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Bromination of dimethyl maleate using bromoform as catalyst under different energy sources: a case study for its role in biotransformations.


Maleic acid (cis-2-butene-l, 4-dioic acid, Lide, 2004) and its corresponding methyl ester, dimethyl maleate (DMME) in which the alkene double bond is in conjugation with a carboxyl group, undergo isomerization on treatment with catalytic amounts of aqueous bromine or [[Br.sub.2]/[CCl.sub.4]] under UV light to form the thermodynamically more stable trans isomer. There are limited reports on the possible formation of any addition products, product selectivity or stereochemistry as affected by the light or heat source. In order to optimize the conditions for a more selective, stereospecific addition or isomerization, and to better understand the similar processes in biological systems, reactions were performed treating dimethyl maleate (DMME) with bromine using different energy sources such as heat, sunlight, and a UV lamp (wavelength, 365 nm) with varied solvent concentration. On treatment with slight excess of bromine (1:1.1 equivalent), the reaction gave the addition product selectively when heated to reflux in [CCl.sub.4] (bp 77[degrees]C). Whereas reaction with a catalytic amount of bromine or bromoform in [CCl.sub.4], isomerization occurred. Treatment of DMME with excess bromoform under UV irradiation for 4-5 days gave selectively the isomerized product in 95 % yield via bromine released as an intermediate. The reaction mechanism, product selectivity, stereochemistry, and the role of such processes in the biological systems are discussed.


While maleic acid, the cis isomer, is a synthetic organic compound, its trans isomer, fumaric acid, is an organic acid widely found in nature (Felthhouse et al., 2001). It is found in plants (Fumaria Officinalis), in humans and in other mammals. It is a key intermediate in the citric acid cycle. Both isomers are useful as building blocks for the synthesis of many organic chiral and achiral compounds (Bradshaw et al., 1969). Maleic acid is highly useful as an intermediate in the industrial preparations of polyester resins, plasticizers, copolymers, and agricultural chemicals (Culbertson, 1987). Fumaric acid is used by cells to produce energy from food. Human skin naturally produces fumaric acid when exposed to sunlight. It is used as a food acidulant and also as an intermediate in the synthesis of certain polyester resins, quick-setting inks, furniture lacquers, paper sizing chemicals and aspartic acid. Recent studies reveal that dimethyl fumarate (DMFE) can be used to treat psoriasis (Schmidta et al., 2007), but there are risk factors involved upon ingestion of this compound. Reactivity of dimethyl fumarate towards glutathione in the preparation of S-substituted thiosuccinic acid esters and its presystemic metabolism has been reported (Langguth et al, 2003).

Bromoform is produced naturally in small amounts by oceanic plants and then readily evaporates into the air due to its high volatility (Goodwin et al., 1997). Most of the bromoform that enters the environment is formed as byproduct when chlorine is added to water to kill bacteria (Richardson et al, 2003). Halogenated compounds are also released into the air from the use of commercial products (Bao et al., 1998) or the use of haloforms as solvents and reagents in research laboratories and industries. The toxicity of these compounds is associated with their biotransformation (Anders and Jacobson, 1985). Glutathione-dependent biotransformation of vicinal-dihaloalkanes to alkenes and its stereochemistry have been reported earlier (Livesey et al., 1982 and Bao et al., 1998). Organic reactions and mechanistic studies form the basis for the understanding of such biotransformations. This bioactivation can be due to the formation of stable, toxic metabolites or the reactive electrophylic or radical intermediates. Our studies on the reactions of alkene derivatives with bromine and bromoform could form the basis for studies of similar processes in biological systems.

Maleic acid and fumaric acid can not normally be interconverted because rotation around the carbon-carbon double bond is restricted. In the laboratory, the conversion of cis isomer into trans isomer (Pasto et al, 1992) is performed by treating maleic acid with aqueous bromine under uv light, and in industry it is produced by catalytic isomerization with mineral acids (Vogel, 1980). Alkenes in general are also known to undergo addition reactions at lower temperatures. Addition of bromine to simple alkenes (Kuwayama et al., 2002) in [CCl.sub.4] solvent forms the corresponding dibromoalkane derivatives at room temperature without any added catalyst. Since this reaction introduces two chiral carbons into the product, the cis alkenes are known to form a racemic mixture, and the trans isomer forms a stereospecific meso diastereomer. According to the literature (Mathai et al., 1956), addition of bromine to maleic acid in chloroform solvent occurs in the dark at room temperature but takes several days. There are limited reports (Kajigaeshi et al., 1988) on the effect of any catalysts or other factors such as reaction temperature, solvent or concentration.

In an attempt to achieve the product selectivity between addition and isomerization, and to better understand the reaction mechanism and stereochemistry, and its role in understanding similar processes in the environment and biological systems, a systematic study on the bromination of DMME using halogenated solvent and reagent was undertaken. Our attempts gave interesting and promising results that are discussed herein.

Materials and Methods

Reactions were performed under different conditions by varying the energy sources, temperature, molar concentration, and reagents/catalysts, and were monitored by color change and TLC. For TLC, Merck KGaA flexible plates of 200 micron thickness coated with silica gel, 60[Angstrom], [F.sub.254] were used. Products were analyzed and identified by melting point determination and spectroscopic methods. Observed melting points were compared with reported values (Lide, 2004) for all known compounds. IR spectra were recorded on Thermo Scientific, Nicolet 6700 FTIR instrument. NMR spectral analysis was performed on Bruker 300 MHz Instrument. Mass spectrum was recorded on MALDI-TOF mass spectrometer. All spectral data were compared with literature data (Erickson, 1965: Velichko, 1980). The following chemicals and materials were used: DMME (Aldrich reagent + grade, 96 %; 4 % fumarate), [CHBr.sub.3] (Aldrich, 99+ %), [CCl.sub.4] (Fischer, ACS, 99.996 %), [Br.sub.2] (Aldrich, reagent + grade), UV lamp (wavelength, 365 nm). UV Reactions (Table 1):
Table 1. Reactions under UV (100 watt, 365 nm wavelength) and results

Substrate        Reagent/Catalyst         Solvent Amount  Molar concn

(a) DMME  --                             [CC1.sub.4] 20     .05 M

(a) DMME   [Br.sub.2] (cat; ~0.1 eq)      [CCl.sub.4]       .05 M
                                          20 mL

(a) DMME   [Br.sub.2] (1 eq)/             [CCl.sub.4]       .5M
           [CHBr.sub.3](cat; ~0.1 eq)     2 mL

(a) DMME   [Br.sub.2] (1 eq)              [CCl.sub.4]       .5 M
           No [CHBr.sub.3]                2 mL

(a) DMME   [Br.sub.2](1 eq)/[CHBr.sub.3]  [CCl.sub.4]       .05 M
           (cat; ~0.1 eq)                 20 mL

(a) DMME   [Br.sub.2](1 eq)               [CCl.sub.4]       .05 M
           No [CHBr.sub.3]                20 mL

(a) DMME   1 eq [CHBr.sub.3]              [CCl.sub.4]       .05 M
           No [Br.sub.2]                  20 mL

(a) DMME   3 eq [CHBr.sub.3]              [CCl.sub.4]       .05 M
           No [Br.sub.2]                  20 mL

                                            % yield

Substrate  (b) Reaction Time  Isomerized Product  Addition Product

(a) DMME          1-48 hr           trace                 -

(a) DMME          0.5 hr            28%                   -

(a) DMME          1 hr              --                  13%

(a) DMME          1 hr              --                  26%

(a) DMME          1 hr              --                  43%

(a) DMME          1 hr              --                  76%

(a) DMME        24 hrs              11.2%                 -

(a) DMME        24-48hrs            33.7%                 -
                72-96hrs            95%                   -

(a) Dimethyl Maleate; (b) Reaction time was determined based on color
change from dark scarlet red to light orange or yellow.

These reactions were conducted in 50 mL conical flasks. The solutions were prepared by taking 20 or 2 mL [CCl.sub.4] then adding 0.13 mL of DMME followed by 0.1 mL of [CHBr.sub.3] The reaction flasks were placed on a magnetic stirrer and under a UV lamp as an energy source. Then, stirring was started. While stirring, 0.1 mL of [Br.sub.2] was added drop wise which gave the solution a scarlet red color. The flasks were left under the UV lamp until the color of the solutions changed from dark red to light orange or yellow (approximately l hr). After

45 min to 1 hr, the solutions were removed from under the UV lamp, and stirring was stopped. The color change of the reaction mixture from deep red to colorless represented the end point of reaction which was confirmed by TLC analysis. When the reaction was over, and the solution had cooled, white crystals formed. The crystals were vacuum filtered, dried, and checked for melting point and percent yield. The product was further characterized by IR and NMR spectral analysis. Reactions with bromoform in the absence of bromine gave different results, as shown in Table 1.

Sunlight Reactions (Table 2): These reactions were done exactly as the UV reactions except that sunlight was substituted for the UV lamp. The solutions were prepared as described under UV reactions. After adding bromine, the reaction flasks were kept under direct sunlight until the deep red bromine color disappeared. The reaction time and results are given in Table 2.
Table 2. Reactions under sunlight and results

Substrate        Reagent/Catalyst            Solvent Amount    Rxn

(a) DMME   [Br.sub.2] (cat; ~ 0.1 eq)       [CCl.sub.4]20 mL  .05 M

(a) DMME   [Br.sub.2] (leq)/[CHBr.sub.3]    [CC1.sub.4]2 mL   .5 M
           (cat; ~0.1 eq)

(a) DMME   [Br.sub.2](leq)/No [CHBr.sub.3]  [CC1.sub.4]2 mL   .5M

(a) DMME   [Br.sub.2](leq)/[CHBr.sub.3]     [CC1.sub.4]20 mL  .05 M
           (cat; ~ 0.1 eq)

(a) DMME   [Br.sub.2](leq)/No [CHBr.sub.3]  [CCl.sub.4]20 mL  .05 M

                                            % yield

Substrate  (b) Reaction Time  Isomerized Product  Addition Product

(a) DMME         05 hr              45%                   -

(a) DMME          1 hr              --                   8%

(a) DMME          1 hr              --                  34%

(a) DMME          1 hr              --                  35%

(a) DMME          1 hr              --                  66%

(a) Dimethyl Maleate; (b) Reaction time was determined based on color
change from dark scarlet red to light orange or yellow.

reactions, except the solutions were heated to reflux at the boiling point of the solvent used, using a heating mantle as a heat source. Solutions were prepared by taking 20 mL of CC14 and then adding 0.13 of DMME. Then Br2 was added to one of the solutions (in this solution CHBr3 was not added), and in the other solution CHBr3 was added without adding the Br2. The reason for this was to see if the Br that is being added is coming from the Br2 or the CHBr3, and also to see if CHBr3 is a better catalyst either for addition or for isomerization to take place. The reactions were continued under reflux conditions for an hour or so, and then they were removed from the heat and left overnight under the hood to cool for the crystals to form. The product crystals were vacuum filtered and left to dry under the hood for another 24 hours. Afterwards, the melting point and the mass of the crystals were measured. The results and data are given in Tables 1, 2 and 3.
Table 3. Reactions under Thermal Heat source (reflux at the BP of
solvent) and results

Subtrate          Reagent/Catalyst       Solvent Amount    Rxn Concen.

(a) DMME Rxn 1  [Br.sub.2] (cat; ~ 0.1  [CCl.sub.4] 20 mL    05 M

(a) DMME Rxn2   [Br.sub.2] (1 eq)/      [CCl.sub.4] 2 mL     0.5 M
                [CHBr.sub.3] (cat; ~
                0.1 eq)

(a) DMME Rxn3   [Br.sub.2](l eq)/       [CCl.sub.4] 20 mL    0.05 M
                [CHBr.sub.3] ((cat: ~
                0.1 eq)

(a) DMME Rxn4   [Br.sub.2] (1 eq) No    [CCl.sub.4] 20 mL    0.05 M

(a) DMME Rxn5   [CHBr.sub.3] (cat; ~    [CCl.sub.4] 20 mL    0.05 M
                0.1 eq) No [Br.sub.2]

(a) DMME Rxn6   [CHBr.sub.3] (l eq) No  [CCl.sub.4] 20 mL    0.05 M

     Subtrate   (b) Rxn Time                % yield

                              Isomerised product  Addition product

(a) DMME Rxn1        4               58 %                -

(a) DMME Rxn2        3               --                48%

(a) DMME Rxn3        6               --                95%

(a) DMME Rxn4        3-4             --                98%

(a) DMME Rxn5        3-4             --             No Reaction-

(a) DMME Rxn6       24            No reaction            -

(a) Dimethyl Maleate: (b) Reaction time was determined based on color
change from dark scarlet red to light orange or yellow.


Addition of Bromine to DMME in 1:1 ratio using CC14 as solvent with 0.05 M concentration under reflux conditions gave the addition product in ~95 % yield with maximum purity (Table 3). Although the yield was lower under sunlight (66 %, Table 2) and UV (76 %, Table 1), the reaction process seemed to be faster than under thermal heat source. The addition product was isolated as pure white, needle-like crystals by simply evaporating the solvent at room temperature. The observed mp range for the pure crystals matched the literature value of 57-580C (Lide, 2004) for the addition product. The IR spectrum showed characteristic saturated ester carbonyl absorption at 1755 cm-1. The product structure was further confirmed by lH NMR (Fig 1).A I3C-NMR. (Fig 2) of the product was also performed and confirmed it to be (d, 1)-2,3-dibromosuccinate. All other reactions gave the addition product but in low yield (20-40 %) along with trace amounts of the isomerized trans-product. We were unsuccessful in isolating the isomerized product in this set of reactions. The reactions performed are shown in Scheme 1 as a general reaction scheme with the reactants and products.



When the reaction was performed using higher concentration solution (0.5 M) for the reaction mixture, only the isomerized trans product was formed in trace amounts with no addition reaction taking place in all three methods. With lower concentration (0.05 M) solution, addition or isomerized product formed in moderate amounts. This is probably because at lower concentration, molecules move around more freely, leading to a greater number of collisions between the substrate and the catalyst or reagent.

When the reaction was performed using [Br.sub.2] as a catalyst without adding any bromoform, only isomerized product was formed with no addition reaction taking place in all three methods. When bromoform was added as a catalyst in the absence of bromine, no reaction occurred even after 4 hrs. This suggests that bromoform has no effect as a catalyst upon treatment with maleic acid ester under the specified conditions. Hence, it should not have much effect on similar processes in the biological system if it is released into the environment in small amounts.

All reactions conducted under sunlight occurred at a faster rate, reaching equilibrium within one hour as observed from the color change and gave poorer yields compared to the other two methods. This is probably because the amount of heat transferred from sunlight to the reaction mixture in a given amount of time will be different and possibly less than from UV light.

Reactions were repeated for longer time period (24 hrs) under UV and reflux conditions to investigate the effect upon prolonged reaction times and also with larger amounts of bromoform with or without bromine. Once again interesting results were observed. When bromine was used as a reagent without any bromoform, only the anticipated addition product was obtained in maximum yield under both UV and reflux conditions. When only bromoform was used in equivalent amount as reagent without bromine, in [CCl.sub.4] solvent, after irradiation under UV for 24 hrs, white cubic crystals of the isomerized product (observed mp 95-99[degrees]C; lit. 102[degrees]C) were isolated in 11.2 % yield ([.sup.1]H NMR, Fig 3) and no addition product formed.


The low yield indicated a slow reaction rate as anticipated. Prolonged reaction time did not improve the yield. The same reaction under reflux conditions resulted in no reaction. However, when the reaction was performed using DMME and bromoform in 1:3 ratio in [CCl.sub.4] solvent, without any added bromine, to our surprise, after 48 hrs of irradiation under UV, the reaction mixture changed from colorless to scarlet red indicating the possible release of bromine from bromoform via radical decomposition. Upon cooling, white crystals (mp 92-94[degrees]C) formed which was filtered and dried and characterized to be the trans-isomer, fumarate, from IR (a broad ester carbonyl band at 1700-1667 [cm.sup.-1]) and NMR with only 85 % purity. The relatively low melting range compared to the reported value (lit. mp. 102[degrees]C), indicated the presence of other compounds as impurities. Further cooling of the mother liquor from the above filtration gave pale yellow crystals (mp 78-80[degrees]C) as second fraction in trace amounts. Both IR (C-H stretch at ~3000 [cm.sup.-1], broad ester carbonyl at ~ 1750 [cm.sup.-1], C-Br at ~ 522 [cm.sup.-1]) and [.sup.1]H NMR ([??] ppm: 3.75, m; 3.9, s; 6.7 s) spectral analyses indicate the possibility of the formation of compound A (Scheme 1) along with tetrabromoethane and other impurities as side products. Light-induced molecular rearrangement of bromoform to tetrabromoethane, bromine and other photochemical products and its role in ozone depletion has been reported earlier (Grecea et al, 2006). Photochemical conversion of halohydrins to ketones via oxidative decomposition and rearrangement has also been reported earlier (Piva, 1992). A mass spectrum of the crude product A (Fig 4a, 4b) showing the base peak at 44 m/e due to [CO.sub.2] fragmentation from the molecule and a peak at 371.92 m/e along with the M+2 (373.8), M+4 (375.9), M+6 (377.9) and M+8 (379.9) isotopic peaks corresponding to fragment B (Scheme 3) supports our proposed structure for A. Attempted recrystallization methods to isolate compound A in purer form were unsuccessful, and further characterization became impossible. However, when the reaction was repeated and continued for longer time (72-96 hrs), once again bromine release was observed after 48 hrs as light brown color, but the color disappeared upon continued irradiation. The solution color kept changing thereafter but with decreased intensity as the reaction continued. After 96 hrs of irradiation under UV, the reaction was stopped and excess solvent was evaporated under vacuum. Upon cooling, white crystals of the isomerized product, dimethyl fumarate, were obtained in better yield and purity. The product identity and purity were determined by melting point (102-3[degrees]C) and IR spectroscopy (Fig. 4a and 4b) using the commercial sample as control. The improved yield of the isomerized product could be due to the bromine released from bromoform, acting as a catalyst for further isomerization of the unreacted DMME and also from possible decomposition of compound A (Scheme 2). A mechanism for the formation of bromine and compound A and further isomerization is proposed and given in Scheme 2.








We successfully optimized the conditions for the synthesis of dimethyl 2,3-dibromosuccinate, the addition product, which was obtained selectively in 95 % yield and high purity by treating DMME with equivalent amount of bromine under reflux conditions. The formation of isomeric product also in high yield (95 %) but under prolonged UV irradiation in presence of excess bromoform infers that by optimizing the conditions, the selective synthesis of the meso-dibromo adduct can be achieved, which will be one of our future goals. Prolonged reaction time led to the formation of several intermediates including compound A, and a reaction mechanism has been proposed based on the data obtained. From these studies, we also conclude that trace amounts of bromoform released in the air from its commercial use and in research laboratories and industries should have minimal adverse effects on similar processes in biological systems. But, the release of large amounts may result in the isomerization process and release of bromine and other unwanted side products, which could have some adverse effects. The proposed mechanism (Scheme 2) for the formation of product A involving radical intermediates could also explain biotransformation of ingested halogenated compounds in organisms. Further exploration of addition versus isomerization reactions of DMME and DMFE under sunlight and UV light using other inorganic catalysts and enzyme catalysts on these reactions will be studied as part of our future research.


The authors would like to thank the Department of Physical and Earth Sciences, The College of Arts and Sciences and the Office of the Vice-President for Academic and Student Affairs, Jacksonville State University, Jacksonville, Alabama for funding. The authors would also like to thank the Department of Chemistry, University of Alabama at Birmingham, for providing the NMR and mass spectral data and Thermoscientific for providing the IR data.


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Nagarajan Vasumathi, Meriem Zettili and Kristin Shirey

Department of Physical and Earth Sciences, Jacksonville State University, 700 Pelham Road, Jacksonville, Al 36265

Correspondence: Nagarajan Vasumathi (
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Date:Jul 1, 2009
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