C. M. Dougherty, R. L.
Baumgarten,
A. Sweeney, Jr., Phthalimide, Anthranilic Acid, Benzyne
and E. Concepcion
Herbert H. Lehman College, CUNY
Bronx. New York 10468 An undergraduate organic laboratory sequence
Much current emphnsis in undrrgraduaw organic chemistry
Irc~urecuurses involves the discussion of theoretical, spectral,
and mechanistic problems. The integration of the lecture
material with the experimental work in the undergraduate
organic laboratory course is often a difficult task. We have
incorporated the following synthetic sequence (phthalic an-
hydride to phthalimide to anthranilic acid to methyl an-
thranilate or to 1,2,3,4-tetraphenylnaphthalene)in the stu-
dents' laboratory work to enhance their understanding of
amine chemistry. The reaction sequence outlined above can
he entered and exited at several points and the cost of the
reagents used is relatively low. The reactions involved are
interestine both for the theoretical, mechanistic, and synthetic
concepts,and the laboratory techniques that the students
learn while comoletinr! the svnthetic sequence. The conversion
of the reactant; into the series as examples of am-
monolysis, Hofmann degradation of amides, esterification,
diazotization, henzyne, and Diels-Alder reactions in the var-
ious steps in the sequence. Although the nmr spectra of the
compounds are all very similar, the ir spectra are quite in-
structive. The change in the carhonyl group absorption in
every compound can he followed easily. The change in the NH
region from a broad hand with only a very small doublet in
anthranilic acid (assigned to the predominance of the zwit-
terion structure NH3+) to a typical doublet in methyl an-
thranilate (assigned to pure primary amine) is easily oh-
served.
The first step in the reaction sequence, the conversion of
phthalic anhydride to phthalimide, illustrates a typical am-
monolysis reaction of an anhydride to an amide (imide). The
Gabriel phthalimide synthesis is an excellent way to prepare
pure primary aliphatic amines.
The next stepin the reaction sequence, the conversion of
phthalimide to anthranilic acid, is an excellent example of a
Hofmann degradation of an amide to an amine, and also shows
the importance of p H adjustment in the precipitation of an-
thranilic acid, an amino acid, at its isoelectric point.
~ N H
A low yield of anthranilic acid is obtained if the p H is not
adjusted carefully prior to precipitation.
At this point in the procedure, the reaction sequence can
he divided in two distinct directions. One half of the laboratory
class can esterify the anthranilic acid into its methyl ester,
methyl anthranilate, which is a component of oil of hitter
oranges, grape juice, jasmine, and gardenias, and has an odor
in dilute solutions which recalls the fragrance of orange
blossoms. The ester shows a distinct blue fluorescence in the
ether solutions utilized in its isolation, and a vacuum distil-
lation can be used in its final purification.
0 0
.
II I
C-OCH,
H*
NH?
The other half of the class can convert the anthranilic acid
into 1,2,3,4-tetraphenylnaphthalene,a reaction which pro-
ceeds thru a transient henzyne intermediate. Anthranilic acid
is used as the precursor to generate the benzyne by conversion
in situ to a diazonium salt, which spontaneously loses carbon
dioxide and nitrogen, and in the presence of tetraphenylcy-
'Noyes, W. A., and Porter, P. K., Organic Synthesis, Coll. Vol. I,
457 (1932).
2The upper end of the glass rod should be inserted into a cork or
ruhher stopper. This precludes any untoward accidents caused by
dropping the stirring rod and breaking the bottom of flask while it
is being heated with the Bunsen burner.
Volume 54, Number 10, October 1977 / 643
clopentadienone is converted t o t h e Diels-Alder a d d u c t ,
1,2,3,4-tetraphenylnaphthalene.
o r n 1
T h e reaction can he followed very easily since t h e reaction
mixture changes from a purple solution to a yellow-orange
solution when t h e t r a p is completely exhausted (similar t o a
titration reaction at t h e endpoint). T h e purificatiqn utilizes
trituration, a seemingly forgotten technique, h u t one which
is still very useful.
Experimental
Phthalimide ' Methyl Anthranilateg
Place 50 g of phthalic anhydride and 45 ml of coned ammonium
hydroxide in a 500-ml round bottom flask (Pyrex!) Fit the flask with
an sir condenser (10 mm minimum i.d.1, then heat with a Bunsen
hurner until the mixture is in a state of quiet fusion (temperature
-:UWC). It requires-1 hr toevaporate all the water andanother hour
before the mixture reaches 300°C. Shake the flask occasionally during
the heating, and push down with a glass rod2 any material which
sublimes into the condenser. Pour the hat reactipn mixture into a
clean porcelain evaporating dish, cover with a piece of white paper
to orevent lass bv sublimation. and allow to cad. Grind the cake of
material obtained and storeuntil ready far the next reaction. The yield
of p h t h a l i ~ i d eshould be 40-47 g; mp 232-235'C (lit.' 238°C); ir (PI:
2.7 (modelate);5.55-5.7 (strong); 7.2-7.6 (moderate);9.5 (weak); 11.0
(strong); in CH2CI2;nmr (6): 2.18, singlet, 4H; 7.70-8.18, multiplet,
1H in CDaCN.
Anthranilic AcidJ
Dissolve 16.8 gof NaOH in 50 ml ofwater in a 500-ml Erlenmeyer
flask and cool in an ice-salt bath until the temperatureis about 10°C.
Add 250 ml of Chlaroxe (sodium hypochlorite)'and coal to below 5%.
Prepare a solution of 22 g of NaOH in 80 ml ofwater and cool to below
20'C. Add 24 gof finely powdered phthalimide in one portion t o the
cold, alkaline Chlorox solution, and swirl vigorously. Add the second
NaOH x,lution tc, the reaction mixture, swirl vigorously, and place
on the bench top. Place a thermometer in the flask to monitor tem-
perature. The solid should dissolve as the temperature rises slowly
to about 25%; the temperature then should rise rapidly to about
50°C. Heat the reaction to 80°C on a steam bath and maintain that
temperature for -3-5 mi". If any undissolved material is present in
the reaction mixture, filter a t this point. Cool the reaction mixture
in an ice bath, then add concd HCI slowly until thereaction mixture
is just slightly basie (wide range p H paper or a p H meter) (about 60
ml of' acid is required). Precipitate the anthfanilie acid by slowly
adding 25 ml of glacial acetic acid (Caution: reaction mixture tends
to foam a t this point). Collect the product an a Buchner funnel and
wash with small portions of very cold water until the odor of acetic
acid is no longer detectable. Air dry the solid until the next laboratory
period. The yield of anthranilic acid should he 12-17 g; mp 142-144T
(lit.V144-1459C)). If desired; the product can be decolorized
(NORIT) and recrystallized from water, but it issufficiently pure to
644 / Journal of Chemical Education
use in either of the following experiments without further purification.
IR ( r ) : 2.6 and 2.8 (weak); 3.2-3.4 (weak); 5.93 (strong); 6.1-6.4
(moderate); in CH&; nmr (6): 2.09-2.27, doublet, 1H, 2.55-2.88,
bmad singlet, 4H; 3.13-3.45, multiplet, 2H; in CDXCN.
1,2,3,4-Tetraphenylnaphthalenes
Dissolve 3.84 g of tetraphenylcyelopentedienone7in 30 ml of 1.2-
dimethaxyethane (monoglyme) and heat toreflux in a 100-ml round
bottom flask equipped with a condenser. Dissolve 1.5 gof anthranilic
acid in 15 ml of 1.2-dimethoxyethane; dissolve 2 ml of isamyl nitrite"
in 15 ml of 1,2-dimethoxyethane. Add these solutions simultaneously
by drops to the refluring reaction mixture aver aperiod of 45min. The
progress of the reaction can be monitored by the slow fading of the
deep purple color of the tetraphenylcyclopentadienone;when com-
pletely reacted, the reaction mixture will turn pale orange. Evaporate
the solvent by heating the reaction flask on a steam bath and simul-
taneously evacuating it on a water aspirator. Triturate the yellowish
residue with methanol; then isolate the product on a Hirsh or small
Buchner funnel. Recrystallize the product by dissolving the residue
in 20 ml of a 1:l mixture of dioxane:ethanol. Heat the solution to
boiling and add water by drops until a few crystals remain undis-
solved. Allow the product to crystallize a t room temperature before
final cooling (-1 hr) in an ice bath. The yield of 1,2,3,4-tetraphenyl-
naphthalene should be 3.5-4.1 g; mp 196-19g°C, remelt 203-204'C
(lit." 203-204°C); ir (P): 3.2 (weak);6.2 (weak); KBr pellet; nmr (6):
6.78 (singlet, 10 H); 7.18 (singlet, 10 H); 7.1-7.8 (multiplet, 4H); in
CCId.
until the p H is definitely basic. Transfer the reaction mixture to a
separatory funnel and extract the product into 3 X 100-ml portions
of ether. Wash the combined ether extracts twice with saturated NaCl
solution; then dry carefully over anhydrous NazS01. Filter, then distill
off the ether. The pure ester is isolated by vacuum distillation bp
140-142°C a t 20 mm (lit.g 127°C at 11 mm); yield 4-7 g; ir (PI: 2.6and
2.8 (moderate);3.2-3.4 (weak);5.8 (strong); 6.1-6.4 (strang);as a neat
liquid: nmr (6):3.72, singlet, 3H; 5.84, singlet, 2H; 6.30-6.70, multiplet,
2H; 6.95-7.25, multiplet, 1H: 7.65-7.90, multiplet, 1H; in CC14.
"The preparation described here was derived from that described
in Vogel, A. I., "A Textbook of Practical Organic Chemistry," 1948,
p. 733.
'One can prepare the sodium hypochlorite in situ by adding 12 g
of chlorine gas to a solution of 30 g of NaOH in about 80-100 ml of
water. This can be done conveniently by adding chlorine gas from a
tank to the NaOH solution until the weight of the solution increases
by 12 gas weighed on a balance. One can also substitute sodium hy-
pobromite (26.2 g of bromine in aqueous NaOH solution described
above) for sodium hypochlorite. We have chosen to use Chlorox" for
reasons of safety, economy, and purity of final product.
Wouben. J., "Die Methoden der Organichen Chemie," Dritte Au-
flage," 1944, p. 480.
Tieser, L. F., and Haddadin, M. J., Con. J. Chem., 43, 1599
119651.
(1955).
81soamyl nitrite is a powerful heart stimulant. The compound
should be used in a hood or in a room with goad ventilation.
T h i s preparation was derived from: Erdman, E., and Erdmsn, H.,
Chem Ber.. 32.1213 (18991.
general organic laboratory