Electrochemical synthesis of alkyl nitroaromatic compounds

Article abstract of DOI:10.1021/jo025898k

Alkyl nitroaromatic compounds were readily prepared via nucleophilic aromatic substitution for hydrogen or a heteroatom by electrochemical oxidation of the a-complex. Butyllithium and butylmagnesium chloride were used as nucleophiles, and several nitrocompounds were tested to explore the possibilities of the NASH and NASX reactions promoted electrochemically.

Full text of DOI:10.1021/jo025898k

compounds (RM with M ) Li, MgX), at o- and p-
positions, yielding the corresponding σH-adducts.
These σH-adducts are relatively stable, particularly at
low temperatures, due to the effective participation of the
nitro group delocalizing the negative charge. Moreover,
the formation of a partial O-M covalent bond aids in
stabilizing the σH-adducts. Those σH-adducts decompose
easily by addition of mineral acids leading to the corre-
sponding alkyl-substituted nitroso benzenes.5 A chemical
oxidation, via external oxidation agents (bromine, dichloro-
dicyano-p-benzoquinone (DDQ), or potassium perman-
ganate) is also possible and leads to alkyl-substituted
nitrocompounds.6
The oxidation step of the σ-complex remains to be
solved, since the use of chemical oxidants represents a
significant environmental hazard when scaling-up the
reactions. Our previous work7 has demonstrated that the
electrochemical oxidation of σ-complexes leads to substi-
tution products. For cyanation, amination, and reaction
with enolate anions, fair to good yields were obtained in
what can be considered a “green” process.
This electrochemical approach to the alkylation of
nitroarenes is reported herein for the first time. The
σ-adducts were prepared, under nitrogen atmosphere, by
careful stoichiometric addition to 5 mL of a 40 mM
solution of nitroaromatic compound in anhydrous THF
at 0 °C to a solution 2.5 M of butyllithium in hexane or
2.0 M butylmagnesium chloride in THF. A 5 mL DMF
solution of the supporting electrolyte (0.40 g of TEABF4)
was prepared under a nitrogen atmosphere. This DMF
solution was carefully added to the nitroaromatic solu-
tion. After exhaustive electrolysis, at 1.30 V vs SCE, the
corresponding alkyl-substituted nitrocompounds were
obtained.
Products and yields from this nucleophilic aromatic
substitution of hydrogen (NASH) by means of electro-
chemical oxidation are presented in Table 1. The global
yield in the reaction nitrobenzene/BuLi was 88%, with
47% yield of disubstitution products. Moreover, a better
yield of monosubstituted products, 75%, is possible in the
reaction nitrobenzene/BuMgCl (global yield of 85%). In
this case, only 10% of disubstitution products was
achieved. We obtained the same results with 1,3-dini-
trobenzene as a reactant; with BuMgCl, only monosub-
stituted products (36%) were obtained, but with BuLi,
mono- (43%) and disubstitution products (30%) were
obtained. Therefore, the reaction can be directed depend-
ing on the desired products (mono- or disubstitution
products). These yields are rather good considering that,
apart from the substitution product, only the nonreacted
starting material was recovered.
Electr och em ica l Syn th esis of Alk yl
Nitr oa r om a tic Com p ou n d s
Iluminada Gallardo,* Gonzalo Guirado, and
J ordi Marquet
Departament de Quı´mica, Universitat Auto`noma de
Barcelona, E-08193 Bellaterra, Barcelona, Spain
Iluminada.Gallardo@uab.es
Received May 3, 2002
Abstr a ct: Alkyl nitroaromatic compounds were readily
prepared via nucleophilic aromatic substitution for hydrogen
or a heteroatom by electrochemical oxidation of the σ-com-
plex. Butyllithium and butylmagnesium chloride were used
as nucleophiles, and several nitrocompounds were tested to
explore the possibilities of the NASH and NASX reactions
promoted electrochemically.
The nitration of alkyl benzenes, in a mixture nitric
acid/acetic anhydride at 0 °C, leads to m-, o-, p-alkyl
nitrobenzenes.1 This process constitutes the main indus-
trial synthesis of alkyl nitro benzenes. The ortho-
substitution is less important when the size of the alkyl
group increases, for instance, when the ratio for toluene
is 50/1.3/60 and that for ethyl benzene is 31/2.3/70. Alkyl
2,4- and 2,6-dinitrobenzenes (ratio ) 80:20) were ob-
tained by nitration of alkyl nitrobenzenes or alkyl
benzenes.
The new methods of alkylation of the aromatic nitro
compound are of remarkable interest in view of the fact
the few classical synthetic methods of preparing alkyl
nitro compounds have serious drawbacks.2 Recently, a
synthesis of alkyl nitro benzenes via nucleophilic aro-
matic substitution has been reported,3 using p-dini-
trobenzene and alkyl boranes as reagents in the presence
of potassium tert-butoxide in tert-butyl alcohol. Its fur-
nishes p-alkyl nitrobenzenes in good yields.
Nucleophilic aromatic substitution is one of the most
widely used approaches for the functionalization of
aromatics and forms the backbone of numerous impor-
tant syntheses of pharmaceuticals and potential drugs.
In this sense, C-C bond formation has been previously
investigated.4 Nitrocompounds react with organometallic
* Fax: (+34) 93-581-2920.
(1) (a) Buehler, C. A.; Pearson, D. E. Survey of Organic Synthesis;
Wiley-Interscience: New York, 1970. (b) Warren, S. G. Organic
Synthesis, the Disconnection Approach; Wiley & Sons, Ltd.: New York,
1982. (c) Carey, F. A.; Sundberg, R. J . Advanced Organic Synthesis.
Part A: Structure and Mechanisms, 3rd ed.; Plenum Publishing
Corporation: New York, 1991. (d) March, J . Advanced Organic
Chemistry, 4th ed.; Wiley: New York, 1992. (e) Franck, H.; Stadelhofer,
J . W. Industrial Aromatic Chemistry. Raw Materials, Processes,
Products; Springer-Verlag: Berlin, 1987.
(5) (a) Kienzle, F. Helv. Chim. Acta. 1978, 61, 449. (b) Bartoli, G.;
Leardini, R.; Lelli, M.; Rosini, G. J . Chem. Soc., Perkin Trans. 1 1997,
884. (c) Bartoli, G.; Leardini, R.; Medici, A.; Rosini, G. J . Chem. Soc.,
Perkin Trans. 1 1998, 692.
(6) Bartoli, G.; Bosco, M.; Baccolini, G. J . Org. Chem. 1980, 45, 522.
(7) (a) Gallardo, I.; Guirado, G.; Marquet, J . Chem. Eur. J . 2001, 7,
1759. (b) Gallardo, I.; Guirado, G.; Marquet, J . ES2000/489. (c)
Gallardo, I.; Guirado, G.; Marquet, J . Eur J . Org. Chem. 2002, 2, 251.
(d) Gallardo, I.; Guirado, G.; Marquet, J . Eur. J . Org. Chem. 2002, 2,
261. (e) Gallardo, I.; Guirado, G.; Marquet, J . J . Org. Chem. 2002, 67,
2548.
(2) (a) Traynelis, V. J .; MacSweeney, J . Y. J . Org. Chem. 1966, 31,
243. (b) Russel, G. A.; Weiner, S. A. J . Org. Chem. 1966, 31, 248. (c)
Terrier, F. Nucleophilic Aromatic Displacement; Feuer, H., Ed.; VCH:
New York, 1991. (d) Chupakhin, O. N.; Charushin, V. N.; van der Plas,
H. C. Nucleopjhilic Aromatic Sustitution of Hydrogen; Academic
Press: London, 1994.
(3) Shifman, A.; Palani, N.; Hoz, S. Angew. Chem., Int. Ed. 2000,
39, 944.
(4) Makosza, M.; Winiarski, J . J . Org. Chem. 1980, 45, 1535.
10.1021/jo025898k CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/24/2002
J . Org. Chem. 2003, 68, 631-633
631

TABLE 1. NASH in Nitr oben zen es by Action of Or ga n om eta llic Com p ou n d s via Electr och em ica l Oxid a tion a t 1.3 V vs
SCE
nitroarene
nitrobenzene
reagent
BuLi
NASH products
yielda [corrected yield]b
1-butyl-4-nitrobenzene
2,4-dibutyl-1-nitrobenzene
1-butyl-2-nitrobenzene
41 [46]
47 [52]
35 [41]
40 [47]
10 [12]
43 [57]
30 [40]
36 [100]
<5c
nitrobenzene
BuMgCl
BuLi
1-butyl-4-nitrobenzene
2,4-dibutyl-1-nitrobenzene
4-butyl-1,3-dinitrobenzene
4,6-dibutyl-1,3-dinitrobenzene
4-butyl-1,3-dinitrobenzene
5-butyl-1,3-dinitrobenzene
5-butyl-1,3-dinitrobenzene
1,3-dinitrobenzene
1,3-dinitrobenzene
1,3,5-trinitrobenzene
1,3,5-trinitrobenzene
BuMgCl
BuLi
BuMgCl
<5c
a
Yields were calculated by gas chromatography. Final products were identified by gas chromatography, mass spectrometry, and 1H
NMR and by comparison with authentic samples. After correction for unreacted starting material. c 1,3,5-Trinitrobenzene was recovered
b
in quantitative yield, after the electrolysis.
TABLE 2. NASX in 1,4-Din itr oben zen e by Action of Or ga n om eta llic Com p ou n d s via Electr och em ica l Oxid a tion
nitroarene
reagent
BuLi
NASX products
yielda [corrected yield]b
1,4-dinitrobenzeneb
1-butyl-4-nitrobenzene
2,4-dibutyl-1-nitrobenzene
4-nitrophenold
1-butyl-4-nitrobenzene
2,4-dibutyl-1-nitrobenzene
2-butyl-1-chloro-4-nitrobenzene
2-hydroxy-1-chloro-4-nitrobenzene
2,4-dinitrophenold
41 [58]
20 [29]
7 [10]
12 [30]
28 [70]
<5c
1,4-dinitrobenzeneb
BuMgCl
1-chloro-2,4-dinitrobenzene
BuLi
BuMgCl
<5c
<5c
1-chloro-2,4,6-trinitrobenzene
BuMgCl
1-butyl-2-chloro-3,5-dinitrobenzene
2-chloro-3,5-dinitrophenol
picric acidd
<5c
<5c
<5c
a
Yields were calculated by gas chromatography. Final products were identified by gas chromatography, mass spectrometry, and 1H
NMR and by comparison with authentic samples. After correction for unreacted starting material. c Only the reactant, apart from
substituted products, was recovered after the electrolysis. From residual water present in the solvent in the presence of BuLi or BuMgCl.
b
d
Good results were obtained when the p-dinitrobenzene
was used as a nitroaromatic compound. A nitro group
can be replaced by a butyl group via electrochemical
oxidation of the σX-complex formed in a NASX process
(Nucleophlic Aromatic Substitution of Heteroatom). As
in a NASH process, the reaction can be directed toward
mono- or disubstitution products by using BuLi or
BuMgCl. The unreacted starting material was the only
product recovered, apart from the substitution product.
No chloro atom displacement by the butyl group was
observed when 1-chloro-2,4-dinitrobenzene and 1-chloro-
2,4,6-trinitrobenzene were used. The results are shown
in Table 2. The SNAr addition-elimination mechanism
was excluded because before the electrolysis the cyclic
voltammogram of the reaction mixture never presented
a reduction wave of alkyl nitrobenzene product (E° )
-1.21 V vs SCE). Only the reduction waves correspond-
ing to 1,4-dinitrobenzene are obtained (E1° ) -0.58 V,
E2° ) -0.83V vs SCE).
The yields obtained applying the “clean” electrochemi-
cal method are comparable with those reported in the
literature using chemical oxidants, and even better in
some cases. In addition, this is the first time that
alkylation of dinitroderivates has been achieved with
reasonable yields.
In the Scheme 1, the established7 oxidation mechanism
of σ-complexes (Meisenheimer complexes) is described.
The use of electrochemical techniques is very attractive
in the field of nucleophilic aromatic substitution reaction.
We are currently working to establish the scope and
limitation of this methodology. A full account will be
published in the foreseeable future elsewhere.
Exp er im en ta l Section
Gen er a l Rem a r k s: Electr och em ica l Mea su r em en ts. The
electrochemical cell and measurement procedures for cyclic
voltammetry have been described previously.7,8 All potentials
are reported vs an aqueous saturated calomel electrode. A glassy
carbon was used as a working electrode (0.05 mm diameter) in
CV experiments. A graphite rod was used as a working electrode
in electrolysis experiments.
Ma ter ia ls. DMF (SDS pour syntheses peptidiques), anhy-
drous tetrahydrofuran 99.9%, and nEt4NBF4 were used without
purification.
Use of equivalent amounts of the nitro aromatic and
organometallic reagents was found to be essential for the
best completion of reaction because an excess of organo-
metallic reagents makes it more difficult to oxidize the
mixture and larger yields of dialkylated substituted
products are obtained.
1-Nitrobenzene, 1,3-dinitrobenzene, 1,4-dinitrobenzene, 1-chlo-
ro-2, 4-dinitrobenzene, and 1,3,5-trinitrobenzene were purchased
commercially.
The butyllithium produces higher yields than the
butylmagnesium chloride in our reactions, although the
mixture reaction is cleaner with butylmagnesium chlo-
ride. The reaction was also carried out in THF (resistive
media). It was not possible perform the reaction in DMF,
since DMF decomposes in the presence of butyllithium.
1-Chloro-2,4,6-trinitobenzene was synthesized in our labora-
tory. Following the method described in the literature,9 15 mL
(8) Andrieux, C. P.; Gallardo, I.; Larumbe, D. J . Electroanal. Chem.
1991, 304, 241.
632 J . Org. Chem., Vol. 68, No. 2, 2003

SCHEME 1
measurements were made with an HP-5 column (cross-linked
5% Ph-Me silicone, 30 m × 0.32 mm × 0.25 µm). Five control
(experimental) variables were used. The following were the
settings: initial temperature, 100 °C; initial time, 1 min; tem-
perature gradient, 12 °C/min; maximum oven temperature, 240
°C; final time, 15 min.
of POCl3 were added to 22 mmol of picric acid. Next, 2.5 mL of
pyridine was added carefully. The mixture was heated to 120-
125 °C for 1 h. After the mixture was cooled to room tempera-
ture, it was poured into ice-water. The solid was collected and
dried. It was identified as 1-chloro-2,4,6-trinitrobenzene 2 (3.9
g, 72%).
The analysis showed the presence of nitro compounds. The
final products were analyzed by gas chromatography/mass
spectroscopy, 1H NMR, and cyclic voltammetry and identified
by comparison of their spectroscopic behavior with that reported
in the literature for them or related compounds depending on
the cases.2d,5,10 The product yields were not optimized and were
calculated by gas chromatography after verification from the 1H
NMR of the crude that only the substitution products and
starting material were present and by cyclic voltammetry.
Butylmagnesium chloride, 2.0 M solution in THF, and butyl-
lithium, 2.5 M in hexane, were purchased commericially.
Gen er a l P r oced u r e for NASH or NASX in Nitr oa r en es.
General Experimental details were given in previous papers.7
A solution of nitroarene (40 mM) in 5 mL of anhydrous THF at
0 °C was prepared under a nitrogen atmosphere. The corre-
sponding σH-complex was prepared by careful addition of the
nucleophile 1:1 (butyllithium or butyllmagnesium chloride solu-
tions in hexane/THF, 2.5 and 2.0 M, respectively) to the solution
of the nitroarene under a nitrogen atmosphere. Finally, the
addition of 5 mL of DMF, which contains 0.4 g of NEt4BF4 (0.1
M) as a supporting electrolyte, was carried out.
Ack n ow led gm en t. Financial support from the DGI
(MCyT of Spain) through Project BQU2000-0336 and
from the “Generalitat de Catalunya” through Project
2001SGR00180.
The oxidation peak potentials of the σH-complexes were
measured by cyclic voltammetry.
Then, electrolysis was carried out at values of potentials ca.
1.3 V using a carbon graphite rod electrode as a working
electrode. The electrolysis was stopped when no σ-complexes
were detected in the mixture (cyclic voltammetric analyses were
carried out to follow the electrochemical oxidation). Then, the
mixture was extracted with water/toluene. The organic layer was
dried with Na2SO4 and evaporated, affording a residue that was
analyzed by gas chromatography. Gas Chromatography. GC
Su p p or tin g In for m a tion Ava ila ble: Cyclic voltammetry
experiments. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O025898K
(10) (a) Susuki, H.; Takeuchi, T.; Mori, T. J . Org. Chem. 1996, 61,
5944. (b) Seko, S.; Miyake, K.; Kawamura, N. J . Chem. Soc., Perkin
Trans. 1 1999, 1437. (c) Makosza, M.; Surowiec, M. J . Organomet.
Chem. 2001, 624, 1-2, 167.
(9) Lam, K.-B.; Miller, J .; Samenho, P. J . J . Chem. Soc., Perkin
Trans. 2 1977, 457.
J . Org. Chem, Vol. 68, No. 2, 2003 633