organic chemistry lab report

5/26/2018 Organic Chemistry Lab Report

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Christine Crawford

Synthetic #2 Formal Final Report

Synthesis of

Piperonylonitrile

TA: Yi-Chun Lin (Jim) Chem 213, Section 2

April 11, 2013


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Introduction

The ability to synthesize nitriles in different compounds is a very critical tool within

organic synthesis reactions. Nitriles are organic substances that contain the cyano (C=N) group

and are functionally known by virtue of their short, polarized triple bond.1These cyano groups

are widely found as starting materials and intermediates in organic synthesis.2 Because these

groups can also be found so widely as starting materials or intermediates, nitriles have a wide

commercial application in use for solvents, synthetic intermediates, pharmaceuticals, and

monomers.1.

The role of nitriles in medicinal agents has been steadily emerging as the number of

nitrile-containing pharmaceuticals has increased over the past couple years. Currently, over 30

nitrile-containing pharmaceuticals are available and prescribed for a diverse variety of medicinal

indications, and there are even more than 20 additional nitrile-containing leads in clinical

development at this time.3These drugs are also extremely effective because the nitrile group is

quite robust and is usually not readily metabolized in the body.3 This means that the nitrile

substituent in most of these nitrile-containing pharmaceuticals can pass through the body

unchanged and be excreted without any extremely unwanted side effects.

Nitriles are not only important for use in the pharmaceutical industry, but they can even

been adapted to microscale work within an educational setting. Specifically, the synthesis of

piperonylonitrile from piperonal allows students to give excellent yields of the corresponding

nitrile in one easy 15-minute step, and is therefore an extremely helpful reaction in order for

organic chemistry students to learn about the improvement in yields achievable by designing a

synthesis that follows the shortest possible route.4 The synthesis of piperonylonitrile from

piperonal and hydroxylamine hydrochloride under acidic conditions is shown in Scheme 1.


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- Hand drawn mechanism of Synthesis of Piperonylonitrile -

Scheme 1.Synthesis of Piperonylonitrile.

In the first step, the lone pair of electrons on the nitrogen of the hydroxylamine attacks

the carbonyl component of piperonal and makes a tetrahedral intermediate with a hydroxylamine

cation and an oxygen anion. This anion then attacks hydrochloric acid to form an alcohol. The

leftover chloride ion then attacks one of the hydrogens of the hydroxylamine cation for reform

hydrochloric acid and produces a hemiaminal. The alcohol substituent attached to the carbon will

then again attack the hydrochloric acid, forming an oxygen cation (R-O+H2)and a chloride ion.

The lone pair of electrons from the hydroxylamine will then attack the adjacent carbon to form a

double bond between the carbon and nitrogen, releasing water as a leaving group and forming


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another nitrogen cation. The chloride ion will then attack the final hydrogen attached to the

nitrogen to form the oxime intermediate. In a final step, the oxygen of the oxime will attack the

hydrochloric acid to form another oxygen cation (R-O+H2)and a chloride ion. The chloride ion

will then attack the hydrogen attached to the carbon of the double bond, therefore pushing these

electrons to form a CN triple bond and expelling water as a leaving group.

The synthesis of nitrile substituents is extremely important for synthetic organic

chemistry, especially for the large scale production of medical agents and pharmaceuticals, as

well as on a smaller scale use for the instruction of organic chemistry students. The purpose of

this lab is to learn the reaction mechanism of the synthesis of nitrile groups from an aldehyde

starting material on a small scale basis and quantify its efficiency of producing the product of

piperonylonitrile from the starting materials. The product can be isolated from the reaction

mixture and then analyzed by IR,1H NMR, and

13C NMR instrumentation in order to quantify

this efficiency.

Experimental

Piperonal (200mg, 1.33mmol) and DMF (1mL) are added to a 5mL long-necked round

bottom flask with attached air condenser and are stirred and heated to a boil (~170C).

Hydroxylamine hydrochloride (120mg, 1.73mmol) is dissolved in DMF (1mL) and added drop

wise to the boiling piperonal solution over a 2 minute period. Solution is then stirred and

refluxed for 90 minutes, as it will gradually change from a colorless solution to a dark golden

brown solution. Upon completion of the reaction, the solution is cooled to room temperature then

placed in to a 50mL Erlenmeyer flask where it will sit in an ice bath for 5 minutes. Solution is

then diluted with 10mL distilled water and allowed to crystalize over a two day period in the


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refrigerator. Crystals are then collected by vacuum filtration using a Hirsch funnel and washed

with 1mL of cold water. The slightly wet crystals are allowed to dry until the next lab period

(132mg, 64.7%) mp 90.5-93.0C;1H NMR (400 MHz, CDCl3) (ppm) 7.19 (d, 1H), 7.01 (s,

1H), 6.84 (d, 1H), 6.08 (s, 2H);13

C NMR (400 MHz, CDCl3) (ppm) 152, 149, 129, 119.5, 111,

109.5, 106, 102 ;IR (ATR) (cm-1

) 2919, 2219, 1606, 1482, 1254, 1026.

Results and Discussion

As a class, nitriles are characterized by the presence of the CN (CN) group.5Nitriles

can be formed in many different ways, including simultaneous replacement of all three hydrogen

atoms of a methyl group by nitrogen, by replacement of both the carbonyl and alcohol portions

of a carboxylic acid group, or by the reaction of an aldehyde with a hydroxylamine.5 More

specifically, reactions of aldehydes with hydroxylamines produce a nitrile substituent through the

use on an oxime intermediate.

The synthesis of piperonylonitrile is characterized by the exchange of the aldehyde of the

piperonal reactant to form a nitrile substituent using hydroxylamine hydrochloride within an

acidic reaction mixture. As the reaction takes place, the reaction mixture should change from a

clear colored solution to a dark yellow/golden brown color. However, the piperonylonitrile does

not precipitate or crystalize out of the solution during the reaction. Instead, the reaction mixture

must be cooled within an ice bath for 5 minutes and then diluted with 10-15mL of distilled water.

This distilled water helps to achieve a better crystallization because the piperonal starting

material is more likely to stay dissolved within the water as the piperonylonitrile product is

crystalized. To allow for an extremely efficient and complete crystallization of the

piperonylonitrile product, the reaction mixture can be left in a refrigerator overnight, or even


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multiple days. The final crystalized product can then be vacuum filtered to isolate the

piperonylonitrile product, which is a brown/grey colored crystal that resembles the looks of

sheep wool.

The product was analyzed by IR spectra data.The most notable change that occurs during

this reaction is the substitution of the aldehyde on piperonal with a nitrile, producing an oxime as

the intermediate product. An aldehyde of piperonal is characterized by the carbonyl C=O bond,

which shows stretching peaks around 1650-1800cm-1

. As can be seen from the spectral data

(Figure 1, Supplemental Information), the isolated product from this experiment showed two

peaks close to or within this range: one peak at 1852cm

-1

and the second peak at 1730cm

-1

. These

peaks are very small, but can support the conclusion that there is potentially a small amount of

starting material still left over in the crystalized product. However, when converting piperonal to

piperonylonitrile, the synthesis goes through an oxime intermediate. This intermediate would

have a most notable stretching frequency around 3200-3600cm-1

which corresponds to the O-H

bond attached to the nitrogen of the oxime. The IR spectral data of the final product of this

synthesis does not show any peaks within this range that could support the conclusion that there

is any intermediate left over within the crystalized product. Instead, only starting materials can

be found in the piperonylonitrile product. Finally, the nitrile group of the piperonylonitrile

product has a characteristic CN triple bond, having a stretching frequency between 2230-

2250cm-1

. As can be seen from the spectral data of the crystalized product (Figure 1,

Supplemental Information), there is a very strong peak that can be found at 2219cm

-1

. Although

this peak does not reside in the normal location for a CN stretching frequency, it is certainly

very close and it can be concluded that this peak corresponds to the nitrile group.


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There are other strong peaks that are present within the IR spectra of piperonylonitrile

(Figure 1, Supplemental Information), however, these peaks do not help to identify the purity of

the sample as much because they are peaks that could be found for all three compounds:

piperonal, the oxime intermediate, and piperonylonitrile. Some of these peaks include the peak at

2919cm-1

that corresponds to the stretching frequency of a C-H (sp3) bond, found on the one

carbon of the 5-membered ring found between the two oxygens, as well as the C-O stretching

frequency found at 1026cm-1

, corresponding to the C-O bonds of the 5-membered ring.

NMR was also a useful technique for characterizing the identity of piperonylonitrile as

our crystalized product. Using a 60 MHz

1

H NMR, spectral data (Figure 2, Supplemental

Information) was indistinguishable as five peaks were all grouped very closely together, but only

had an integral value of 3 hydrogens. To distinguish this data, 400MHz1H NMR was used to

produce a total of four peaks (Figure 3, Supplemental Information). The first three peaks of this

spectra correspond to the hydrogens attached to the benzene ring of piperonylonitrile. The first

peak is the appearance of 1 proton at 7.19ppm, which splits into a doublet. This one hydrogen

can be associated with the C-H bond of the benzene ring closest to the nitrile group and having a

single hydrogen on the adjacent carbon. Normal C-H bonds of benzene rings are found between

6.5-8.0ppm. The reason for this hydrogen to be found at the higher end of this spectral range is

from the deshielding effects of the nitrile group attached to the benzene on the adjacent carbon.

The other hydrogen located next to the nitrile group is located at 7.01ppm and forms a singlet

peak. This peak is a singlet because there are no other hydrogens on adjacent carbons next to this

C-H bond. However, the peak is not at as high of a ppm value as the first hydrogen because

although there are deshielding effects from the adjacent nitrile group, there are also shield effects

from the adjacent ether group of the 5-membered ring. Finally, the last of the hydrogens from the


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benzene ring can be associated with the peak at 6.84ppm. This peak again is a doublet because of

the hydrogen on the adjacent carbon, but it is again lesser in ppm value because of the shielding

effects of the ether group attached at the other adjacent carbon of the 5-membered ring.

The final peak found on the 400 MHz1H NMR is a singlet peak located at 6.08ppm, and

has an integral value of almost 2. This last peak is associated with the two hydrogens attached to

the carbon of the 5-membered ring, in between the two oxygens of the ring. There are no other

peaks found on the NMR spectra of the crystalized product, so from this data we can conclude

that the crystals are extremely pure. If there were some of the piperonal starting material left over

in this sample, there should have been a peak around 9.0-10.0ppm, corresponding to the

hydrogen of the aldehyde substituent in piperonal. Also, if any of the oxime intermediate were

present in the final crystals, there would be a broad peak visible somewhere between 0.5-5.0ppm

corresponding to the O-H bond of the oxime. However, because this peak is also not present in

the spectra, we can conclude that this intermediate is also not present in the final synthesized

sample, and only piperonylonitrile has been isolated from the reaction.

A further examination of the synthesized crystals by 400 MHz 13C NMR (Figure 4,

Supplemental Data) can conclude the crystals are pure piperonylonitrile. The13

C NMR spectra

shows 9 different signals of carbon atoms. Piperonylonitrile contains only 8 carbon atoms,

however the one extra carbon found in this spectra is due to the carbon of the chloroform-d

(CDCl3) used as the solvent for the NMR tube. Discounting, this chloroform-d peak located at

78ppm, the 8 peaks found on the

13

C NMR spectra are located at 152ppm, 149ppm, 129ppm,

119.5ppm, 111ppm, 109.5ppm, 106ppm, and 102ppm. The first two peaks at 152ppm and

149ppm fall within the range of carbons that are part of a benzene ring. These two specific

carbons of the benzene are most likely the two carbons that are attached to the oxygens of the 5-


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membered ring as well. This is most likely the case because the extra attachment of these oxygen

groups will tend to increase the displacement of the peaks along the spectra. The third peak,

found at approximately 129ppm corresponds to the carbon of the benzene ring that is attached to

the nitrile group. Nitriles are usually located between 110-125ppm on a13

C NMR spectra, and so

a carbon of a benzene ring attached to this nitrile should be just slightly above the range of a

nitrile. The nitrile carbon is then found at the next peak at about 119.5ppm. It is known that this

carbon corresponds to the CN of the piperonylonitrile because it falls within the range of nitrile

groups.

After this, the next 3 peaks of the

13

C NMR spectra (Figure 4, Supplemental Information)

pertain to the three last carbons that are a part of the benzene ring. The first peak, located at

111ppm, most likely corresponds to the carbon of the benzene ring located in between the

adjacent carbons with attachments of the nitrile group and the oxygen of the 5-membered ring.

The next peak at 109.5ppm corresponds to the carbon located on the opposite side of the nitrile

group. The last of the benzene carbons resides with a peak at 106ppm. Finally, the last carbon of

piperonylonitrile found on the13

C NMR spectra is located at the tip of the 5-membered ring in

between to the two oxygen atoms, and shows a peak at about 102ppm. This peak is the lowest of

the 8 carbons of piperonylonitrile because it is an R2CH2group. Usually, these groups are found

more towards the lower end of the NMR spectrum, but because the two R-groups attached to the

carbon are ethers, the peak gets shifted up the spectra more towards the carbon-oxygen single

bond ppm range.

The IR,1H NMR, and

13C NMR analysis spectra for the synthesized product have

confirmed the identity of piperonylonitrile as the pure crystals formed from this synthesis

process, and show little to no signs of any possible impurities. Although there were signs of


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possible leftover starting materials found in the IR spectral data, there were no signs of this

contamination from either the hydrogen or carbon NMRs, therefore it is possible to conclude that

this reaction was carried out to produce a yield of a very pure product. The amount of

piperonylonitrile crystallized and isolated during this experiment returned a 67.4% yield.

Although this yield may be slightly lower than desired, it is still a significantly decent yield for

the product in this reaction. This lower percent yield could be due to the fact that not all of the

starting materials had actually reacted during the 90 minute time period, as seen from the trace

amount of piperonal in the IR spectra, and so this would lead to some sources of error and

instead would need to find the corrected percent yield of piperonylonitrile from only the amount

of piperonal and hydroxylamine hydrochloride that reacted during the experiment.

In order to further test the purity of the 67.4% yield of piperonylonitrile, melting point

range determination was carried out. Melting point of the isolated product produced values of

about 90.5-93C. The accepted melting temperature range for piperonylonitrile is between 91-

93C, so this observed melting temperature range is almost exactly on point with the accepted

vales. The barely lower starting temperature of this range may be due to the trace amounts of

piperonal found in the sample, but overall it can be concluded that the crystalized and isolated

compound from this synthesis is a pure piperonylonitrile crystal.

The synthesis of nitrile substituents is an extremely important aspect of organic chemistry

and synthetic organic reactions. Nitriles, such as the piperonylonitrile synthesized in this lab, are

useful for not only the large scale production of medical agents and pharmaceuticals, but for use

in model reactions to teach organic chemistry students the mechanism of the synthesis of nitrile

groups from an aldehyde starting material. This experiment was able to focus on the synthesis of

piperonylonitrile and then analyze the product for both quantity and percent yield as well as the


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purity of the sample. The product was analyzed by IR,1H NMR, and

13C NMR in order to

determine the identity and purity of the product.


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Works Cited

1. DeVito , Stephen C. Chapter 10: Designing Safer Nitriles. In Designing SaferChemicals.American Chemical Society: Washington D.C., United States, 1996; pp

194-223.http://pubs.acs.org/doi/pdf/10.1021/bk-1996-0640.ch010 (accessed 4/9/13)

2. Prasad, Shreenath; Bhalla, Tek Chand. Nitrile Hydratases (NHases): At the Interfaceof Academia and Industry. Biotechnology Advances. [Online] 2010, 28, 725-741.

http://www.sciencedirect.com/science/article/pii/S0734975010000716 (accessed

4/9/13)

3. Fleming, Fraser F.; Yao, Lihua; Ravikumar, P. C.; Funk, Lee; and Shook, Brian C.Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore.

J. Med. Chem. [Online] 2010, 53, 79027917.

http://pubs.acs.org/doi/pdf/10.1021/jm100762r (accessed 4/9/13)

4. DeMott Jr , James M; Kelley, Charles J. An Alternative One-Step Procedure for theConversion of Piperonal to Piperonylonitrile. J. Chem. Educ., 2001, 78, 780.

http://pubs.acs.org/doi/pdfplus/10.1021/ed078p780 (accessed 4/9/13)

5. Nitriles. InNomenclature of Organic Compounds: Principles and Practice. Fletcher,John H., Ed.; Dermer, Otis C., Ed.; Fox, Robert B., Ed. American Chemical Society:

United States, 1973; pp241-245. http://pubs.acs.org/doi/pdf/10.1021/ba-1974-

0126.ch031
http://pubs.acs.org/doi/pdf/10.1021/bk-1996-0640.ch010http://www.sciencedirect.com/science/article/pii/S0734975010000716http://pubs.acs.org/doi/pdf/10.1021/jm100762rhttp://pubs.acs.org/doi/pdfplus/10.1021/ed078p780http://pubs.acs.org/doi/pdf/10.1021/ba-1974-0126.ch031http://pubs.acs.org/doi/pdf/10.1021/ba-1974-0126.ch031http://pubs.acs.org/doi/pdf/10.1021/ba-1974-0126.ch031http://pubs.acs.org/doi/pdf/10.1021/ba-1974-0126.ch031http://pubs.acs.org/doi/pdfplus/10.1021/ed078p780http://pubs.acs.org/doi/pdf/10.1021/jm100762rhttp://www.sciencedirect.com/science/article/pii/S0734975010000716http://pubs.acs.org/doi/pdf/10.1021/bk-1996-0640.ch010

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