The present invention relates to a process for the production of 2-nitrobenzaldehyde, a valuable intermediate as for example in the preparation of pharmaceutically active4-(2'-nitrophenyl)-1,4-dihydropyridine derivatives.
If you want to learn more, please visit our website.
2-Nitrobenzaldehyde is a known compound which is difficult to obtain, see e.g., L. F. and M. Fieser, Organische Chemie, Verlag Chemie, Weinhem (), page 1,004. One recommended method of synthesis is the nitration of cinnamic acid or its esters; see e.g., J. Chem. Soc. (London) , 204, separation of the resulting isomer mixture of 4- and 2-nitrocinnamic acids and subsequent oxidation of 2-nitrocinnamic acid with potassium permanganate in accordance with the following equations: ##STR1##
Since, however, at most 40% of 2-nitrocinnamic acid can be isolated in the course of the expensive separation of the isomers, the overall yield of this process, namely approximately 25%, is not satisfactory. Furthermore, in this process the yield of 64% in the oxidation stage can only be achieved when using very dilute solutions; e.g. 5 g/1,000 ml.
The problem of separating the isomers can be circumvented, according to another process, by using 2-nitrophenylpyruvic acid, which is easily accessible by condensation of 2-nitrotoluene and diesters of oxalic acid, see e.g., A Reissert, Ber. dtsch. Chem. Ges. 30, (). According to this method, 2-nitrophenylpyruvic acid when treated with potassium permanganate in dilute solution yields 2-nitrobenzoic acid as the main product, accompanied by a maximum of only 33% of 2-nitrobenzaldehyde: ##STR2## Reissert noted that in no way did it prove possible to obtain the aldehyde as the main product.
The unsubstituted phenylpyruvic acid similarly can only be converted to benzaldehyde in 14% yield; see e.g., Liebigs Ann. Chem. 462, 138, 146.
In accordance with the present invention, a 2-nitrobenzaldehyde of the formula ##STR3## can be obtained in high purity and good yields if an alkali metal salt of 2-nitrophenylypyruvic acid of the formula: ##STR4## is oxidized with potassium permanganate in alkaline aqueous solution at temperatures from about -10° to about +50° C. Following the oxidation, the solution can be acidified with advantageous results, described below.
It is rather surprising that 2-nitrobenzaldehyde is produced in such good yield by this process since from the state of the art, 2-nitrobenzoic acid would be expected to be the main product.
The alkali metal salt of 2-nitrophenylpyruvic acid may be obtained by reacting 2-nitrotoluene of the formula: ##STR5## with an oxalic acid diester of the formula:
(COOR).sub.2 (III)
wherein R is a lower alkyl or aralkyl group. Since the R group does not enter into the reaction and is saponified in the course of this preparation, its nature is not critical. When the 2-nitrophenylpyruvic acid as a salt is so prepared, it is not necessary to isolate it before subjecting it to the oxidation reaction in accordance with the invention, which is also conducted under basic conditions.
The process according to the invention has a number of advantages. Thus, the starting products, 2-nitrotoluene and oxalic acid diesters, are readily available and inexpensive. The requisite starting material, an alkali metal salt of 2-nitrophenylpyruvic acid, can be conveniently synthesized as an intermediate product and then treated without isolation so that the process is easy to carry out industrially. Acidification of the resulting reaction mixture after the last oxidation stage (IV&#; I) gives oxalic acid, which reduces the voluminous manganese-(IV) oxide, which has precipitated, to give soluble manganese-(II) salts and is itself oxidized to gaseous carbon dioxide. This avoids the filtration and adsorption problems usually caused by manganese dioxide. Moreover, the potassium permanganate can be introduced in solid form so that the volume yield is improved decisely compared to prior art methods.
If you are looking for more details, kindly visit Lianhe Aigen.
If 2-nitrotoluene, oxalic acid dimethyl ester and potassium methylate are used as starting materials, the course of the reaction can be represented by the following equations: ##STR6##
The oxidation with potassium permanganate (component IV &#; I) can be carried out in aqueous solution and the resulting 2-nitrobenzaldehyde can be isolated by extraction. However, preferably an additional water-immiscible solvent (forming a two-phase system) is present from the start.
The term alkali metal preferably denotes sodium or potassium. In the formula III, (COOR)2, R preferably represents alkyl with 1 to 6 carbon atoms, especially methyl, ethyl, propyl, isopropyl, n-butyl, tert.-butyl, pentyl and hexyl, or represents benzyl.
Preferably, the reaction solution is acidified with sulphuric acid. Other acids such as hydrochloric acid are entirely operable but may undergo undesirable chemical reactions with manganese-(IV) oxide such as the formation of toxic chlorine gas.
The reaction Iv&#; I is carried out at temperatures between -10° and +50° C, preferably between -2° and +30° C.
2-Nitrobenzaldehyde is used, inter alia, as an intermediate for the preparation of coronary-dilating pharmaceuticals, especially 1,4-dihydropyridines; see, e.g., German Offenlegungsschrift 1,670,827.
The following examples will serve to further typify the nature of the invention without being a limitation on the scope thereof.
EXAMPLE 1383 g (7.1 mols) of sodium methylate are dissolved in ethanol and 985 g (6.75 mols) of oxalic acid diethyl ester and 925 g (6.75 mols) of 2-nitrotoluene are poured in. The mixture is heated under reflux for 30 minutes and is allowed to cool, 300 ml of ice water are next added cautiously and after the exothermic reaction has subsided 1,600 ml of water are added. After boiling additionally for 90 minutes under reflux, the mixture is steam-distilled until two phases no longer pass over. The organic phase is separated from the distillate and 310 g of 2-nitrotoluene are recovered from it. The residual aqueous phase of the distillate is filtered, 600 g of (anhydrous) sodium carbonate and 2,000 ml of toluene are added and the mixture is cooled to +3° C. 650 g of solid potassium permanganate are added over the course of 70 minutes and the reaction temperature is kept at between +2° and +6° C. The mixture is stirred for a further 45 minutes at +5° C and then warmed to 40° C, and 50% strength sulphuric acid is then added dropwise (gas being evolved). The exothermic reaction is kept at 35°- 40° C by cooling. Insoluble material is then filtered off and the toluene phase is separated from the filtrate. The filter residue is washed with hot toluene and the combined toluene phases are extracted by shaking with 15% strength sodium carbonate solution and with water and are then dried with the sodium sulphate. On concentrating the toluene phase in vacuo, 2-nitrobenzaldehyde is obtained as a viscous oil which crystallizes immediately on cooling. Melting point 40°- 41° C.
Yield 272 g (40.3% of theory, based on 2-nitrotoluene converted).
EXAMPLE 250 g (0.24 mol) of 2-nitrophenylpyruvic acid of melting point 115° C are introduced into 500 ml of aqueous sodium carbonate solution until a clear solution is obtained. After addition of 350 ml of toluene, the mixture is cooled to 0° C and 40 g of solid potassium permanganate are then added in portions at 0°- 3° C. After one hour at 0°- 3° C, 95 ml of 50% strength sulphuric acid are added dropwise and the temperature is not allowed to rise above 30° C. The reaction mixture is filtered and the toluene phase is separated from the filtrate. The filter residue is washed with toluene and the combined toluene phases are extracted with 15% strength sodium carbonate solution and with water. The toluene phase is then dried with sodium sulphate and concentrated in vacuo. The residue which remains consists of 19.7 g (54.7% of theory) of 2-nitrobenzaldehyde, which crystallizes on cooling. Melting point 41° C.
I am a high school student who is interested in organic chemistry.I was searching for syntheses of indigo when I came across two interesting papers on ortho-nitration of benzaldehyde.This is the first one:Synthesis of 2-nitrobenzaldehydeConcentrated HNO3 (5 mL) was cautiously added to the benzaldehyde at 0 degrees Celsius. Then the mixture was stirred for 40 min at 15 degrees Celsius. On pouring the reaction mixture into ice water, insoluble material precipitated. The precipitate was filtered out to afford the crude product.Yield: 90%; yellow colour compound; mp: 42 degrees Ceisius; IR (KBr, cm1): CHO (), C&#;N (), C&#;H aromatic (), C=C aromatic (), NO2 ( symmetric), NO2 ( asymmetric).Now when I saw this for the first time, I was rather skeptical because they did not provide the amount of benzaldehyde or the NMR spectra values. Also, the reaction looked unlikely since sulfuric acid was not added.That was until I managed to search up another paper they mentioned in the references section:5-(Benzyloxy)-4-methoxy-2-nitrobenzaldehyde (3a)3-(Benzyloxy)-4-methoxybenzaldehyde (10 g, 41 mmol) was added cautiously to 40 mL of concentrated nitric acid at 0 ºC. The mixture was then stirred at 15 °C for 40 min. On pouring the reaction mixture into ice water, the precipitate was filtrated to afford 5-(benzyloxy)-4-methoxy-2-nitrobenzaldehyde (10.4 g, 93%) as a yellow solid. Mp 131 ºC (lit[28], mp 133 ºC). 1H NMR (CDCl3): δ 10.4 (s, 1H, CHO), 7.6 (s, 1H, Ph-H), 7.3&#;7.5 (m, 5H, Ph-H),7.20 (s, 1H, Ph-H), 5.25 (s, 2H, PhCH2O), 4.0 (s, 3H, CH3O).4-(Benzyloxy)-5-methoxy-2-nitrobenzaldehyde (3b) The compound was prepared in 91% yield according to the procedure for 3a using 4-(benzyloxy)-3-methoxybenzaldehyde. Mp 131 ºC (lit[28], mp 133 ºC). 1H NMR (CDCl3): δ 10.4 (s, 1H, CHO), 7.60 (s, 1H, Ph-H), 7.3&#;7.5 (m, 5H, Ph-H), 7.2 (s, 1H, Ph-H), 5.25 (s, 2H, PhCH2O), 4.0 (s, 3H, CH3O).Now when I saw this paper I was like "what..?"I knew that benzaldehyde is a meta-directing deactivator, so I was quite surprised that the ortho-nitration was possible in such high yields. (I don't think the the benzyloxy or methoxy groups gave much effect in regio-determination since the 3a and 3b compounds both reacted well, at least seemingly.) I looked it up on the Internet and found a few more papers on this phenomenon. It was interesting enough that I decided to try out the reaction in the school lab.I did a dropwise addition of 7.5mL of 60% nitric acid to 2mL of benzaldehyde while stirring vigorously. The whole addition step took about 30~40 minutes, and I then left it stir for 40 minutes, making sure that the temperature stayed around 14~16 degrees Celsius. The reaction mixture when I stopped stirring it had two layers: the top one was yellow and relatively clear, but the bottom one was whitish and opaque. Then I poured the reaction mixture into ice water as they said, only to find out that there were only a few pink oily drops resting at the bottom and a big drop of transparent oil floating on the top. No precipitate resulted.I think the transparent oil floating on the top was the benzaldehyde that did not react for some reason, but I can't seem to get a clue of what the others are and why the reaction did not take place.At first I thought the product did not separate because it somehow was produced in an oily state. However, coming across another paper which reacted conc. nitric acid and benzaldehyde in dichloromethane, I tried that method too only to fail again. (It said the benzaldehyde and only the HNO3 molecules react in the dichloromethane layer, so this brings an increase in the nitric acid concentration in the dichloromethane layer...)My school isn't really into chemistry, so there are no IR or NMR equipment. We ran out of TLC plates recently, and it will take a while for them to arrive. So I'm just left with my head to assume what might have happened....Can anybody guess or explain or at least hint about what might have happened during the experiment? I believe that my starting materials are in a fairly pure state because I just opened the benzaldehyde container lid yesterday (though it probably sat around for two years or more, of course in a dark room) and the nitric acid container lid was very tightly shut.I didn't think that it would be such a fail since those papers "had been published," but....P.S. It would be great if we had 2-nitrobenzaldehyde in the first place, but we don't, and the purchase would take at least a few weeks...Thanks in advance!
Want more information on 4 methoxy 2 nitrobenzaldehyde? Feel free to contact us.