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HE RELATION BETWEEN PHYSICAL PROPERTIES AND
PHYSIOLOGICAL ACTION OF CERTAIN
LOCAL ANESTHETICS
BY
CHARLES HEMAN PEET
A.B., Hope College, 1914
M.S., University of Illinois, 1921
AN ABSTRACT OF A THESIS
SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS
FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN CHEMISTRY
IN THE GRADUATE SCHOOL OF THE UNIVERSITY
OF ILLINOIS, 1923
URBANA, ILLINOIS





THE RELATION BETWEEN PHYSICAL PROPERTIES AND
- PHYSIOLOGICAL ACTION OF CERTAIN
LOCAL ANESTHETICS
BY
CHARLES HEMAN PEET
A.B., Hope College, 1914
M.S., University of Illinois, 1921
AN ABSTRACT OF A THESIS -
SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS
* FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN CHEMISTRY
IN THE GRADUATE SCHOOL OF THE UNIVERSITY
OF ILLINOIS, 1923
URBANA, ILLINOIS
-2%./zz?
THE RELATION BETWEEN PHYSICAL PROPERTIES AND
e PHYSIOLOGICAL ACTION OF CERTAIN LOCAL"
A.NESTHETICS
The most commonly accepted theories regarding the causation of
anesthesia have been proposed by Overton' and Meyer” and by
Traube” but neither theory has been tested against an extended
homologous series. Accordingly such a test was planned using an
extensive series with established anesthetic properties and the series
chosen was the dialkaminoalkyl p-aminobenzoates. -
The Overton-Meyer hypothesis, although it may satisfactorily
explain ether or chloroform anesthesia, did not appear applicable to
such anesthetics as these because the lipoid solubility of their hydro-
chlorides would be too low to give a significant ratio and if the amino
ester exists free in the alkaline body fluids, the water solubility would
be so low that the partition coefficient would approach infinity. This
criticism was verified by Burnett” and Jenkins.”
Traube's theory seemed more applicable to the anesthetics under
consideration. If the direction of the surface energy effect of the
anesthetic is such as to decrease the surface tension of its solution,
the surface concentration of anesthetic must increase in accordance
with the Gibbs equation, since the effect of local anesthetics is un-
questionably produced through action upon cells, it follows that that
substance which is present in maximum concentration at the cell
boundary must be most effective. But the cell boundary is at the
surface of the anesthetic solution where the anesthetic is at maximum
concentration. Agreement between surface tension lowering and
physiological effects would confirm the validity of this theory, at least
with regard to the series under consideration.
Since the body fluids are alkaline, that fact should be related to
the action of the anesthetics in the body and accordingly the surface
tension changes in KH,PO,-NaOH buffer solution of pH 7.4 produced
by the hydrochlorides of the esters under consideration were meas-
ured by the simple and accurate drop number method.
The surface tension curves thus obtained accorded with the
physiological data and brought out the somewhat surprising fact
that esters with a beta nitrogen were more active than those with a
gamma nitrogen. This may be due to their differing basicities.
Drop Numbers of Ester Hydrochlorides at 20°C.
co. Ester co. of
Sol. in Buffer
Water only Sol.
A B
50.4 .......
& e º ſº tº º e 50.8
51.2 51.5
52.1 51.8
50.7 51.6
& C G & & © tº 51.1
49.9 50.2
Key
Ester
Drop Numbers of
C
D
beta-Dimethylaminoethyl p-Aminobenzoate
gamma-Dimethylaminopropyl p-Aminobenzoate
beta-Diisoamylaminoethyl p-Aminobenzoate
beta-Diamylaminoethyl p-Aminobenzoate
gamma-Diisoamylaminopropyl p-Aminobenzoate
0 100
20 80
40 60
70 30
80 20
90 10
95 5
100 0
Symbol
A.
B
C
D
E
F.
gamma-Diamylaminopropyl p-Aminobenzoate
Conc. Used
.05 M
.05 M
.0005 M
.0005 M
.0005 M
.0005 M
Experimental Part e
Beta-Dimethylaminoethyl p-Aminobenzoate Monohydrochloride
This ester was made by the method of Einhorn and the constants
recorded by him were verified.
Gamma-Dimethylaminopropyl p-Aminobenzoate Monohydrochloride
The Hofmann condensation of dimethyl amine with trimethylene
chlorohydrine yielded gamma-dimethyl amino propanol, a colorless
liquid boiling at 163°. This alcohol was condensed with p-nitro-
benzoyl chloride in benzene yielding gamma-dimethylaminopropyl
p-nitrobenzoate hydrochloride, m.p. 161°. This ester was reduced
with platinum and dimethylaminopropyl p-aminobenzoate mono-
hydrochloride, m.p. 164-165°, was obtained. -
This ester was also made by condensing dimethylamine with
gamma-chloropropyl p-nitrobenzoate and reducing with iron. The
nitro ester was stirred into a paste with water and powdered iron,
the reduction mixture was made decidedly acid with tartaric acid,
filtered, the filtrate made alkaline, the ester extracted with ether, this
solution dried, the ether evaporated off, the ester taken up in abso-
lute alcohol and titrated with hydrochloric acid until neutral to
litmus, yielding the amino ester salt.
Beta-Diisoamylaminoethyl p-Aminobenzoate Monohydrochloride
Diisoamylamine was condensed with beta-chloroethyl p-nitro-
benzoate and the nitro ester was extracted with ether yielding a thick
oil. This ester was reduced with iron, the amino ester was extracted
with alcohol from which it was thrown out by dilute sodium hydrox-
ide, taken up in ether, dried, thrown out by dry hydrochloric acid,
taken up in water and titrated with sodium hydroxide until neutral
to litmus. The monohydrochloride thus obtained melted at 152-152.5°.
Gamma-Diisoamylaminopropyl p-Aminobenzoate Monohydrochloride
Trimethylene chlorohydrin was condensed with diisoamylamine
to yield diisoamylaminopropanol. This alcohol was esterified with
p-nitrobenzoyl chloride in benzene to yield oily nitro ester. This nitro
ester reduced with iron as described above yielded the amino ester
monohydrochloride, m.p. 172-172.5°. The dihydrochloride melted at
194-195°.
*
Beta-Diºn-amylaminoethyl p-Aminobenzoate Monohydrochloride.
The hydrolysis of p-nitrosodiamyl aniline proved unsatisfactory
so amyl bromide was condensed with amylamine to yield of diamyl-
amine. The secondary amine was condensed with ethylene oxide to
give beta-diamylaminoethanol. A similar condensation between the
amine and ethylenechlorohydrin yielded the alcohol. This alcohol
was esterified with p-nitrobenzoyl chloride in benzene and the result-
ing ester was reduced with iron as described above. The monohydro-
chloride of the amino ester melts at 154°.
Gamma-Diamylaminopropyl p-Aminobenzoate Monohydrochloride
Diamylamine was condensed with trimethylene chlorohydrin to
obtain gamma-diamylaminopropanol. This alcohol was esterified with
p-nitrobenzoyl chloride in benzene and the oily nitro ester resulting
was reduced with iron to yield the dihydrochloride of the amino ester,
m.p. 193-194°. This dihydrochloride was titrated back to yield the
monohydrochloride, m.p. 137°.
Summary
In order to investigate a possible correlation between their sur-
face tension effects in dilute solutions and their anestheticities, a
series of methyl, isoamyl and amyl alkamino esters of p-aminobenzoic
acid were synthesized. It developed that those compounds causing
the greatest decrease in surface tension were most anesthetic and that
it made no considerable difference whether the alkyl groups were
normal or forked.
BIBLIOGRAPHY
*Overton, “Studien ueber die-Narkose,” Gustave Fischer, Jena, 1901.
“Meyer, Arch. Exp. Path. Pharm., 42, 109 (1899). -
*Traube, Biochem. Zeit. 10, 371 (1908); 24, 323 (1910); 42, 560 (1912);
Arch. Ges. Phys., 140, 109 (1911); 160, 501 (1915).
*Burnett, Doctor's Thesis, Univ. of Ill. (1923). -
“Jenkins, Doctor's Thesis, Univ. of Ill. (1923).
VITA
The writer was born at Jamestown, Michigan, Oc-
tober 12, 1892. He received his elementary and
secondary education in the schools of Grand Rapids,
Michigan. In 1910 he entered Hope College, and was
granted the degree of Bachelor of Arts from that in-
stitution in 1974. After teaching in high school for
almost four years, he entered the service during the
World War. He came to the University of Illinois
in February, 1920, and was granted the degree of
Master of Science in June, 1921. During the years
1920-1922 he was a graduate assistant in chemistry
in the University of Illinois.
UNIVERSITY OF MICHIGAN
3 9015 08038 3303
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