a 1:3
mixture of the two diastereoisomers of 7 assigned by a COSY experi-
ment (ꢀ408C, [D8]THF, d [ppm], in parentheses: J [Hz]).
UV/Vis spectra show a slow decrease of the absorbance of 7 at
lmax = 408 nm (< 10% within 30 min), which is accompanied
by the appearance of a new absorption band with lmax
534 nm arising from the elimination process 7!8 formulated
in Scheme 2. The small value of the absorbance at l = 534 nm
in Figure 1 indicates that this subsequent reaction
is almost negligible during the formation of 7 from
5 and 6.
Treatment of the purple solution of 8 with trifluoroacetic
acid (TFA) led to decolorization because of the formation of
9, which gave spectra consistent with those in the literature
(Scheme 4).[6]
=
In accord with previous investigations,[2b] the
conversion of 7 into 8 can be accelerated by the
addition of extra base, for example tBuOK, the
standard base for vicarious nucleophilic substitu-
tion on a preparative scale. Figure 3 illustrates that
7 and 8 have comparable absorption coefficients at
lmax of both ions, and the observation of the
isosbestic point demonstrates the absence of
further long-lived intermediates. Since the rate of
the conversion of 7 into 8 does not increase linearly
with the concentration of tBuOK, rate constants
for this process have not been determined.
Scheme 4. Chemical shift values from 1H NMR spectroscopy of the nitrotosyl-sub-
stituted benzyl anion 8 and its protonation product, 9 (in [D8]THF).
Since the same reaction cascade, quantitative formation of
a sH adduct followed by slow elimination of HCl was also
NMR spectroscopic investigation of the conversion of 7
into 8 showed different behavior of the two diastereoisomers.
When a 0.02m solution of the potassium [18]crown-6 salt of 7
in [D8]THF was warmed to ꢀ208C, slow disappearance of the
signals of the minor diastereoisomer of 7 and the growth of
signals arising from 8 was observed, while the signals of the
major diastereoisomer of 7 remained unaffected. Conversion
of both diastereoisomers of 7 into 8 occurred when 7 was
treated with an excess of tBuOK at approximately ꢀ408C and
warmed to room temperature.
observed by the reaction of 6 with 4-bromonitrobenzene, it is
concluded that in contrast to current opinion[2a] the initially
formed sH adducts are often not high-energy intermediates,
but are usually formed in exergonic reactions of a halocar-
banions with nitroarenes.
Received: March 7, 2003 [Z51352]
Keywords: aromatic substitution · carbanions · elimination ·
.
kinetics · nucleophilic substitution
2794
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Chemie
[1] a) M. Ma˛kosza, J. Winiarski, Acc. Chem. Res. 1987, 20, 282 – 289;
b) M. Ma˛kosza, Synthesis 1991, 103 – 111; c) M. Ma˛kosza, Pol. J.
Chem. 1992, 66, 3 – 23; d) M. Ma˛kosza, Chem. Unserer Zeit 1996,
30, 134 – 140; e) M. Ma˛kosza, Russ. Chem. Bull. 1996, 45, 491 –
503; f) M. Ma˛kosza, K. Wojciechowski, Liebigs Ann. 1997, 1805 –
1816; g) F. Terrier, Nucleophilic Aromatic Displacement: The
Influence of the Nitro Group, VCH, New York, 1991; h) O. N.
Chupakin, V. N. Charushin, H. C. van der Plas, Nucleophilic
Aromatic Substitution of Hydrogen, Academic Press, San Diego,
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[2] a) M. Ma˛kosza, A. Kwast, J. Phys. Org. Chem. 1998, 11, 341 – 349;
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A. Kwast, Tetrahedron 1997, 53, 4739 – 4750.
[3] For reactions of carbanions, which contain leaving groups, with
highly electrophilic arenes yielding stable sH adducts which do
not undergo b elimination, see: a) G. P. Stahly, B. C. Stahly, J. R.
Maloney, J. Org. Chem. 1988, 53, 690 – 692; b) G. P. Stahly, J.
Fluorine Chem. 1989, 45, 431 – 433; c) S. Ostrowski, M. Ma˛kosza,
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1249; see also: e) F. Terrier, R. Goumont, M. J. Pouet, J. C.
Halle, J. Chem. Soc. Perkin Trans. 2 1995, 1629 – 1637.
[4] The carbanion 6 (lmax = 317 nm) formed instantaneously (< 0.1 s)
when a solution of tBuOK (0.2mmol) in THF (0.8 mL) was added
to a solution of 1 equivalent of chloro 4-tolylsulfonyl methane and
1 equivalent of [18]crown-6 in DMF (20 mL) at ꢀ408C.
[5] 13C NMR ([D8]THF, 100.7 MHz): d = 21.77 (q, CH3), 41.98 (d),
54.56 (q, OCH3), 74.09 (d), 87.99 (d), 109.59 (d), 113.27 (s), 127.13
(d), 129.68 (d), 130.67 (d), 136.73 (s), 145.92 (s), 157.97 ppm (s).
[6] a) W. Verboom, E. O. H. Orlemans, H. J. Berga, H. W. Scheltinga,
D. N. Reinhoudt, Tetrahedron 1986, 42, 5053 – 5064; b) M.
Ma˛kosza, Z. Wrꢁbel, J. Prakt. Chem. 1992, 334, 131 – 134.
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