Exp't 15

Fisher Indole Synthesis of 2-Phenylindole

Adapted by Modi, Monarch, Perriello, Pohland, and Minard (PSU '92) from A.I. Vogel's Elementary Practical Organic Chemistry, Longman Group Ltd., London (1966).
Revised 4/9/01

Introduction:
Indoles are a very important class of heterocyclic compounds that play a major role in cell
physiology. The parent structure and three examples are:
H

CO2H
N H2

5 4

6 7

N H2

HO

CH3

H
Indole:
the parent heterocycle

H
L-Tryptophan:
an essential amino acid

N
Skatole: H
Responsible for the
unpleasant odor of feces.

H
Serotonin:
a potent vasoconstrictor

Indoles with various substituents in the 2 and 3 position can be synthesized via the Fisher indole
synthesis which involves two steps and utilizes a phenylhydrazine and an aliphatic or aromatic
aldehyde or ketone as starting materials. The synthesis of the 2-phenyl derivative prepared in this
experiment involves the reaction of phenylhydrazine with the ketone acetophenone to produce a
phenylhydrazone as shown in step 1 below. Cyclization with subsequent loss of one of the
nitrogens as ammonia is catalyzed by the addition of a strong acid as shown in step 2.
CH3
+
* N H2
CH3
N
H
O
acetophenone
phenylhydrazine

CH3

* N
N
H
acetophenone
phenylhydrazone

methanesulfonic
N

*
N
H
acetophenone
phenylhydrazone

acid

*
N

N H3

step 1

step 2

H
2-phenylindole
mp 188-189

Various acid catalysts, such as zinc chloride, sulfuric acid, boron trifluoride and polyphosphoric acid
have been used to catalyze the second reaction. However, a group of four Chem 36 honors
students (see citation above) tried methanesulfonic acid and found this to be an easy-to-handle
and quite effective acid catalyst.
Although Emil Fisher reported the discovery of this type of indole synthesis in 1883, it was not until
1943 that Allen and Wilson answered the fascinating mechanistic question: Which nitrogen in the
phenylhydrazone intermediate is spit out as ammonia? This was done by labeling the a nitrogen
of the phenylhydrazine with the stable isotope,15N, then carrying out the reaction and examining
the products for the presence of the 15N isotope. The result is shown above, i.e. the labeled
nitrogen (marked with an *) shows up in the indole product, so it is the b nitrogen that is expelled
as ammonia.

The most common use of 2-phenylindole is as a photoconductor in electrophotography.

Prelaboratory Exercises:
15N is not radioactive; how is its presence in a molecule determined?

Write an arrow-pushing mechanism for the formation of the hydrazone in step 1.

Cautions:
Phenylhydrazine is a suspected cancer-causing agent; therefore, gloves should be worn
whenever you are in contact with this compound. Methanesulfonic acid is very corrosive. Avoid
skin contact with these chemicals. If you should spill either on your skin wash immediately with
soap and water.
Synthesis:
Into a 4-mL reaction tube, place 0.56 g of acetophenone and 0.50 g of phenylhydrazine. Mix well
and heat this solution on a boiling water bath for one hour. Pour this phenylhydrazone intermediate
into a 25-mL Erlenmeyer flask containing 6.0g of methanesulfonic acid which has previously been
heated in a hot water bath for 10 min. Heat and stir with a stirring rod for an additional 10 min.
Isolation and Purification:
The hot reaction solution is added to 25 mL of ice/water and stirred. The 2-phenylindole is
insoluble in water and therefore will precipitate out. Collect the product by vacuum filtration using a
Hirsch funnel and wash the crystals several times with distilled water. After drying, obtain the
weight and melting point of the crude product. If you do not observe a melting point between 185
to 189C, recrystallize the solid from an ethanol/water mixed solvent system. Determine the final
weight and % yield and mp.
Cleaning Up:
Filtrates from the reaction can be disposed of by flushing down the drain with water.
Analysis:
Analyze your product by the method described in your experimental assignment sheet.
Final Report:
Write the structure and spectral interpretation on the spectrum. Give yields and mp's of crude and
recrystallized product. Answer this questions at the end of your report:
1. Indole is not as basic as an aliphatic amine. Explain why, based on indole's structure.
2. Read the short section in the Lab Guide (Chapter 3) on solvent pair recrystallization. What is a
solvent pair recrystallization, how was ethanol and water chosen, and suggest a second pair that
should work comparably well.

Synthetic Experiment PreLab Grading Sheet

Name(s):
TA:
Date:

PreLab For Exp't # 15

Fisher Indole Synthesis of 2-Phenylindole
Possible
Points

Date, Name, Desk #, Experiment # & Title(abbreviated after 1st pg), Section & TA
Name

Summary

Goals

Reactions, structures, conditions, diagrams

14

Completeness of Chemical Data Table(s)

14

Chromatographic Behavior Comparison

16

Spectral Features Comparison

12

Work-up - Explanation of the product isolation and purification process

12

PreLab Questions

12

TOTAL FOR PRELAB

Missed
Points

100

Date Handed in:

General Comments:

Total Points:

Synthetic Experiment Final Report Grading Sheet

Name:
TA:
Date:

Final Report For Exp't # 15

Fisher Indole Synthesis of 2-Phenylindole
Possible
Points

Name, Date, Experiment Title (abbreviated after 1st page) and every page numbered

OBSERVATION and DATA - Overall organization, readability, completeness

Data: Weighing data, molecular weights, moles, density, volumes, analysis

conditions. i.e. solvent for UV/Vis and wavelength range, weight of sample and
KBr for IR, or ionization mode for MS.

12

Yield: Show % yield calculations with limiting reagent clearly stated.

Purity: Record melting points, color, or other indicators of purity.

12

RESULTS AND DISCUSSION - Overall organization, readability, completeness

Results; Achievement of goals

Missed
Points

8
16

Product Analysis Data: Quality and Interpretation Structure(s) drawn on each

Spectrum or Chromatogram
Discussion of all UV/Vis lmax in terms of conjugation. Interpret all major MS
or IR peaks

24

See Lab Guide Chapter 3, Section 3.4 for guidelines in annotating spectra and
Ch 11 for help with interpretation.
POSTLAB QUESTIONS
TOTAL POINTS

16
100

Date Handed in:

General Comments:

Total Points:

Exp't 15