Synthesis of Some Acetophenone Oximes and Their Corresponding Bridged Terphthaloyl Oxime Esters

The objective of this study is to synthesize a number of oximes along with their terphthaloyl oxime esters derived from acetophenone, 4-methylacetophenone, 4-hydroxyacetophenone, 4-aminoacetophenone and 4nitroacetophenone as a part of ongoing research. Five acetophenone oximes have been synthesized by refluxing the acetophenone derivative with a solution of hydroxylamine hydrochloride in the presence of potassium hydroxide. The corresponding acetophenone oximes were obtained as solid materials in moderate to good yields. The structures of the resulting oximes were confirmed using IR, NMR and mass spectrometer. The HNMR data revealed that one oxime of the synthesized oximes was obtained as a mixture of two E/Z isomers in a ratio of (8:1). These resulting oximes were subjected into an esterification process with the terphthaloyl chloride in molar ratio of (1:2) respectively. The esterification reaction was carried out under basic conditions at 0 – 5 oC then room temperature. The five corresponding bridged terphthaloyl oxime esters have been formed as solid materials in moderate yields. The structures of the obtained terphthaloyl esters were also confirmed by spectroscopic techniques such as IR, NMR and mass spec.


Introduction
Oximes are found in many bioactive molecules. These molecules have a wide range of activities, including antibacterial, antifungal, anti-inflammatory, antioxidant, anti-diabetes and cytotoxic activities as well as their use as precursors in the synthesis of photosensitive materials [1,2]. The mono oxime, 4-(hydroxyimino) pentan-2-one, was synthesized through a solvent-free procedure yielding a E/Z isomeric mixture in a ratio of (9:1) according to the 1 HNMR data of crude product. The MM2 molecular mechanics method expectedly showed that the E-isomer of the (E)-4-(hydroxyimino) pentan-2-one was the favored as it has the lower total energy than the Z-isomer, (Z)-4-(hydroxyimino)pentan-2-one [1]. The corresponding benzoyl ester of the mono oxime, 4-(hydroxyimino)pentan-2one, was also reported to be obtained in two isomeric conformations Z/E in a ratio of (9:1) according to the 1 HNMR data of crude product. However, the MM2 method unexpectedly predicted that the Z-isomer of the benzoyl ester has a lower energy than its counterpart E-isomer [1]. Oxime esters could be obtained by the reaction of keto-or aldoximes with acid chlorides or acid anhydrides. Oxime esters are important molecules for the synthesis of biologically active heterocyclic compounds [3]. Oxime esters have also been used to cleavage DNA [4][5][6], herbicidal and antitumor activities [7,8]. Unsymmetrical dioxime esters such as (2E,4E)- (4- pentane have been synthesized and characterized [9].

Synthesis of acetophenone oxime 1:
A literature procedure [1] was adapted towards the synthesis of the desired oxime. Solution of hydroxylamine hydrochloride (5.0 gm, 71.94 mmol in 10 cm 3 of distilled water) and a solution of potassium hydroxide (3.0 gm, 53.48 mmol in 5 cm 3 of distilled water) were placed in a round-bottomed flask and stirred at room temperature. Acetophenone (8.0 gm, 66.58 mmol) was then added while stirring and the reaction mixture was refluxed. At the start of boiling, small amounts of ethanol (5 cm 3 ) were added from time to time to reaction mixture through the condenser until the boiling solution becomes clear. The reaction was left under reflux for further an hour after which the reaction vessel was allowed to cool gradually to room temperature. The pH of the reaction mixture was measured and found as expected to be acidic. A solution of 1N KOH was added to the reaction mixture until the solution became neutral. The reaction mixture was then refluxed for further 30 min, cooled to room temperature. The pH was measured and found to be still acidic. Addition of 1N KOH solution was required and the reaction mixture was refluxed for another 10 min, cooled, pH was measured and found to be neutral. The reaction mixture was transferred into a beaker containing icewater (100 cm 3 ), the acetophenone oxime was precipitated rapidly, filtered, washed with cold water (3 × 10 cm 3 ) and air dried to give a white powder of the desired compound (

Synthesis 4-methyl acetophenone oxime 2:
A literature procedure [1] was adapted towards the synthesis of the desired oxime. Solution of hydroxylamine hydrochloride (5.0 gm, 71.94 mmol in 10 cm 3 of distilled water) and a solution of potassium hydroxide (3.0 gm, 53.48 mmol in 5 cm 3 of distilled water) were placed in a round-bottomed flask and stirred at room temperature. 4-Methyl acetophenone (8.0 gm, 59.62 mmol) was then added while stirring and the reaction mixture was refluxed. At the start of boiling, small amounts of ethanol (5 cm 3 ) were added from time to time to reaction mixture through the condenser until the boiling solution becomes clear. The reaction was left under reflux for further an hour after which the reaction vessel was allowed to cool gradually to room temperature. The pH of the reaction mixture was measured and found as expected to be acidic. A solution of 1N KOH was added to the reaction mixture until the solution became neutral. The reaction mixture was then refluxed for further 30 min, cooled to room temperature. The pH was measured and found to be still acidic. Addition of 1N KOH solution was required and the reaction mixture was refluxed for another 10 min, cooled, pH was measured and found to be neutral. The reaction mixture was transferred into a beaker containing icewater (100 cm 3 ), the 4-methyl acetophenone oxime was precipitated rapidly, filtered, washed with cold water (3 × 10 cm 3 ) and air dried to give a white powder of the desired compound (4.50 gm, 30.16 mmol, 51% yield). The product was recrystallized from diethyl ether; mp 93 ºC; IR  max (cm −1 ) 3212 (OH), 1513(C=N). 1

Synthesis of 4-hydroxy acetophenone oxime 3:
A literature procedure [1] was adapted towards the synthesis of the desired oxime. Solution of hydroxylamine hydrochloride (5.0 gm, 71.94 mmol in 10 cm 3 of distilled water) and a solution of potassium hydroxide (3.0 gm, 53.48 mmol in 5 cm 3 of distilled water) were placed in a round-bottomed flask and stirred at room temperature. 4-Hydroxy acetophenone (8.0 gm, 58.76 mmol) was then added while stirring and the reaction mixture was refluxed. At the start of boiling, small amounts of ethanol (5 cm 3 ) were added from time to time to reaction mixture through the condenser until the boiling solution becomes clear. The reaction was left under reflux for further an hour after which the reaction vessel was allowed to cool gradually to room temperature. The pH of the reaction mixture was measured and found as expected to be acidic. A solution of 1N KOH was added to the reaction mixture until the solution became neutral. The reaction mixture was then refluxed for further 30 min, cooled to room temperature. The pH was measured and found to be still acidic. Addition of 1N KOH solution was required and the reaction mixture was refluxed for another 10 min, cooled, pH was measured and found to be neutral. The reaction mixture was transferred into a beaker containing icewater (100 cm 3 ), the 4-hydroxy acetophenone oxime was precipitated rapidly, filtered, washed with cold water (3 × 10 cm 3 ) and air dried to give a white powder of the desired compound

Synthesis 4-amino acetophenone oxime 4:
A literature procedure [1] was adapted towards the synthesis of the desired oxime. Solution of hydroxylamine hydrochloride (5.0 gm, 71.94 mmol in 10 cm 3 of distilled water) and a solution of potassium hydroxide (3.0 gm, 53.48 mmol in 5 cm 3 of distilled water) were placed in a round-bottomed flask and stirred at room temperature. 4-Amino acetophenone (8.0 gm, 59.19 mmol) was then added while stirring and the reaction mixture was refluxed. At the start of boiling, small amounts of ethanol (5 cm 3 ) were added from time to time to reaction mixture through the condenser until the boiling solution becomes clear. The reaction was left under reflux for further an hour after which the reaction vessel was allowed to cool gradually to room temperature. The pH of the reaction mixture was measured and found as expected to be acidic. A solution of 1N KOH was added to the reaction mixture until the solution became neutral. The reaction mixture was then refluxed for further 30 min, cooled to room temperature. The pH was measured and found to be still acidic. Addition of KOH solution 1 N was required and the reaction mixture was refluxed for another 10 min, cooled, pH was measured and found to be neutral. The reaction mixture was transferred into a beaker containing icewater (100 cm 3 ), the 4-amino acetophenone oxime was precipitated rapidly, filtered, washed with cold water (3 × 10 cm 3 ) and air dried to give a deep brown solid of the desired compound (5.0 gm, 33.29 mmol, 56% yield). The product was recrystallized from diethyl ether; mp 150 ºC (lit. 153 ºC, chemical book website); IR  max (cm

Synthesis 4-nitro acetophenone oxime 5:
A literature procedure [1] was adapted towards the synthesis of the desired oxime. Solution of hydroxylamine hydrochloride (5.0 gm, 71.94 mmol in 10 cm 3 of distilled water) and a solution of potassium hydroxide (3.0 gm, 53.48 mmol in 5 cm 3 of distilled water) were placed in a round-bottomed flask and stirred at room temperature. 4-Nitro acetophenone (8.0 gm, 48.44 mmol) was then added while stirring and the reaction mixture was refluxed. At the start of boiling, small amounts of ethanol (5 cm 3 ) were added from time to time to reaction mixture through the condenser until the boiling solution becomes clear. The reaction was left under reflux for further an hour after which the reaction vessel was allowed to cool gradually to room temperature. The pH of the reaction mixture was measured and found as expected to be acidic. A solution of 1N KOH was added to the reaction mixture until the solution became neutral. The reaction mixture was then refluxed for further 30 min, cooled to room temperature. The pH was measured and found to be still acidic. Addition of KOH solution 1N was required and the reaction mixture was refluxed for another 10 min, cooled, pH was measured and found to be neutral. The reaction mixture was transferred into a beaker containing icewater (100 cm 3 ), the 4-nitro acetophenone oxime was precipitated rapidly, filtered, washed with cold water (3 × 10 cm 3

Synthesis of o,o'-terephthaloyl bis-1-(p-tolyl)-1-(p-tolyl)ethan-1-one oxime 7:
An adapted literature procedure [1] was followed to synthesis title compound. The 4-methyl acetophenone oxime (3.27 g, 0.022 mmol) in chloroform (40 cm 3 ) in the presence of triethyl amine (0.66 g, 1.3 mmol) were placed in a round-bottomed flask and stirred at 0 -5 °C. A solution of terphthaloyl chloride (2.03 g, 0.01 mmol) in chloroform (50 cm 3 ) was then added dropwise over 30 min. The reaction mixture was left stirring at room temperature for 2 hours, after which distilled water (30 cm 3 ) was added to the mixture and stirred for further 10 min. The organic layer was extracted, dried over anhydrous Na 2 SO 4 and filtered. The solvent was evaporated in vacuo to obtain the desired oxime ester in moderate yield (3.

Synthesis of Acetophenone Oximes 1 -5
The acetophenone derivative was refluxed with a solution of hydroxylamine hydrochloride in the presence of potassium hydroxide. The corresponding acetophenone oximes were formed as solid materials in moderate to good yields (Scheme 1).

Scheme-1. Synthesis of acetophenone oximes 1 -5
The spectroscopic analysis for the resulting compounds revealed the formation of the acetophenone oximes 1 -5. The IR data showed the absorption of the hydroxyl group and the imino group (C=N) at the expense of the carbonyl group (C=O) of the acetophenone derivative. The mass spectrometer gave the expected molecular masses along with the fragmentation patterns for all acetophenone oximes 1 -5. The 1 HNMR further confirmed the formation of all oximes 1 -5. The 1 HNMR spectroscopic data showed that the acetophenone oximes 2 -5 were obtained as single isomers except the acetophenone oxime 1, which was obtained in two isomeric forms E/Z in ratio of about (8:1) (Fig 1) [Mona's 3 rd conference paper]. Synthesis of the bridged terphthaloyl acetophenone oxime esters 6 -10: An adapted literature procedure [1] was followed towards the synthesis of the oxime esters 6 -10. The acetophenone oxime derivative was reacted with terphthaloyl chloride in the ratio of (2:1 mole/mole) under mild basic conditions at 0 °C to room temperature. The desired terphthaloyl oxime esters 6 -10 were obtained in moderate yields as solid materials (Scheme 2).

Scheme-2. Synthesis of oxime esters 6 -10
The IR data revealed the disappearance of the oxime hydroxyl group and the formation of the ester groups (COO) as strong absorption bands for all oxime esters 6 -10. The 1 HNMR data of the oxime ester 6 revealed the formation of this ester as all expected chemical shifts for all different protons were seen in the spectrum and the disappearance of the oxime hydroxyl proton of the starting oximes. The mass spectrometer gave a further evidence on the formation of the oxime ester 6. The molecular ion peak was observed at 400, 428, 432, 430 and 490 m/z along with other molecular fragments for the oxime esters 6 -10 respectively, which were in a line with the expected theoretical fragmentation patterns.

Conclusion
Five oximes derived from the acetophenone have been synthesized in moderate to good yields. Only the acetophenone oxime was obtained in two E/Z isomeric forms in a ratio of (8:1). These five resulting oximes were subjected into an esterification reaction with the terphthaloyl chloride in molar ratio of (1:2) through which five bridged terphthaloyl oxime esters have been formed in moderate yields.