Science in China Series B: Chemistry
© 2007
Science in China Press
Springer-Verlag
An efficient synthesis of substituted
benzene-1,2-dicarboxaldehydes
ZHU Peter C1†, WANG Der-Haw1, LU Kaitao1 & MANI Neelakandha2
1
2
Advanced Sterilization Products, Johnson & Johnson, 33 Technology Drive, Irvine, CA 92618, USA;
Pharmaceutical Research and Development La Jolla, Johnson & Johnson, 3210 Merryfield Row, San Diego, CA 92121, USA
Substituted-benzene-1,2-dicarbaldehydes were synthesized by the reaction of substituted-1,2-bis
(dibromomethyl) benzenes with fuming sulfuric acid, followed by hydrolysis. The yields were significantly improved by introducing solid sodium bicarbonate into the reaction mixture before hydrolysis
and workup.
aromatic aldehyde, 1,2-bis(dibromomethyl)arene, hydrolysis, oxidation, sodium bicarbonate, fuming sulfuric acid
1 Introduction
Aromatic dicarboxaldehydes are an important class of
compounds used for synthetic intermediates, polymer
synthesis, analytical reagents, and disinfectants[1,2]. For
example, o-phthalaldehyde (OPA) is widely used as an
analytical reagent for proteins analysis and also as a
disinfectant for medical devices in hospitals. OPA-like
compounds are a fairly new class of compounds being
developed as new germicidal compounds for disinfec－
tion or sterilization[3 6]. Although relatively stable, these
compounds are nevertheless susceptible to oxidation[7],
－
reduction [8 10] and strongly basic [11] conditions, as
shown in Figure 1[12]. Thus, despite the numerous synthetic methods reported for the preparation of aromatic
－
aldehydes[13 15], only a few can be used for the synthesis
of OPA-like compounds. One of the most widely-used
synthetic methods to this class of compounds involved
the hydrolysis of gem-dihalides to aldehydes[16,17]. From
a practical standpoint, this method is especially useful
since the requisite tetrahalo-1,2-xylenes can be easily
obtained by radical halogenation. A major drawback to
this approach, however, has been the lack of an efficient
and general method for the hydrolysis of the gem dihalides due to the sensitivity of the dialdehyde product to
the hydrolytic conditions, resulting in poor yields and
0H
1H
2H
3H
4H
5H
6H
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side products in many instances. We wish to report here
an improved procedure for this reaction in which solid
bicarbonate was used to initially neutralize excess acid
in the reaction mixture, which was then subjected to hydrolysis leading to cleaner products in higher yields.
2 Experimental
The following chemicals were purchased from Aldrich
Fine Chemicals and were used without purification:
bromine, carbon tetrachloride, 4-chloro-o-xylene, 4-bromo-o-xylene, 4-nitro-o-xylene, sodium bicarbonate, sodium hydroxide, potassium bicarbonate, calcium hydroxide, calcium carbonate and triethylamine. Fuming
sulfuric acid (Oleum) with 20% free SO3 and 4-fluoro-oxylene was purchased from Fisher Scientific.
2.1 4-Chloro-OPA
2.1.1 Bromination of 4-chloro-o-xylene. In a typical
example, the following modified bromination procedures were employed[18]. 4-chloro-o-xylene (5.0 g) and
about 200 mL of CCl4 were added into a 250 mL
three-neck round-bottom flask equipped with a magnetic
stirring bar, a 200 mL addition funnel, a condenser, and
a stopper. The outlet of the condenser was connected via
8H
Received April 11, 2006; accepted May 16, 2006
doi: 10.1007/s11426-007-0031-y
†
Corresponding author (email: pzhu1@alzus.jnj.com)
9H
Sci China Ser B-Chem | April 2007 | vol. 50 | no. 2 | 249-252
Figure 1 Possible OPA byproducts via redox or disproportionation reactions.
Tygon tubing and a funnel to a beaker filled with a
Na2CO3 solution to trap HBr generated during bromination. The solution in the flask was first heated to reflux
(oil bath). Liquid bromine was then added dropwise
from the addition funnel. The bromine addition rate was
controlled in order to control the concentration of the
bromine in the solution in the flask. Additional bromine
was added if the color of the solution became lighter, or
colorless. Two 250 W tungsten lamps were used to irradiate the mixture to enhance the bromination. If desired,
the progression of the reaction was monitored for the
reaction progress. The reaction was allowed to proceed
for about 6 h. CCl4 was removed at normal pressure by
distillation at 130℃ until about 180 mL of the CCl4 was
removed. Then, a series of five additions of methanol, of
about 20 mL each, were added to the residual in the
flask to azeotropically remove residual CCl4 by distillation at 130℃. On the final distillation, when about 20
mL of solution remained in the flask, the solution was
cooled to room temperature. The remaining solvent was
removed at 40℃ with a rotary evaporator at about 10
mmHg to produce a solid. The solid was recrystallized
in
about 150
mL of
hexane
to
yield
4-chloro-1,2-bis-dibromomethyl-benzene as white needle crystals (12.0 g, yield ~72%, GC indicated a purity
of 99%).
2.1.2 Hydrolysis of substituted-1,2-bis-dibromomethyl-benzene.
(i) Procedure 1 (Modified for 4-chloro-1,2-bis-dibromomethyl-benzene).
About 6.4 g of 4-chloro-1,2-bis-dibromomethyl-ben250
zene were ground into a powder and added to a dry 100
mL round-bottom flask equipped with a magnetic stirring bar. About 20 mL of fuming sulfuric acid was
poured into the flask while stirring. The mixture was
stirred at room temperature for about 1 h. During the
hour, the powder was dissolved, and the solution gradually became dark brownish. The solution was poured
into a 100 mL beaker immersed in a dry ice/acetone bath.
The brownish solution was gradually added to about 25
g of crushed ice with stirring so that the temperature of
the solution was controlled. Then the solution was allowed to gradually warm to room temperature, and extracted with ethyl acetate (2×100 mL). The organic
phase was washed with 5% Na2CO3 (3×50 mL). The
resultant organic phase was dried with Na2SO4 overnight.
After drying, the remaining solvent was removed at
40℃ by rotary evaporator at about 10 mmHg to obtain a
yellow solid. The yellow solid was recrystallized in
about 30 mL of hexane to yield 4-chloro-OPA as white
crystals (1.7 g, GC purity 99%, yield = 72%).
(ii) Procedure 2 (Optimized using NaHCO3 for 4-substituted-1,2-bis-dibromomethyl-benzene).
To a round bottom flask, 1 equivalent of the brominated compound, or product of the bromination reaction,
and 12 mole equivalents of fuming sulfuric acid were
added. The flask was equipped with a rubber stopper and
a CaCl2 drying tube. The mixture was stirred until all
bromides were dissolved. Eight mole equivalents of
solid sodium bicarbonate powder were added while the
mixture was being stirred in an ice bath. After the mixture stopped bubbling, ice was slowly added for the hydrolysis. The remaining processes were the same as
ZHU Peter C et al. Sci China Ser B-Chem | April 2007 | vol. 50 | no. 2 | 249-252
Procedure 1, giving the desired dialdehyde.
2.2 4-Bromo-OPA and 4-fluoro-OPA
method involves treatment with fuming sulfuric acid or
sulfur trioxide followed by quenching with water. Li et
al. [18] reported the preparation of several aromatic
polyaldehydes, including OPA, by the hydrolysis of
gem-dibromides using this procedure. Even though the
exact mechanism of this reaction remains unclear, pioneering studies by Hart and Freedman indicate that in
strongly ionic media, halomethyl groups attached to an
aromatic nuclei, undergo ionization to form multica－
tionic species[20 22]. These dicationic species, thus formed
on hydrolysis with water, yield the dicarboxaldehyde
(Scheme 2, Eq. (1)). Mark et al. described[23] the suggested formation of polyhaloaralkyl (halosulfonyl) sulfoxonium inner salts compounds by the reaction of benzal halides with sulfur trioxide (Scheme 2, Eq. (2)).
The hydrolysis was carried by following Li’s procedure, using fuming sulfuric acid at room temperature
followed by quenching with water. Even though this
procedure worked reasonably well with unsubstituted
OPA, less than satisfactory yields and purity were obtained with many substituted derivatives. To improve the
11H
The synthesis of other 4-halo-OPA’s, 4-bromo-OPA and
4-fluoro-OPA followed similar procedures as described
for 4-chloro-OPA. The oil 4-fluoro-OPA was purified by
silica column chromatograph (hexane︰ethyl acetate =
2︰1). Others were purified by recrystallization. Key
reaction and workup conditions are summarized Table 1.
12H
3 Results and discussion
Our general synthetic route to substituted ortho-phthalaldehydes is outlined in Scheme 1. Radical bromination
of xylenes was carried out by a reported procedure. Thus,
bromine was added to a refluxing solution of the substituted xylene in carbon tetrachloride while the reaction
was irradiated, using two 250 W tungsten lamps. The
desired tetrabromoderivatives were obtained in very
good yields and in excellent purity.
Several methods have been reported for the hydrolysis of gem-dihalides [19]. The most widely reported
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Table 1 Summary and comparison of key reaction and workup conditions for the two-step synthesis of 4-halo-OPA’s
Condition variables
4-chloro-OPA
4-bromo-OPA
4-fluoro-OPA
bromination time
~6h
~2h
~6h
Bromination
crystallization
workup
crystallization
solventa)
fuming H2SO4
24 equivalents
12 equivalents
12 equivalents
Hydrolysis
workup
recrystallization
recrystallization
silica column
a) Hot hexane was used to isolate 4-bromo-1,2-bis(dibromomethyl)benzene from 3-bromo-1-bromomethyl-2-dibromomethylbenzene (from an isomeric
impurity came with starting material).
Scheme 1 General two-step synthesis of 4-substituted o-phthalaldehydes.
(1)
(2)
Scheme 2 Possible mechanisms for the hydrolysis.
ZHU Peter C et al. Sci China Ser B-Chem | April 2007 | vol. 50 | no. 2 | 249-252
251
Table 2 Yield comparison of three reaction/work up conditions
Product
Process
Equivalents of H2SO4
reference method
28.4
OPA
with controlled acid
12
12
with added NaHCO3
reference method
28.4
4-chloro-OPA
with controlled acid
12
with added NaHCO3
12
reference method
28.4
4-bromo-OPA
with controlled acid
12
with added NaHCO3
12
reference method
28.4
4-nitro-OPA
with controlled acid
12
with added NaHCO3
12
yield and purity of the aldehyde, we decided to improve
the Li’s hydrolysis protocol by reducing the amount of
sulfuric acid used and changing the work-up procedure.
Thus, the amount of acid was reduced from 28.4
equivalents to 12 equivalents, and instead of directly
adding the reaction mixture to ice, the excess acid was
neutralized prior to quenching with water. Several inorganic bases such as Na2CO3, NaOH, K2CO3, KOH, and
CaCO3 were screened for neutralizing the reaction.
Adding 8 equivalents of solid NaHCO3 gave the best
results. This modification significantly improved the
yield of the product in the case of all four products: OPA,
4-chloro-OPA, 4-bromo-OPA, and 4-nitro-OPA. The
yields of products obtained using Li’s procedure, and our
improved synthesis processes are outlined in Table 2.
1
2
3
Russell A D. Introduction of biocides into clinical practice and the
impact on antibiotic-resistant bacteria. Society for Applied Microbiology Symposium Series 31. In Antibiotic and Biocide Resistance in
Bacteria. Boston: Blackwell Science, 2002. 31: 121S－135S
Boucher R M G. Biocidal mechanisms in the aldehyde series. Can J
Pharm Sci, 1975, 10(1): 1－7
Walsh S E, Maillard J-Y, Russell A D. Ortho-phthalaldehyde: a possible alternative to glutaraldehyde for high level disinfection. J Appl
Microbiol, 1999, 86(6): 1039－1046[DOI]
Zhu P C, Roberts C G, Favero M S. Ortho-phthalaldehyde: a possible
alternative to glutaraldehyde for high level disinfection. Curr Org
Chem, 2005, 9(12): 1155－1166[DOI]
Brewer B N, Mead K T, Pittman C U Jr, Lu K, Zhu P C. Smart solution
chemistry: Prolonging the lifetime of ortho-phthalaldehyde disinfection solutions. Heterocycl Chem, 2006, 43(12): 361－363
Zhu P C, Wang D-H. Improved process for the preparation of
4-substituted phthalaldehydes. U.S. Patent 6,891,069, 2005
Zhu P. Non-hazardous oxidative neutralization of aldehydes. U.S.
Patent 6,531,634, 2003
Armstrong A. Synthetic methods Part (ii) Oxidation and reduction
methods. Annu Rep Prog Chem B, 2003, 99: 21－48[DOI]
Gomez S, Peters J A, Maschmeyer T. The reductive amination of aldehydes and ketones and the hydrogenation of nitriles: Mechanistic
aspects and selectivity control. Adv Synth Catal, 2002, 344(10):
1037－1057[DOI]
Murray B A. Reactions of Aldehydes and Ketones and Their Derivatives in Organic Reaction Mechanisms. New Jersey: John Wiley &
Sons Ltd, 2001. 1－35
Zhu P, Roberts C G, Chan-Myers H. Non-hazardous basic neutralization of aldehydes. U.S. Patent Appl Publ, 2003, 065,239, 2003
4 Conclusions
Significant improvement to the hydrolysis of gem-dibromomethylarenes to the corresponding dialdehydes
has been achieved. Our improvements (1) adding solid
NaHCO3 before workup under cooling or (2) minimizing the amount of sulfuric acid in the reaction appear to
be suitable for preparing a variety of substituted OPAs
——an important class of compounds used as synthetic
intermediates, polymer starting compounds and important antimicrobial agents.
12
13
14
15
15H
5
6
7
8
16H
9
16
17
18
19
20
21
17H
10
11
252
Yield (%)
79
86
91
66
88
88
17
88
92
2
28
48
It is important to note that adding excess of base should
be avoided to prevent Cannizaro type reactions, which
will reduce the yield and purity of the product.
14H
4
Equivalents of NaHCO3
0
0
8
0
0
8
0
0
8
0
0
8
22
23
Zhu P C, Roberts C G, Wu J. Chemical detoxifying neutralization of
o-phthalaldehyde: Seeking the “greenest”. In: Gan J, Zhu P C, Aust S
D, Lemley A T eds, Pesticide Decontamination and Detoxification.
ACS Symposium Series 863. Washington DC: American Chemical
Society, 2004. 85－97
Lawrence N J. Aldehydes and ketones. J Chem Soc Perk T 1, 1998,
(10): 1739－1749
Hollingworth G J. Aldehydes: Aryl and heteroaryl aldehydes. In:
Katrizky A R, Meth-Cohn O, Rees C W, eds, Comprehensive Organic
Functional Group Transformations 3. Oxford: Elsevier, 1995.
81－109, 733－856
Roberts S M. Aldehydes and ketones [general and synthetic methods].
Gen Synth Methods, 1978, 1: 76－110
Bill J C, Tarbell D S. o-Phthalaldehyde. Org Synth, 1954, 34: 82－85
Thiele J, Guenther O. Preparation of three phthalaldehydes. Liebigs
Ann Chem, 1906, 347: 106－111
Li M, Fan N. Preparation of aromatic polyaldehydes by hydrolysis of
gem-dibromides. Chem World (in Chinese), 1985, 26(5): 168－70
Liu H, Liu X, Song C. Side-chain chlorination of o-xylene and the
synthesis of phthalaldehyde. J Jiangxi Normal U (Nat Sci Ed) (in
Chinese), 2001, 25(3): 227－230
Hart H, Fish R. Multicharged carbonium ions. III. Long-lived ions
from trichloromethylpolymethylhenzenes. J Am Chem Soc, 1961,
83(21): 4460－4466
Hart H, Fleming J S. Multicharged carbonium ions. IV. Stable crystalline salts. Tetrahedron Lett, 1962, 3(22): 983－986
Freedman H H, Frantz Jr A M. Tetraphenylcyclobutadiene derivatives.
V. The tetraphenylcyclobutenium dication. J Am Chem Soc, 1962,
84(21): 4165－4167
Mark V, Mark C A. Halosulfonyl sulfooxonium compounds, U.S.
Patent 3,869,491, 1975
ZHU Peter C et al. Sci China Ser B-Chem | April 2007 | vol. 50 | no. 2 | 249-252