EXP 2 V1 - Experimental practical in order understand and explain the concept of Fischer-indole PDF

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Experimental practical in order understand and explain the concept of Fischer-indole synthesis of the indoles by synthesis of acetophenone phenylhydrazone from acetophenone and phenylhydrazine and to synthesis of 2phenylindole using acetophenone phenylhydrazone....

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CHM3202 ORGANIC CHEMISTRY II EXPERIMENT 2: INDOLE – FISCHER SYNTHESIS – PREPARATION OF 2-PHENYLINDOLE NAME: DZAIDATU AQMAL BINTI RAMLEE MATRIC NO: 187999 DEMO: ATIKAH AB. AZIZ : NURUL NABIHAH MOHAMAD ISHAK LECTURER: PROF. MADYA DR INTAN SAFINAR ISMAIL

EXPERIMENT TITLE: EXPERIMENT 2: INDOLE – FISCHER SYNTHESIS – PREPARATION OF 2-PHENYLINDOLE

OBJECTIVES 1. To understand and explain the concept of Fischer-indole synthesis of the indoles. 2. To

synthesis

of

acetophenone

phenylhydrazone

from

acetophenone

and

phenylhydrazine. 3. To synthesis of 2-phenylindole using acetophenone phenylhydrazone.

INTRODUCTION The Fischer indole synthesis is a chemical reaction that produces the aromatic heterocycle indole from a (substituted) phenylhydrazine and an aldehyde or ketone under acidic conditions. The reaction was discovered in 1883 by Hermann Emil Fischer. Indoles are among the most important of all biologically active organic compounds. The indole ring system is found in diverse naturally occurring molecules including tryptophan (an essential amino acid), 3-indoleacetic acid (the main plant growth hormone of higher plants), and serotonin (a bioregulator that plays an essential role in our mental health). Skatole (3methylindole), arising from the digestion of proteins, is responsible for the repulsive odor of feces, but in mores dilute form it has a pleasant floral fragrance and is a common ingredient in perfumes.

Figure 1 Some examples of indoles

In this experiment, 2-phenylindole will be prepared by acid catalyzed rearrangement of acetophenone phenylhydrazone, with elimination of ammonia. While the formation of the phenylhydrazone from acetophenone and phenylhydrazine is catalysed by mild acid (glacial acetic acid), the Fischer indole synthesis of 2-phenylindole from the phenylhydrazone requires a very strong acid. The Fischer indole synthesis is accelerated an acidic environment. Both protic and Lewis acids have been shown to help break the nitrogennitrogen bond in the sigmatropic shift. Hydrochloric or sulfuric acids are frequently used, and zinc chloride is the most effective Lewis acid. However, the synthesis is not completely dependent on an acid. Indolization can also occur under thermal conditions without a catalyst in solvents such as ethylene glycol, diethylene glycol, sulfolane or pyridine. For this purpose we will use “polyphosphoric acid” (PPA), made by heating a mixture of phosphoric acid and phosphorus pentoxide. It consists of about 55% triphosphoric acid and 45% other polyphosphoric acids.

PROCEDURE

A solution of 1.1g phenylhydrazine added in 5ml of ethanol

1.2g of acetophenone in a 50ml beaker

The mixture is warmed at 100° for 15 mins

+ 1-2 drops glacial acetic acid

A small portion of the crude acetophenone phenylhydrazine is recrystallized to obtain white crystalline solid.

1.0 g of the crude phenylhydrazone transferred into a 50ml beaker containing 7.0 gof polyphosphoric acid.

It was washed with dilute HCL, then with 3ml cold ethanol

The cold reaction product is filtered

Heated in boiling water bath at 100-120° for 10 mins

15ml of cold water is added + Stirred well

It was filtered with suction IR spectrum, yield and melting point is recorded

+ Washed with water + Washed with ethanol

Safety Precautions

Table 1: Safety precautions for compounds used Acetophenone

H227: Combustible liquid H302: Harmful if swallowed H316: Causes mild skin irritation H319: Causes serious eye irritation (Serious eye damage/eye irritation) H336: May cause drowsiness or dizziness P201 Obtain special instructions before use. P261 Avoid breathing dust/fume/gas/mist/vapours/spray. P271 Use only outdoors or in a well-ventilated area. P304+P340 IF INHALED: Remove person to fresh air and keep comfortable for breathing. P305+P351+P338 IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses if present and easy to do - continue rinsing. P332+P313 IF SKIN irritation occurs: Get medical advice/attention

Phenylhydrazine

Glacial acetic acid

H301: Toxic if swallowed H311: Toxic in contact with skin H315: Causes skin irritation [Warning Skin corrosion/irritation] H317: May cause an allergic skin reaction [Warning Sensitization, Skin] H319: Causes serious eye irritation H331: Toxic if inhaled H350: May cause cancer P301+P310 IF SWALLOWED: Immediately call a POISON CENTER/doctor/... P302+P352 IF ON SKIN: wash with plenty of water P304+P340 IF INHALED: Remove person to fresh air and keep comfortable for breathing. P305+P351+P338 IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses if present and easy to do continue rinsing. P308+P313 IF exposed or concerned: Get medical advice/attention. P361 Take off immediately all contaminated clothing H226: Flammable liquid and vapour [Warning Flammable liquids] H314: Causes severe skin burns and eye damage P301+P330+P331 IF SWALLOWED: Rinse mouth. Do NOT induce vomiting P303+P361+P353 IF ON SKIN (or hair): Take off Immediately all contaminated clothing. Rinse SKIN with water [or shower] P304+P340 IF INHALED: Remove person to fresh air and keep comfortable for breathing. P305+P351+P338 IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses if present and easy to do -

Ethanol

Hydrochloric acid

Acetone phenylhydrazon e

Phosphoric acid

continue rinsing H225: Highly Flammable liquid and vapour H302: Harmful if swallowed H319: Causes serious eye irritation P309+P311 IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. P303+P361+P353 IF ON SKIN (or hair): Take off Immediately all contaminated clothing. Rinse SKIN with water [or shower] P305+P351+P338 IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses if present and easy to do continue rinsing P337+P313 IF eye irritation persists: Get medical advice/attention. P301+P312 IF SWALLOWED: call a POISON CENTER/doctor/... IF you feel unwell Very hazardous in case of skin contact (corrosive, irritant, permeator), of eye contact (irritant, corrosive), of ingestion. Slightly hazardous in case of inhalation (lung sensitizer). Non-corrosive for lungs. Liquid or spray mist may produce tissue damage particularly on mucous membranes of eyes, mouth and respiratory tract. Skin contact may produce burns. Eye Contact: Check for and remove any contact lenses. In case of contact, immediately flush eyes with plenty of water for at least 15 minutes. Cold water may be used. Get medical attention immediately. Skin Contact: In case of contact, immediately flush skin with plenty of water for at least 15 minutes while removing contaminated clothing and shoes. Cover the irritated skin with an emollient. Cold water may be used. Wash clothing before reuse. Thoroughly clean shoes before reuse. Get medical attention immediately. Inhalation: If inhaled, remove to fresh air. If not breathing, give artificial respiration. If breathing is difficult, give oxygen. Get medical attention immediately. Ingestion: If swallowed, do not induce vomiting unless directed to do so by medical personnel. Never give anything by mouth to an unconscious person. Loosen tight clothing such as a collar, tie, belt or waistband. Get medical attention immediately. If inhaled If breathed in, move person into fresh air. If not breathing, give artificial respiration. In case of skin contact: Wash off with soap and plenty of water. Consult medical assistant. In case of eye contact: Rinse thoroughly with plenty of water for at least 15 minutes If swallowed: Never give anything by mouth to an unconscious person. Rinse mouth with water. Consult a medical assistant. Very hazardous in case of skin contact (irritant), of eye contact (irritant), of ingestion. Hazardous in case of skin contact (corrosive, permeator), of eye contact (corrosive). Slightly hazardous in case of inhalation (lung sensitizer). Liquid or spray mist may produce tissue damage particularly on mucous membranes of eyes, mouth and respiratory tract. Skin contact may produce burns. Inhalation of the spray mist may produce severe irritation of respiratory tract, characterized by coughing, choking, or shortness of breath Eye Contact: Check for and remove any contact lenses. In case of

contact, immediately flush eyes with plenty of water for at least 15 minutes. Cold water may be used. Get medical attention immediately. Skin Contact: In case of contact, immediately flush skin with plenty of water for at least 15 minutes while removing contaminated clothing and shoes. Cover the irritated skin with an emollient. Cold water may be used. Wash clothing before reuse. Thoroughly clean shoes before reuse. Get medical attention immediately. Serious Skin Contact: Wash with a disinfectant soap and cover the contaminated skin with an anti-bacterial cream. Seek immediate medical attention. Inhalation: If inhaled, remove to fresh air. If not breathing, give artificial respiration. If breathing is difficult, give oxygen. Get medical attention immediately. Serious Inhalation: Evacuate the victim to a safe area as soon as possible. Loosen tight clothing such as a collar, tie, belt or waistband. If breathing is difficult, administer oxygen. If the victim is not breathing, perform mouth-to-mouth resuscitation. Ingestion: Do NOT induce vomiting unless directed to do so by medical personnel. Never give anything by mouth to an unconscious person. If large quantities of this material are swallowed, call a physician immediately. Loosen tight clothing such as a collar, tie, belt or waistband.

RESULTS AND CALCULATIONS

a) Synthesis of acetophenone phenylhydrazone Table 2: Results for synthesis of acetophenone phenylhydrazone Filter paper Filter paper + product Product Melting point

0.334 gram 0.485 gram 0.151 gram 120 °C

Equation for the reaction: C8H8O + C6H8N2

C14H14N2 + H2O

For Acetophenone, Mass =1.20g Molar mass =120.15 g/mol

No. of mole =

=

mass of substance molar mass 1.20 g 120.15 g/mol

=0.01 mol

For phenylhydrazine, Mass = 1.10g Molar mass = 108.14 g/mol

No. of mole =

=

mass of substance molar mass 1.1 g 108.14 g /mol

= 0.01 mol

∴Theoretical yield = 0.01 mol x Molar mass of acetophenone phenylhydrazone

= 0.01 mol x 210.28 g/mol = 2.1028 gram

Percentage yield =

0.151 g 2.1028 g/mol

x 100

= 7.18 %

b) Synthesis of 2-phenylindole Table 3: Results for synthesis of 2-phenylindole Filter paper Filter paper + product Product Melting point

0.337 gram 0.673 gram 0.336 gram 90 °C

Equation for the reaction: C14H14N2 + H3PO4 (catalyst)

C14H14N + NH3

For acetophenone phenylhydrazone, Mass =1.0g Molar mass = 210.28 g/mol

No. of mole =

=

mass of substance molar mass 1.0 g 210.28 g/mol

=0.005 mol

From the equation, 1 mol of C14H14N2 produces 1 mol of C14H14N Thus, 0.005 mol of C14H14N2 produces 0.005 mol of C14H14N ∴Theoretical yield = 0.005 mol x Molar mass of 2-phenylindole

= 0.005 mol x 193.25 g/mol = 0.966 gram

Percentage yield =

0.336 g 0.966 g /mol

x 100

= 34.78 %

Figure 2: IR spectrum for 2-phenylindole

Table 4: Functional groups that are present in the IR spectrum for 2-phenylindole (as in figure 2) Functional groups

Wavenumber (cm-1)

N-H C-H stretches C=C Benzene ring C=N C-N C-H bending R2C=CH2

3315.63 & 3400.50 2837.29, 2954.95 & 3055.24 1672.28 1446.61, 1490.97m& 1506.41 1597.06 1172.72, 1244.091296.16 & 1303.88 650.01 & 746.45 881.47 & 914.26

DISCUSSION Initially the reaction condition was optimized by the investigation of model reaction of phenyl hydrazine and acetophenone using glacial acetic acid in ethanol solvent at about 100°C for 15 minutes to obtain desired product which is acetophenone phenylhydrazone after it is filtered. The product then recrystallized from ethanol to obtain white crystalline solid with a percentage yield of 7.18%.

Figure 3: Structure of Acetophenone phenylhydrazone The melting point of acetophenone phenylhydrazine obtained experimentally is 120°C which was differ from its theoretical value (106°C). For the second synthesis, which is 2-phenylindole. With same reaction condition, the product of the first synthesis which is acetophenone phenyl hydrazine is used to synthesis 2phenylindole. It was mixed with the polyphosphoric acid as an acid catalyst.

Figure 4: Structure of 2-phenylindole The product obtained was in powder form of brown colour with a percentage yield of 34.78%. The melting point is 90°C which was also differ from the theoretical value (187°C). This is because the product obtained is not pure. It may contain soluble impurities which makes it melts at a lower temperature than the pure compound. Foreign substances that present in a crystalline solid disrupt the repeating pattern of forces that holds the solid together. So a smaller amount of energy is required to melt the part of the solid surrounding the impurity. Thus, the more impure the solid is, the more the structure is disrupted and the greater the variation in intermolecular forces in different areas of the solid.

For the reaction of this synthesis experiment, the mechanism begins with formation of a phenylhydrazone through the acid catalysed reaction of the hydrazine with the carbonyl. The phenylhydrazone then rearranges to the enamine and gets protonated on the phenyl nitrogen. An "ene reaction" (3, 3-sigmatropic rearrangement) ensues, resulting in a diimine and loss of aromaticity. Additional key steps include rearomatization, formation of a cyclic aminal, and the expulsion of ammonia to give the indole product: [1][2] Lastly, the IR spectrum of 2-phenylindole is obtained as shown in figure 2. Based on the spectrum, the functional group were interpreted as shown in table 2. Error might occurred for this part because as we can see the resolution of the spectrum is not quite good especially for the background. This occurrence of errors may be associated with errors originating from the sample and or instrumental errors. The apparatus might not well cleaned completely as it will give the contamination with the samples. It is important for use to be more careful and make the precaution while conducting the experiment to avoid undesirable errors. PRECAUTION 1. Make sure the KBr plates is cleaned with acetone to remove the moisture to avoid the low resolution of spectrum. 2. All the apparatus need to be cleaned completely in order to avoid any contamination with the samples. 3. Do not add acid into water. So much heat is released that the solution may boil very violently, splashing concentrated acid out of the container and all this because the reaction is exothermic. 4. Make sure the product is completely dry before running the sample with the IR spectroscopy because IR spectroscopy is very sensitive to the moisturisers. Moisture sample will affect the intensity of spectrum.

CONCLUSION

1. Fischer- Indole synthesis is the reaction between aryl hydrazone and an aldehyde or ketone in the presence of acid catalyzed at elevated temperature. Bronsted acids and Lewis acids are WERE used successfully as catalyst in this reaction. PAST TENSE! 2. Acetophenone phenylhydrazone was synthesized from phenylhydrazine and acetophenone with percentage yield of 7.18% and melting point of 120°C 3. Acetophenone phenylhydrazone is used to synthesis 2-phenylindole with percentage yield of 34.78% and melting point of 90°C

REFERENCES

1.

1. Fischer, E.; Jourdan, F. Ber. Dtsch. Chem. Ges. 1883, 16, 2241–2245. Ueber die Hydrazine der Brenztraubensäure.DOI: 10.1002/cber.188301602141 2. Klein D., Organic Chemistry, 6th Edition, Pearson: USA, 2012, pp 1043 3. “Table

of

IR

Absorptions”.

Retrieved

from

https://webspectra.chem.ucla.edu/irtable.html 4. “Infrared Spectroscopy”. Retrieved from https://chem.libretexts.org/Core/Physical_and_Theoretical_Chemistry/Spectroscopy/ Vibrational_Spectroscopy/Infrared_Spectroscopy QUESTION 1. Draw the mechanism for the reaction...