Preparing nitriles from carbonyl compounds is useful in reactions because nitriles are versatile functional groups1. Not only are they versatile functional groups but they serve as precursors in several transformations. The cyano-group is found in many bioactive molecules and plays a role in hydrogen bonding to certain biological receptors. 4 Nitriles are carboxylic acid derivatives because they can easily be converted to carboxylic acid under either basic or acidic conditions. Piperonal is an aromatic compound that is present in vanilla, camphor wood, and olive leaves. It is typically used as a fragrance or a flavor.2 Piperonal also has the ability to inhibit foodborne pathogens and to improve hepatic insulin and ER stress response2. It does this by increasing the circulating adiponectin concentrations2.
Not only does piperonal have the ability to improve hepatic insulin and ER stress response but it is also shown to be a dominant odor signature in the drug ecstasy3. Piperonal is commonly used in the fragnace and flavor industry. It is a very versatile compound. Piperonylonitrile is a nitrile that and nitriles are popular amongst the pharmaceutical industry. The number of nitrile containing pharmaceuticals have increased in the last 30 years.5 In this experiment, a nucleophilic substitution was used to synthesize piperonylonitrile from piperonal and dimethylformamide (DMF) and hydroxylamine Hydrochloride.
Figure 1: Synthesis of piperonylonitrile Scheme 1: Synthesis of piperonylonitrile The mechanism for the formation of piperonylonitrile begins when the lone pairs on the nitrogen of the hydroxylamine attacks the carbonyl portion of piperonal creating a tetrahedral intermediate. The oxygen anion then attacks the hydrochloride portion to create an alcohol. The chloride ion attacks hydrogen in the hydroxylamine to create hydrochloric acid. The alcohol will then attack the HCl to create an oxygen cation. The lone pair on the hydroxylamine will attack the carbon, releasing water and creating a double bond between the nitrogen and carbon. The remaining hydrogen will be attached by a chloride ion to create the oxime intermediate.
To create the desired product, the oxygen in the intermediate will attack the HCl that was formed making another oxygen cation and chloride ion. The Clwill attack the hydrogen connected to the carbon of the double bond, forming the nitrile and expelling water. The purpose of this experiment was to use a nucleophilic substitution to synthesize piperonylonitirle and purify it through flash chromatography. The product was then analyzed using NMR and IR. Experimental Piperonylonitrile. Piperonal (206 mg, 1.33 mmol) and DME (1 mL). were refluxed until a boil began before hydroxylamine (120 mg, 1.73 mmol) in DME (1 mL) was added and refluxed for 90 minutes until a light gold solution formed. The reaction was monitored by TLC. (2:8 ethyl acetate/hexanes).
Upon completion, solution was cooled and diluted with water (15 mL) and sat on ice for 15 minutes. Following the ice bath solution was vacuum filtrated and washed with cold water (1 mL) and yielded fuzzy crystals (. 089g, 45%). Flash column chromatography (15:75 ethyl acetate/hexanes) afforded a pale yellow crystal (.071g, 36%). mp 86.8- 88.0 °C; 1H NMR (400 MHz, CDC13) 8 (ppm) 6.06 (s, 2H), 6.8 (d, 1H), 7.0 (s, 1H), 7.2 (d, 1H); 130 NMR (400 MHz, CDC13) S (ppm) 102.13, 104.82, 109, 04, 111.31, 118.82, 128.14, 147.93, 151.44; IR (ATR) vmax (cm-1) 2920, 2359, 1483, 1437, 1254. Results and Discussion In the experiment, the product was synthesized via nucleophilic acyl addition between a benzaldehyde and hydroxylamine. The product was then purified by flash chromatography and analyzed by IR, 1 H NMR and 13C NMR. The synthesis of piperonylontitrile was successful.
There was a yield of a pale yellow crystal of 36%. The average recovery is 51% with there being a range from 0-94 %1. A reason for a smaller yield than notable reported could have been due to transfer of the product from glassware to glassware. Some may have been left behind. Another reasoning for a smaller yield could be due to the fact that as soon as the column was ran the product immediately eluted the column so a small amount was collected. Although this is a possible reason the desired product still formed. Column chromatography was chosen to purify the compound because it can purify almost any mixture of solids and/or liquids.
Using a solvent mixture that was composed of 15% ethyl acetate in hexanes, the product eluted straight from the column. It was predicted that the starting material would elute first but there was none present when the column was ran. Since there was not much of a separation, what eluted from the column was analyze to confirm that it was the pure product. The melting point could also be used to indicate that the product was formed. The reported melting point was slightly depressed with it being 86-88°C with the known melting point being 91-93°C. A reason for this depression could be that there was a small trace of starting material still present. With the melting point alone not being enough to determine the identity other data was collected.
The IR supports that piperonylonitrile was successfully synthesized. The most important stretch was the nitrile that is at 2359 cm-1. The present of this peak alone is a strong indicator that the desired product was synthesized. On the IR there is a minor carbonyl stretch but this is the only data analysis that it appears. It is not in a large enough quantity to interfere with the formation of the product. The 1 H NMR shows that there are a total of 4 different protons present; this would be the correct number of protons desired. The first peak is at 6.0 ppm integrates for two protons and is a singlet. This is indicative to the 2 protons that are adjacent to the ether. The cause for the protons being deshielded is because they are adjacent to a heteroatom. There are three different signals in the aromatic region.
There is a doublet at 6.8 pm that integrates for 1 proton and it belongs to the proton between the nitrile and a neighboring hydrogen. That neighboring hydrogen is that reason that it has a splitting pattern of a double. The singlet at 7.0 ppm that integrates for 1 proton is indicative of the lone proton adjacent to the nitrile and the carbon bonded to the five-membered ring. The final peak that suggests that product formed is ideal is the peak at 7.2 ppm that integrates for one proton and has a splitting pattern of a doublet. This belongs to the hydrogen that is adjacent to a carbon bonded to the five-membered ring and a proton.
With there only being four protons present this is a great signal that the product formed. If there had been a proton in the aldehyde region then it would suggest that there was a trace of the starting material present. In the final spectral analysis, the 13C NMR it was useful in determining the identity of the product. The most important shift is the nitrile that is seen at 118. If this had not been present then what was formed was not the desired product. There is a lack of the carbonyl carbon so this is also a food indicator that the product did indeed form.
Since for the starting material and product are similar expect for the formation of the nitrile the data would be similar. In conclusion, the nucleophilic substitution was successful in forming the desired product, piperonylonitrile with an overall yield of 36%, and the IR, 1 H NMR and 13C NMR together indicated that the product that was formed was relatively pure. Future experiments could possibly try to synthesize piperonylonitrile in a two-step conversion as opposed to the one step or use the easy 15-minute step that was reported1. At times taking shortcuts could produce lower yields than if one was to take the longer route.
