Aldoxime Synthesis Essay

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An oxime is a chemical compound belonging to the imines, with the general formula R1R2C=NOH, where R1 is an organicside-chain and R2 may be hydrogen, forming an aldoxime, or another organic group, forming a ketoxime. O-substituted oximes form a closely related family of compounds. Amidoximes are oximes of amides with general structure RC(=NOH)(NRR').

Oximes are usually generated by the reaction of hydroxylamine and aldehydes or ketones. The term oxime dates back to the 19th century, a combination of the words oxygen and imine.[1]

Structure and properties[edit]

If the two side-chains on the central carbon are different from each other, the oxime can have two geometric stereoisomeric form: a syn isomer and an anti isomer, depending on which of the two side-chains is closer to the hydroxyl. Both forms are often stable enough to be separated from each other by standard techniques.

Oximes have three characteristic bands in the infrared spectrum, at wavenumbers 3600 cm−1 (O−H), 1665 cm−1 (C=N) and 945 cm−1 (N−O).[2]

In aqueous solution, aliphatic oximes are 102- to 103-fold more resistant to hydrolysis than analogous hydrazones.[3]

Preparation[edit]

Oximes can be synthesized by condensation of an aldehyde or a ketone with hydroxylamine. The condensation of aldehydes with hydroxylamine gives aldoxime, and ketoxime is produced from ketones and hydroxylamine. In general, oximes exist as colorless crystals and are poorly soluble in water. Therefore, oximes can be used for the identification of ketone or aldehyde.

Oximes can also be obtained from reaction of nitrites such as isoamyl nitrite with compounds containing an acidic hydrogen atom. Examples are the reaction of ethyl acetoacetate and sodium nitrite in acetic acid,[4][5] the reaction of methyl ethyl ketone with ethyl nitrite in hydrochloric acid.[6] and a similar reaction with propiophenone,[7] the reaction of phenacyl chloride,[8] the reaction of malononitrile with sodium nitrite in acetic acid[9]

A conceptually related reaction is the Japp–Klingemann reaction.

Reactions[edit]

The hydrolysis of oximes proceeds easily by heating in the presence of various inorganic acids, and the oximes decompose into the corresponding ketones or aldehydes, and hydroxylamines. The reduction of oximes by sodium metal,[10]sodium amalgam, hydrogenation, or reaction with hydride reagents produces amines.[11] Typically the reduction of aldoximes gives both primary amines and secondary amines; however, reaction conditions can be altered (such as the addition of potassium hydroxide in a 1/30 molar ratio) to yield solely primary amines.[12]

In general, oximes can be changed to the corresponding amide derivatives by treatment with various acids. This reaction is called Beckmann rearrangement. In this reaction, a hydroxyl group is exchanged with the group that is in the anti position of the hydroxyl group. The amide derivatives that are obtained by Beckmann rearrangement can be transformed into a carboxylic acid by means of hydrolysis (base or acid catalyzed). And an amine by hoffman degradation of the amide in the presence of alkali hypoclorites at 80 degrees Celsius, the degradation is itself prone to side reactions, namely the formation of biurets or cyanate polymers., To avoid this side-reaction, strict temperature control is necessary; the reaction must be conducted at sufficient temperature to isomerise the cyanate to the isocyante. Also, good solvation is also crucial to be successful. Beckmann rearrangement is used for the industrial synthesis of caprolactam (see applications below).

The Ponzio reaction (1906)[13] concerning the conversion of m-nitrobenzaldoxime to m-nitrophenyldinitromethane with dinitrogen tetroxide was the result of research into TNT-like high explosives:[14]

In the Neber rearrangement certain oximes are converted to the corresponding alpha-amino ketones.

Oximes can be dehydrated using acid anhydrides to yield corresponding nitriles.

Certain amidoximes react with benzenesulfonyl chloride to substituted ureas in the Tiemann rearrangement:[15][16]

Uses[edit]

In their largest application, an oxime is an intermediate in the industrial production of caprolactam, a precursor to Nylon 6. About half of the world's supply of cyclohexanone, more than a billion kilograms annually, is converted to the oxime. In the presence of sulfuric acidcatalyst, the oxime undergoes the Beckmann rearrangement to give the cyclic amide caprolactam:[17]

[edit]

Oximes are commonly used as ligands and sequestering agents for metal ions. Dimethylglyoxime (dmgH2) is a reagent for the analysis of nickel and a popular ligand in its own right. In the typical reaction, a metal reacts with two equivalents of dmgH2 concomitant with ionization of one proton. Salicylaldoxime is a chelator and an extractant in hydrometallurgy.[18]

Amidoximes such as polyacrylamidoxime can be used to capture trace amounts of uranium from sea water.[19][20] In 2017 researchers announced a configuration that absorbed up to nine times as much uranyl as previous fibers without saturating.[21]

Other applications[edit]

  • Oxime compounds are used as antidotes for nerve agents. A nerve agent inactivates acetylcholinesterase by phosphorylation. Oxime compounds can reactivate acetylcholinesterase by attaching to phosphorus, forming an oxime-phosphonate, which then splits away from the acetylcholinesterase molecule. Oxime nerve-agent antidotes are pralidoxime (also known as 2-PAM), obidoxime, methoxime, HI-6, Hlo-7, and TMB-4.[22] The effectiveness of the oxime treatment depends on the particular nerve agent used.[23]
  • Perillartine, the oxime of perillaldehyde, is used as an artificial sweetener in Japan. It is 2000 times sweeter than sucrose.
  • Diaminoglyoxime is a key precursor to various compounds, containing the highly reactive furazan ring.
  • Methyl ethyl ketoxime is a skin-preventing additive in many oil-based paints.
  • Buccoxime and 5-methyl-3-heptanone oxime ("Stemone") are commercial fragrances.[24]

See also[edit]

References[edit]

  1. ^The name "oxime" is derived from "oximide" (i.e., oxy- + amide). According to the German organic chemist Victor Meyer (1848–1897) – who, with Alois Janny, synthesized the first oximes – an "oximide" was an organic compound containing the group (=N−OH) attached to a carbon atom. The existence of oximides was questioned at the time (ca. 1882). (See page 1164 of: Victor Meyer und Alois Janny (1882a) "Ueber stickstoffhaltige Acetonderivate" (On nitrogenous derivatives of acetone), Berichte der Deutschen chemischen Gesellschaft, 15: 1164–1167.) However, in 1882, Meyer and Janny succeeded in synthesizing methylglyoxime (CH3C(=NOH)CH(=NOH)), which they named "Acetoximsäure" (acetoximic acid) (Meyer & Janny, 1882a, p. 1166). Subsequently, they synthesized 2-propanone, oxime ((CH3)2C=NOH), which they named "Acetoxim" (acetoxime), in analogy with Acetoximsäure. From Victor Meyer and Alois Janny (1882b) "Ueber die Einwirkung von Hydroxylamin auf Aceton" (On the effect of hydroxylamine on acetone), Berichte der Deutschen chemischen Gesellschaft, 15: 1324–1326, page 1324: "Die Substanz, welche wir, wegen ihrer nahen Beziehungen zur Acetoximsäure, und da sie keine sauren Eigenschaften besitzt, vorläufig Acetoxim nennen wollen, …" (The substance, which we – on account of its close relations to acetoximic acid, and since it possesses no acid properties – will, for the present, name "acetoxime," … )
  2. ^Reusch, W. "Infrared Spectroscopy". Virtual Textbook of Organic Chemistry. Michigan State University. 
  3. ^Kalia, J.; Raines, R. T. (2008). "Hydrolytic stability of hydrazones and oximes". Angew. Chem. Int. Ed. 47 (39): 7523–7526. doi:10.1002/anie.200802651. PMC 2743602. PMID 18712739. 
  4. ^Fischer, Hans (1943). "2,4-Dimethyl-3,5-dicarbethoxypyrrole". Organic Syntheses. ; Collective Volume, 2, p. 202 
  5. ^Fischer, Hans (1955). "Kryptopyrrole". Organic Syntheses. ; Collective Volume, 3, p. 513 
  6. ^Semon, W. L. and Damerell, V. R. (1943). "Dimethoxyglyoxime". Organic Syntheses.  ; Collective Volume, 2, p. 204 
  7. ^Hartung, Walter H. and Crossley, Frank (1943). "Isonitrosopropiophenone". Organic Syntheses.  ; Collective Volume, 2, p. 363 
  8. ^Levin, Nathan and Hartung, Walter H. (1955). "ω-chloroisonitrosoacetophenone". Organic Syntheses.  ; Collective Volume, 3, p. 191 
  9. ^Ferris, J. P.; Sanchez, R. A. and Mancuso, R. W. (1973). "p-toluenesulfonate". Organic Syntheses.  ; Collective Volume, 5, p. 32 
  10. ^Suter, C. M.; Moffett, Eugene W. (1934). "The Reduction of Aliphatic Cyanides and Oximes with Sodium and n-Butyl Alcohol". Journal of the American Chemical Society. 56 (2): 487–487. doi:10.1021/ja01317a502. 
  11. ^George, Frederick; Saunders, Bernard (1960). Practical Organic Chemistry, 4th Ed. London: Longman. p. 93 & 226. ISBN 9780582444072. 
  12. ^Hata, Kazuo (1972). New Hydrogenating Catalysts. New York: John Wiley & Sons Inc. p. 193. ISBN 9780470358900. 
  13. ^Ponzio, Giacomo (1906). "Einwirkung von Stickstofftetroxyd auf Benzaldoxim". J. Prakt. Chem.73: 494. doi:10.1002/prac.19060730133. 
  14. ^Fieser, Louis F. and Doering, William von E. (1946). "Aromatic-Aliphatic Nitro Compounds. III. The Ponzio Reaction; 2,4,6-Trinitrobenzyl Nitrate". J. Am. Chem. Soc.68 (11): 2252. doi:10.1021/ja01215a040. 
  15. ^Tiemann, Ferdinand (1891). "Ueber die Einwirkung von Benzolsulfonsäurechlorid auf Amidoxime". Chemische Berichte. 24 (2): 4162–4167. doi:10.1002/cber.189102402316. 
  16. ^Plapinger, Robert; Owens, Omer (1956). "Notes – The Reaction of Phosphorus-Containing Enzyme Inhibitors with Some Hydroxylamine Derivatives". J. Org. Chem.21 (10): 1186. doi:10.1021/jo01116a610. 
  17. ^Ritz, Josef; Fuchs, Hugo; Kieczka, Heinz; Moran, William C. (2005), "Caprolactam", Ullmann's Encyclopedia of Industrial Chemistry, Weinheim: Wiley-VCH, doi:10.1002/14356007.a05_031.pub2 
  18. ^Smith, Andrew G.; Tasker, Peter A.; White, David J. (2003). "The structures of phenolic oximes and their complexes". Coordination Chemistry Reviews. 241: 61. doi:10.1016/S0010-8545(02)00310-7. 
  19. ^Rao, Linfeng (15 March 2010). "Recent International R&D Activities in the Extraction of Uranium from Seawater". Lawrence Berkeley National Laboratory. 
  20. ^Kanno, M (1984). "Present status of study on extraction of uranium from sea water". Journal of Nuclear Science and Technology. Journal of Nuclear Science and Technology. 21: 1. doi:10.1080/18811248.1984.9731004. 
  21. ^Dent, Steve (2017-02-17). "Endless nuclear power can be found in the seas". Engadget. Retrieved 2017-02-22. 
  22. ^Rowe, Aaron (27 November 2007). "New Nerve Gas Antidotes". Wired. 
  23. ^Kassa, J. (2002). "Review of oximes in the antidotal treatment of poisoning by organophosphorus nerve agents". Journal of Toxicology: Clinical Toxicology. 40 (6): 803–16. doi:10.1081/CLT-120015840. PMID 12475193. 
  24. ^Johannes Panten and Horst Surburg "Flavors and Fragrances, 2. Aliphatic Compounds" in Ullmann's Encyclopedia of Industrial Chemistry, 2015, Wiley-VCH, Weinheim.doi:10.1002/14356007.t11_t01

Introduction

Oximation has attracted intensive attention for several decades as an efficient method for characterization and purification of carbonyl compounds. Due to the nucleophilic character of oximes, they have been widely used for the preparation of a variety of nitrogen-containing compounds such as amides [1], hydroximinoyl chlorides [2], nitrones [3] and nitriles [4]. Oximes were usually prepared by the reaction of carbonyl compounds and hydroxylamine hydrochloride with adjustment of pH using a basic aqueous medium. Recently, some new techniques such as microwave irradiation [5] and solvent-free heating [6] were applied to this reaction. Oxidation of amines or hydroxylamines was another usual method for the synthesis of oximes [7].

On the other hand, the use of water as a reaction medium has attracted notable interest and offers a clean, economical and environmentally-safe protocol for many reactions [8]. In fact, more and more reactions have been reported to proceed smoothly and efficiently in water. In continuation of our interest in organic reactions in water [9], herein we report the unexpected formation of aldoximes from the one-pot reaction of aromatic aldehydes and ethylenediamine with Oxone® in water.

Results and Discussion

Fujioka’s, Konwar’s and Sayama’s groups have reported the reactions of aldehydes and ethylenediamine with oxidation by N-bromo(chloro)succinimide (NXS) [10], I2/KI/K2CO3/H2O system [11] or pyridinium hydrobromide perbromide (PHPB) [12]. These reactions afforded dihydro-imidazole-type products. Oxone® has been widely used in organic reactions in recent years as an efficient and clean oxidant [13]. When we employed Oxone® as the oxidant for the reactions of aromatic aldehydes 1a-j and ethylenediamine (2) in pure water, to our surprise, no dihydroimidazoles were observed, and instead, aldoximes 3a-j were produced in excellent yields (Scheme 1).

Scheme 1.

The procedure involves addition of ethylenediamine to an aqueous mixture of aldehyde and Oxone® in water, followed by vigorous stirring in an oil bath to afford the aldoximes. The reaction was affected prominently by the quantity of Oxone® employed and the optimum amount of this reagent was found to be one equivalent. If 1.5 equivalents or more of Oxone® were used, the aromatic aldehydes could be partially oxidized to the corresponding benzoic acids. If 0.5 equivalents or less of Oxone® were used, the conversions were relatively low. The ethylenediamine was used in slight excess. The reaction yields for the one-pot synthesis of aldoximes with the optimum molar ratio of 1, 2 and Oxone® as 1:1.1:1 are listed in Table 1, along with the melting points of the products.

Table 1. One-pot synthesis of aldoximes from aldehydes, 2 and Oxone®.

EntryRProductYield / %aMp (lit) / oC
1H3a9230-32 (33-35 [5] )
24-CH33b9373-74 (76-78 [14] )
34-CH3O3c9247-49 (48-49 [15] )
43,4-CH33d9067-68 (69 [16] )
54-Cl3e93110-111 (107-109 [14] )
62-Cl3f9174-75 (74-75 [17] )
73,4-Cl3g95120-121
84-NO23h88131-132 (132-133 [17] )
93-NO23i86123-124 (121-122 [17] )
104-CN3j88180-181 (174-176 [18] )

From Table 1 it can be seen that all of the reactions of aldehydes 1a-j with 2 and Oxone® gave very good yields of aldoximes 3a-j. All of the products except for 3g were known compounds and their structures were confirmed by comparison of their melting points, 1H- and 13C-NMR and IR spectra with reported data [5,14,15,16,17,18].

The use of other amines replacing ethylenediamine was studied under the same conditions. Diamines such as 1,3-diaminopropane and 1,3-diaminohexane and aliphatic amines such as methylamine and butylamine afforded very low yields of the aldoximes, while p-tolylamine and hydrazine gave no aldoximes. These results demonstrated the advantage and special activity of ethylenediamine for the formation of aldoximes.

Other oxidants such as FeCl3, (NH4)2Ce(NO3)6, KMnO4, PhI(OAc)2 and K2S2O8 instead of Oxone® have also been examined. None of these oxidants gave any aldoxime products, but rather generated the corresponding benzoic acids, thus clearly exhibiting the effectiveness of Oxone® for producing aldoximes from aldehydes and ethylenediamine. Aliphatic aldehydes have also been used for these reactions, but unfortunately, they did not react with ethylenediamine and Oxone® to afford aldoximes.

Additional control experiments were conducted to gain insight into the reaction mechanism. If the aqueous solution of 2 and Oxone® was stirred at 80 oC for 3 h, and then an aldehyde was added and the resulting mixture stirred for another 3 h, no aldoxime was obtained. When Oxone® was added after the aqueous solution of an aldehyde and 2 was stirred at 80 oC for 3 h, the desired aldoxime was successfully prepared in high yield. Consequently, the reaction mechanism is believed to proceed via the imine intermediate 4, which was then oxidized by Oxone® to form the aldoxime product 3. Indeed, the reaction of the imine preformed from an aldehyde and 2 with Oxone®for 3 h at 80 oC (Scheme 2) gave yields comparable to those obtained with the three-component one-pot process. Thus, for example, the oxidation of the imine 4a prepared from 1a and 2 with Oxone®for 3 h at 80 oC afforded 3a in 89% yield, close to the 92% yield observed for the one-pot procedure (Table 1, entry 1). In contrast, the Oxone®oxidation of the imines formed from 1a and 1,3-diaminopropane, 1,3-diamino-hexane, methylamine or butylamine gave only small amounts of 3a, in contrast with the three-component one-pot process. These results again demonstrated the unique property of ethylenediamine for the generation of aldoximes.

Scheme 2.

Experimental

General

1H-NMR and 13C-NMR spectra were recorded at 300 MHz and 75 MHz respectively on a Bruker Avance-300 spectrometer using CDCl3 as solvent. Chemical shifts (δ) are given in ppm relative to TMS as an internal standard and coupling constants (J) in Hz. IR spectra were taken on a Bruker Vector-22 spectrometer in KBr pellets and are reported in cm-1. Melting points were determined on a XT-4 apparatus and are uncorrected.

General procedure for aldoxime synthesis

Typically, to an aqueous mixture of aldehyde 1a-j (0.5 mmol) and Oxone® (307.4 mg, 0.5 mmol) in water (2 mL) was added 2 (40 µL, 0.55 mmol), then the reaction mixture was stirred vigorously in an oil bath preset at 80 oC for 3 h (monitored by TLC). After the reaction mixture had cooled, the precipitated-out solid was filtered and washed with water (10 × 2 mL) to give the crude product, except for 3a and 3c. Because of the lower m.p. of 3a and 3c, the crude product failed to precipitate out from the reaction mixtures, and required extraction with ethyl acetate (15 mL × 2). The extract was dried over anhydrous sodium sulfate and then filtered. The filtrate was evaporated under vacuum to afford the crude product. All of the crude products were purified by column chromatography over silica gel with petroleum ether/ethyl acetate as the eluent to give pure aldoximes 3a-j. All products 3a-j, except for the previously unknown compound 3,4-Dichloro-benzaldehyde oxime (3g) have been reported previously and their identities have been confirmed by their 1H-NMR, 13C-NMR, IR spectra and melting point. The spectral data of 3g were as follows: IR (KBr) υ 3311, 1632, 1556, 1480, 1460, 1377, 1325, 1269, 1215, 1135, 1032, 993, 966, 947, 915, 883, 872, 816, 776, 697, 675, 576, 551; 1H-NMR (CDCl3) δ 7.40 (dd, J = 8.2, 1.5 Hz, 1H, ArH), 7.46 (d, J = 8.2 Hz, 1H, ArH), 7.68 (d, J = 1.5 Hz, 1H, ArH), 7.68 (s, 1H, CH), 8.06 (s, 1H, OH); 13C- NMR (CDCl3) 148.5, 134.2, 133.4, 132.1, 131.0, 128.8, 126.2

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