Reexamination of the bromination of 2-nitrobenzaldehyde with NBS or NaBr-NaIO4 in sulfuric acid

Article abstract of DOI:10.1080/00397911.2013.838790

Two literature procedures for selective bromination of 2-nitrobenzaldehyde using N-bromosuccinimide (NBS) or NaBr-NaIO₄ in sulfuric acid were examined. In contrast to the reports that 4-bromo-2-nitrobenzaldehyde is formed as a single product in good yield, reactions using NBS gave a number of isomeric mono- and dibrominated products identified by spectroscopical methods and by sodium borohydride reduction to the corresponding benzyl alcohol, and reactions using NaBr-NaIO₄ did not furnish any product. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.]

Full text of DOI:10.1080/00397911.2013.838790

Synthetic Communications1, 44: 954–958, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.838790
REEXAMINATION OF THE BROMINATION OF
2-NITROBENZALDEHYDE WITH NBS OR NaBr-NaIO4
IN SULFURIC ACID
¨
¨
Matthew M. Cummings and Bjorn C. G. Soderberg
C. Eugene Bennett Department of Chemistry, West Virginia University,
Morgantown, West Virginia, USA
GRAPHICAL ABSTRACT
Abstract Two literature procedures for selective bromination of 2-nitrobenzaldehyde using
N-bromosuccinimide (NBS) or NaBr-NaIO4 in sulfuric acid were examined. In contrast to
the reports that 4-bromo-2-nitrobenzaldehyde is formed as a single product in good yield,
reactions using NBS gave a number of isomeric mono- and dibrominated products identified
by spectroscopical methods and by sodium borohydride reduction to the corresponding
benzyl alcohol, and reactions using NaBr-NaIO4 did not furnish any product.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Bromination; N-bromosuccinimide; nitrobenzaldehyde
INTRODUCTION
A mild and attractive method for the bromination of deactivated aromatic
compounds[1] using N-bromosuccinimide (NBS) in sulfuric acid was reported by
Rajesh et al. in 2007.[2] Nine different substrates were examined and 60–92% yields
of single products were reported. For eight of the starting materials, the directing
effect of the functional groups present on the aromatic ring for aromatic electrophilic
bromination coincided in the same position. Thus, the regioselectivity of the
incoming electrophile was not an issue. The last substrate examined by the authors,
2-nitrobenzaldehyde (1), does not have this luxury, but nevertheless 4-bromo-2-
nitrobenzaldehyde (2) was reported as the only product in more than 60% yield
(Scheme 1). In addition to the reaction of 1 with NBS in sulfuric acid, a related
regioselective bromination using sodium bromide–sodium periodate in sulfuric
Received June 5, 2013.
Address correspondence to Bjo¨rn C. G. So¨derberg, C. Eugene Bennett Department of Chemistry,
West Virginia University, Morgantown, WV 26506-6045, USA. E-mail: bjorn.soderberg@mail.wvu.edu
954

BROMINATION OF 2-NITROBENZALDEHYDE
955
Scheme 1. Previously reported brominations of 2-nitrobenzaldehyde.
acid–water to afford 2 in 88% isolated yield was reported by Kumar et al. in 2012
(Scheme 1).[3] These two procedures were of interest to us because gram scale
amounts of 2 were needed as a starting material for a total synthesis currently
pursued in our laboratories.
The experimental procedures, as described in the literature, were repeated a
number of times. However, in our hands, we were unable to duplicate the reported
results in any of these experiments. Reaction with NBS gave a complex mixture of
brominated products and attempted reaction using NaBr-NaIO4 resulted only in
quantitative recovery of starting material. Herein is reported the outcome of the
experiments using NBS and a characterization of products from the complex reac-
tion mixtures obtained. It should be noted that each of the products obtained are
potentially useful building blocks in organic chemistry, although they are obtained
in relatively poor yields.
RESULTS AND DISCUSSION
In an attempt to decipher the composition of the complex reaction mixtures
obtained, 2-nitrobenzaldehyde (1) was reacted with NBS in sulfuric acid at the orig-
inally reported reaction temperature (25 ꢀC) and at 60 ꢀC. In addition, experiments
employing different amounts of NBS were performed, and the results are summar-
ized in Table 1. Complex mixtures containing the four possible monobrominated
compounds (2–5) and three dibrominated products (6–8) were observed in the crude
reaction mixtures of all reactions performed (Scheme 2).
Table 1. Molar ratiosa and isolated yieldsb of brominated products
Total
isolated
Equivalent(s)
NBSc
yield
(%)
1
2
3
4
5
6
7
8
0.75
1.25
1.25d
2.5
45.1 (41) 17.8 (19) 2.9 (4) 10.6 (12) 19.3 (24) 1.6
18.4 (17) 24.9 (21) 4.0 (4) 14.4 (9) 24.9 (20) 5.0 (5)
1.2 (1)
3.5 (1)
5.2 (9) 10.3 (2)
1.6 (2)
5.0 (3)
4.8 (1)
62
63
32
84
64
17.6 (4) 25.9 (10) 3.2 (3) 12.1 (3) 20.9 (8)
2.6 (3) 27.0 (20) 3.1 (8) 12.0 (8) 17.1 (14) 14.0 (12) 9.7 (9) 13.8 (13)
0 13.5 (4) 0.6 3.4 1.1 28.7 (24) 26.7 (19) 26.1 (17)
5.0
aThe first number represents the molar ratios of products from 1H NMR spectra of crude reaction mix-
tures.
bThe number in parenthesis represents isolated yields of products after chromatography. Yields in par-
entheses and italics were calculated from 1H NMR spectra of mixtures.
cThe brominations were performed at ambient temperature.
dBromination at 60 ꢀC.

¨
M. M. CUMMINGS AND B. C. G. SODERBERG
956
Scheme 2. NBS bromination followed by NaBH4 reduction of 2-nitrobenzaldehyde.
Starting material (1) was detected in all reactions except for the reaction using 5
equivalents of NBS. Chromatographic purification on silica gel was only partially
successful in separating the isomers. Pure 3 was isolated using <5 equivalents of
NBS, pure 7 could be isolated at any NBS amount, and pure 6 and 8 were isolated
at 5 equivalents of NBS. Compounds 2, 4, and 5 were always isolated as inseparable
mixtures containing two or three components. The identities of compounds 2–5 and
8 were verified by comparison with literature NMR, infrared (IR), and melting-point
data. Compound 6 has not been previously reported and for the dibrominated pro-
duct 7, only a melting point was found in the literature. 1H NMR, 13C NMR, and IR
spectra and HRMS (for 6) were obtained, all in agreement with the structure of 6
and 7.
To further corroborate the identity of each isomeric compound, all pure com-
pounds and some of the mixtures were reduced using sodium borohydride to give the
corresponding benzylalcohols, and the results are summarized in Scheme 2.
Reduction of 3 gave the known benzylalcohol 9 in 81% isolated yield. The aromatic
1H NMR splitting pattern, consisting of two doublets and a triplet, and a nuclear
Overhauser effect (nOe) between the methylene and one of the aromatic doublets
confirmed the structure of 9 and thus of isomer 3. This transformation also verified
the structure of 5, the other monobrominated product with the same aromatic doub-
1
let–doublet–triplet H NMR splitting pattern. We were unable to separate 1, 5, and
8; however reducing the mixture with sodium borohydride gave pure 12, the
reduction product of 5.
Compounds 2 and 4 could not be separated but upon treatment with sodium
borohydride gave a separable mixture of the known benzyl alcohols 10 and 11.
The benzyl alcohols also provided the opportunity to corroborate the structure of
2 and 4 by nOe experiments.
As expected, no nOe was observed between the methylene protons of 15
derived from 8 and either of the two aromatic protons. Compound 7 was the only
1
isomer exhibiting two singlets in the H NMR spectrum. Reductions to give 13
and 14 corroborated the structures of 6 and 7, because the expected nOes were
observed between the benzylic CH2 and one of the aromatic protons.
Monobrominated products dominated at lower amounts of NBS and, not sur-
prisingly, dibrominated products were the major products using a large excess of

BROMINATION OF 2-NITROBENZALDEHYDE
957
NBS. A much lower total yield of bromination products was obtained at 60 ꢀC using
2.5 equivalents of NBS (compared to entries 2 and 3). Because only a small amount
of dibrominated products were formed using 0.75 equivalents of NBS, the ratio of
2–4 is a rough measure of the reactivity of the different positions in 1 toward elec-
trophilic aromatic bromination. The reactivity was normalized to compound 3,
the minor monobrominated product, and was calculated to be 6.1:1:3.7:6.7 (in order
of 2 to 5). This order of reactivity probably reflects the electron-withdrawing ability
of the nitro group, compared to the aldehyde, wherein the former more effectively
deactivates the 3 and 5 positions that would lead to formation of 3 and 4. The data
for the reactions using 0.75 and 5.0 equivalents of NBS also suggest that compounds
3, 4, and 5 were brominated a second time at a much faster rate compared to 2,
because a significant amount of the latter remains even at 5.0 equivalents of NBS.
A rough order of reactivity for the second bromination can be calculated by compar-
ing the ratios of monobrominated products at 0.75 and 5.0 equivalents of NBS. The
reactivity order was 5 > 3 > 4 > 2.
In summary, we were unable to duplicate the reported selective bromination of
2-nitrobenzaldehyde (1) using NBS in sulfuric acid to give 4-bromo-2-nitrobenzalde-
hyde (2). Four monobrominated and three dibrominated products were isolated and
identified and reduced to the corresponding benzyl alcohol. It should be noted that
the methodology works very well for deactivated aromatic substrates wherein the
directing effects of substituents do not conflict. Bromination of 2-nitrobenzaldehyde
(1) using NaBr-NaIO4 in sulfuric acid resulted only in the recovery of starting
material.
EXPERIMENTAL
All NMR spectra were recorded in CDCl3 at 600 MHz (1H NMR) and
150 MHz (13C NMR). The chemical shifts are expressed in d values relative to Me4Si
1
(0.0 ppm, H and 13C) or CDCl3 (77.0 ppm, 13C) internal standards. The yields and
1
weights of compounds in the mixtures were calculated from H NMR spectra.
N-Bromosuccinimide was recrystallized from water. All other reagents and sol-
vents were obtained from commercial sources and used as received. Solvents were
removed from reaction mixtures and products on a rotary evaporator at water aspir-
ator pressure.
Bromination of 1 Using 1.25 Equivalents of NBS
N-Bromosuccinimide (NBS) (1.48 g, 8.32 mmol) was added to a solution of 1
(1.01 g, 6.71 mmol) in H2SO4 (concentrated 5.0 mL). The resulting mixture was stir-
red at ambient temperature (3 h). The reaction was quenched with ice and extracted
with ethyl acetate (3 ꢁ 20 mL). The combined organic phases were washed with satu-
rated NaCl (aqueous, 30 mL), dried (MgSO4), and filtered through a silica gel plug,
and the solvents were evaporated under reduced pressure. The resulting brown oil
was purified by column chromatography (hexanes=EtOAc, 8:2) to afford the follow-
ing fractions in order of elution: (I) 7 (28 mg, 0.09 mmol, 1%) as an off-white solid;
(II) 2 (328 mg, 21%), 4 (140 mg, 9%), and 3,4-dibromo-2-nitrobenzaldehyde

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M. M. CUMMINGS AND B. C. G. SODERBERG
958
(6) (94 mg, 5%); (III) 5 (310 mg, 20%), 8 (65 mg, 3%), 1 (168 mg, 17%); (IV) 3 (54 mg,
0.23 mmol, 4%).
Data for 7: mp ¼ 105–106 ꢀC (lit. mp ¼ 105–107 ꢀC[4]); 1H NMR d 10.39 (s, 1H),
8.39 (s, 1H), 8.19 (s, 1H); 13C NMR d 185.9, 147.7, 134.3, 132.5, 130.8, 130.4, 129.6;
IR (ATR) 3088, 2890, 1687, 1525, 1338, 1178 cmꢂ1
.
3-Bromo-2-nitrobenzylalcohol (9)[5]
Sodium borohydride (37 mg, 0.98 mmol) was added to a solution of 3 (105 mg,
0.46 mmol) in THF (3 mL) and H2O (1 mL). The resulting solution was stirred at
ambient temperature (20 min), water was added (20 mL), and the mixture was
extracted with EtOAc (3 ꢁ 20 mL). The combined organic phases were dried
(MgSO4) and filtered, and the solvents were removed under reduced pressure to give
9 (87 mg, 0.37 mmol, 81%) as a pale yellow oil. No further purification was required.
Spectral data were in accordance with literature data.
FUNDING
The C. Eugene Bennett Department of Chemistry at West Virginia University is
gratefully acknowledged for financial support for this research project.
SUPPORTING INFORMATION
1
Full experimental details and H and 13C NMR spectra for new compounds
can be found via the ‘‘Supplementary Content’’ section of this article’s Web page.
REFERENCES
1. For a review of brominations of deactivated aromatic compounds, see: Andrievsky, A. M.;
Gorelik, M. V. Russ. Chem. Rev. 2011, 80, 421–428.
2. Rajesh, K.; Somasundaram, M.; Saiganesh, R.; Balasubramanian, K. K. J. Org. Chem.
2007, 72, 5867–5869.
3. Kumar, L.; Mahajan, T.; Agarwal, D. D. Ind. Eng. Chem. Res. 2012, 51, 11593–11597.
4. Nodiff, E. A.; Saggiomo, A. J.; Shinbo, M.; Chen, E. H.; Otomasu, H.; Kondo, Y.;
Kikuchi, T.; Verma, B. L.; Matsuura, S.; Tanabe, K.; Tyagi, M. P.; Morosawa, S. J.
Med. Chem. 1972, 15, 775–780.
5. For a synthesis, mp, and spectral data, see: Jacquart, A.; Tauc, P.; Pansu, R. B.; Ishow, E.
Chem. Commun. 2010, 46, 4360–4362.