Surface-Active Quaternary Ammonium Germicides

257 Pages·1950·4.322 MB·English

by  Carl A. Lawrence (Auth.)

Surface-Active
Quaternary
Ammonium Germicides
By CARL A. LAWRENCE, PH.D.
Department of Bacteriology, University of Michigan Medical School,
Ann Arbor, Mich.; formerly of Winthrop-Stearns, Inc.,
Rensselaer, New York
1950
ACADEMIC PRESS INC., PUBLISHERS
NEW YORK
Copyright 1950, by
ACADEMIC PRESS INC.
125 EAST 23RD STREET, NEW YORK 10, N. Y.
All Rights Reserved
No part of this book may be reproduced in any
form, by photostat, microfilm, or any other means,
without written permission from the publishers.
PRINTED IN THE UNITED STATES OF AMERICA
FOREWORD
To the best of the author's knowledge no comprehensive review of
the entire field of quaternary ammonium surface-active germicides
exists in the literature. As he has worked in this field for the past
decade, he has found the need for such a compilation. This has not
only been reflected in his own work but also in comments and dis-
cussions with other investigators.
In preparing this review the writer is cognizant of the fact that
with the most careful scrutiny of the literature important publica-
tions on this subject may be overlooked and space limitations often
necessitate inadequate consideration of others. For this reason due
apologies are herewith made to authors of articles on quaternary
ammonium compounds of which inadequate or no mention is made
in this monograph. Comments and suggestions of the reader will be
welcome so that the present text can be kept up-to-date in future
editions.
The author is grateful to Drs. M. L. Tainter, C. M. Suter and
F. C. Nachod, of the Sterling-Winthrop Research Institute, for their
helpful comments and suggestions in preparing this monograph.
CARL A. LAWRENCE
V
1. Introduction
The quaternary ammonium surface-active antiseptics have se-
cured a prominent and important place in the fields of medicinal
and general disinfection during the past decade. These compounds
are of particular interest in that, unlike most other disinfectants,
they exhibit not only germicidal action but also surface-active, de-
tergent, and wetting properties.
Jacobs, Heidelberger, and their co-workers at the Rockefeller In-
stitute reported as early as 1916 on the bactericidal properties of a
large number of quaternary ammonium salts of hexamethylenetetra-
mine. However, almost 20 years elapsed before any further signifi-
cant contributions to this field were published. It remained for
Domagk (1935) to focus attention on surface-active quaternary am-
monium compounds as germicides and antiseptics.
The number of publications on the clinical use of alkyldimethyl-
benzylammoniuma chloride, soon after Domagk's initial paper, and
the extensive series of publications through the intervening years
on this and related compounds exemplify the important role the
quaternary ammonium salts play in the search for an ideal anti-
septic.
The purpose of this monograph is to accumulate in the pages of
one volume a review of the history, chemistry, biology, and applica-
tion of the quaternary ammonium salts that have appeared in print
to date.
2. Historical
Probably no other investigator or group of investigators has made
a more thorough study of the chemistry and bacteriology of a single
series of quaternary ammonium salts than the Jacobs group at the
Rockefeller Institute. The synthesis and chemistry of approximately
200 hexamethylenetetraminium salts were described by them in the
first group of eight publications.
While most of the current reviews on the quaternary ammonium
antiseptics tend to indicate that the Jacobs papers were the original
contributions on these salts, reference is made in one of their pub-
a See page 198 for trade names and distributors.
1
1. Introduction
The quaternary ammonium surface-active antiseptics have se-
cured a prominent and important place in the fields of medicinal
and general disinfection during the past decade. These compounds
are of particular interest in that, unlike most other disinfectants,
they exhibit not only germicidal action but also surface-active, de-
tergent, and wetting properties.
Jacobs, Heidelberger, and their co-workers at the Rockefeller In-
stitute reported as early as 1916 on the bactericidal properties of a
large number of quaternary ammonium salts of hexamethylenetetra-
mine. However, almost 20 years elapsed before any further signifi-
cant contributions to this field were published. It remained for
Domagk (1935) to focus attention on surface-active quaternary am-
monium compounds as germicides and antiseptics.
The number of publications on the clinical use of alkyldimethyl-
benzylammoniuma chloride, soon after Domagk's initial paper, and
the extensive series of publications through the intervening years
on this and related compounds exemplify the important role the
quaternary ammonium salts play in the search for an ideal anti-
septic.
The purpose of this monograph is to accumulate in the pages of
one volume a review of the history, chemistry, biology, and applica-
tion of the quaternary ammonium salts that have appeared in print
to date.
2. Historical
Probably no other investigator or group of investigators has made
a more thorough study of the chemistry and bacteriology of a single
series of quaternary ammonium salts than the Jacobs group at the
Rockefeller Institute. The synthesis and chemistry of approximately
200 hexamethylenetetraminium salts were described by them in the
first group of eight publications.
While most of the current reviews on the quaternary ammonium
antiseptics tend to indicate that the Jacobs papers were the original
contributions on these salts, reference is made in one of their pub-
a See page 198 for trade names and distributors.
1
2 SURFACE-ACTIVE QUATERNARY AMMONIUM GERMICIDES
lications to earlier studies on these compounds as follows: "The
preparation of quaternary salts by the addition of hexamethylene-
tetramme to halogen ketones has already been the subject of a
study by Mannich and Hahn (1911)x who used these substances as
the starting preparation of a few aminoketones according to the
method of Delepine (1897) ."2 Reference may also be made at this
point to the early publication of Reychler (1913)3 who described the
synthesis and colloidal properties of cetyltriethylammonium iodide.
A review of the first series of papers by Jacobs and Heidelber-
ger4-11 failed to reveal any evidence that the hexamethylenetetramine
salts had been tested for antiseptic or germicidal action. Neverthe-
less, in subsequent publications1214 by these authors and their co-
workers, in which additional derivatives were synthesized on the
hexamethylenetetramine nucleus, details of the bacteriology as well
as the chemistry of these compounds were given. The authors again
acknowledge an earlier publication relative to their investigations
as follows : "Our attention was attracted first to this group of sub-
stances by the powerful bactericidal properties of the simplest rep-
resentative, that obtained by the addition of hexamethylenetetra-
mine to chloroacetylaminomethanol.
HO—CH NHCOCH (CH N)
2 2 6 12 4
</
The compound was first prepared by Einhorn and Göttler (1908) 15
who also recognized its antiseptic properties." While this publica-
tion first suggests that a quaternary ammonium compound may
have antibacterial properties, an article by Einhorn and his co-
workers in 190516 makes mention of the pharmacological·action and
effects of hexamethylenetetramine upon fungi.
It is apparent, therefore, that contrary to the statement made by
McCulloch, Hauge, and Migaki17 that the discovery of the quater-
nary ammonium germicides originated from Jacobs and his co-
workers, the latter authors themselves acknowledge that the pri-
ority of their description belongs to European investigators.
The extensive and classical studies on the relationship of chemical
structure to antibacterial activities of the hexamethylenetetramin-
ium salts, described in the Jacobs papers, apparently failed to arouse
any interest in their use as antiseptics by other investigators. This
may be inferred from the failure of the literature of the following
years to reveal any evidence that the more active compounds were
used as medicinals or general disinfectants. Almost 20 years elapsed
HISTORICAL 3
before any further significant contributions were made to studies
on germicidal quaternary ammonium compounds.
While Hartmann and Kagi1819 described the synthesis and referred
to the antibacterial action of quaternary ammonium compounds in
1928 and 1929, beyond doubt the greatest contribution to the present-
day use of surface active quaternary ammonium salts as germicides
aiid antiseptics was made by Domagk2021 in 1935, who focused at-
tention on the high antibacterial activity of alkyldimethylbenzyl-
ammonium chloride solutions. This is evident from 25 or more
publications that appeared in foreign journals in the same and
following year on the successful use of the compound in surgical
procedures.
One of the earliest publications on the use of alkyldimethylbenzyl-
ammonium chlorides as antiseptics in this country was made by
Dunn in 1936.22 The number of papers that have been published on
the latter and related groups of compounds since that date is evi-
dence of the important part that the quaternary ammonium com-
pounds play in the field of antisepsis.
Preparations of most of the quaternary ammonium compounds
that have been described during the past several years consist mainly
of variations of substituents attached to the nitrogen nucleus. These
new derivatives include the following: (a) cyclic amines, pyridine,
picoline, lutidine, etc., of the type cetylpyridinium chloride (Shelton
et αΖ.23'24'25·26·27) ; (b) compounds in which two long-chain alkyl rad-
icals (C to Ci ) are introduced on the nitrogen atom to give a series
4 6
of dialkylmethylbenzylammonium chlorides (Kuhn, Jerchel, and
Westphal;28 Kolloff, Wyss, Himelick, and Mantele29) ; (c) those com-
pounds in which amide linkages are introduced in the long chain
giving rise to compounds of the type Af-Oauric acid ester of colam-
inoformylmethyl)pyridinium chloride (Epstein, Harris, and Katz-
mann30'31'32) ; (d) compounds containing an aromatic ring in the
long chain of the type p-tertiaryoctylphenoxyethoxyethyldimethyl-
benzylammonium chloride monohydrate (Rawlins, Sweet, and
Joslyn33) ; and (e) compounds containing unsaturated links in
the long-chain alkyl groups of the type 9-octadecenyldimethylben-
zylammonium chlorideb (Valko and DuBois34). Some compounds,
however, have been described in which the benzene ring has been
substituted by chlorine or nitro groups. They will be discussed later.
The early application of the surface-active quaternary ammonium
compounds (alkyldimethylbenzylammonium chlorides) was in sur-
gical procedures. This included not only sterilizing or cleansing the
b See page 198 for trade names and distributors.
4 SURFACE-ACTIVE QUATERNARY AMMONIUM GERMICIDES
operative field for surgery but scrubbing the surgeon's hands and
arms to destroy organisms. With the evidence that was accumulated
on the high germicidal action of the compounds against pathogenic,
as well as nonpathogenic bacteria, consideration was given to their
application as a general disinfectant. At the present time some of
the surface-active germicides are being employed in many food in-
dustries such as fisheries, bakeries, cold storage warehouses, egg-
breaking, dehydrating, dairy, and pasteurizing plants. Three of the
compounds are listed in New and Nonofficial Remedies, 1949 and one
(alkyldimethylbenzylammonium chloride) appears in the Xlllth
edition of the United States Pharmacopoeia under the name Ben-
zalkonium Chloride.
3. Definition
The surface-active quaternary ammonium compounds have fre-
quently been designated in the literature as "cationic detergents,"
or "cationic wetting agents." In general, the quaternary ammonium
germicides marketed today materially lower the surface tension of
water, and thus are surface-active agents. Surface agents may have
both a wetting action and a detergent action. These terms are not
synonymous ; it is entirely possible for a surface agent to have good
wetting and poor detergent properties, or vice versa. Most of the
present quaternary ammonium germicides have relatively good wet-
ting action and relatively poor detergent action. Many investigators
today object to the use of the term "cationic detergents" in describ-
ing the surface-active quaternary ammonium antiseptics. However,
in order to justify references which have already been cited in the
literature on these compounds, the expression will be used when
reviewing these publications.
The term "quaternary ammonium" represents one of four possi-
ble classes of organic nitrogen compounds that may be derived from
ammonia The first three types are obtained by replacing the
three primary valences on the N atom while the fourth type is
concerned with its additional co-valent bond. By replacing one of
the hydrogens on ammonia with an alkyl group, i.e., methyl (CH ),
3
ethyl (C H ), dodecyl (Οι Η ), etc., a primary amine is obtained
2 5 2 25
Replacement of two hydrogens by alkyl groups results in a
4 SURFACE-ACTIVE QUATERNARY AMMONIUM GERMICIDES
operative field for surgery but scrubbing the surgeon's hands and
arms to destroy organisms. With the evidence that was accumulated
on the high germicidal action of the compounds against pathogenic,
as well as nonpathogenic bacteria, consideration was given to their
application as a general disinfectant. At the present time some of
the surface-active germicides are being employed in many food in-
dustries such as fisheries, bakeries, cold storage warehouses, egg-
breaking, dehydrating, dairy, and pasteurizing plants. Three of the
compounds are listed in New and Nonofficial Remedies, 1949 and one
(alkyldimethylbenzylammonium chloride) appears in the Xlllth
edition of the United States Pharmacopoeia under the name Ben-
zalkonium Chloride.
3. Definition
The surface-active quaternary ammonium compounds have fre-
quently been designated in the literature as "cationic detergents,"
or "cationic wetting agents." In general, the quaternary ammonium
germicides marketed today materially lower the surface tension of
water, and thus are surface-active agents. Surface agents may have
both a wetting action and a detergent action. These terms are not
synonymous ; it is entirely possible for a surface agent to have good
wetting and poor detergent properties, or vice versa. Most of the
present quaternary ammonium germicides have relatively good wet-
ting action and relatively poor detergent action. Many investigators
today object to the use of the term "cationic detergents" in describ-
ing the surface-active quaternary ammonium antiseptics. However,
in order to justify references which have already been cited in the
literature on these compounds, the expression will be used when
reviewing these publications.
The term "quaternary ammonium" represents one of four possi-
ble classes of organic nitrogen compounds that may be derived from
ammonia The first three types are obtained by replacing the
three primary valences on the N atom while the fourth type is
concerned with its additional co-valent bond. By replacing one of
the hydrogens on ammonia with an alkyl group, i.e., methyl (CH ),
3
ethyl (C H ), dodecyl (Οι Η ), etc., a primary amine is obtained
2 5 2 25
Replacement of two hydrogens by alkyl groups results in a
CHEMISTRY 5
R
secondary amine (N—R). A tertiary amine is formed by substituting
three alkyl groups in the position held by the three hydrogens on
R
the molecule (N—R).
\
R
In the three classes of amines mentioned, the nitrogen has a
valence of 3. However, a fourth amine is possible where the nitrogen
has a co-valence of 5, or where five atoms may be considered as per-
taining to the nitrogen nucleus. These compounds are then desig-
nated "quaternary ammonium,, and are of the following general
configuration :
[R/ NN—RJ 4 x-
where X represents a halogen, hydroxyl, or alkoxy radical. The lat-
ter are ions and satisfy the "5th valence." They are "bound" differ-
ently from the remainder of the atoms in the molecule in that they
assume a negative electric charge.
Surface-active agents may be classified as (1) nonionic; or (2)
ionic. The ionic class may be subdivided as (a) cationic, in which
the lipophilic (oil attracting) group becomes the cation ( + ) ; (b)
anionic, in which the lipophilic group becomes the anion ( —). The
surface-active quaternary ammonium compounds ionize in water
as cationic compounds in which the long-chain part of the molecule
is positively charged.
4. Chemistry
SYNTHESIS
1. The Quaternary Salts of Hexamethylenetetramine. In the in-
troductory paragraphs of the first of the series of the Jacobs and
Heidelberger papers3 on the quaternary hexamethylenetetraminium
salts are given the principal reasons for the interest of the authors
in synthesizing quaternary compounds on the hexamethylenetetra-
mine nucleus. The latter had been used, since its introduction in
medicine by Nicollaier in 1894, as an internal antiseptic. This action
was later believed to be due to the liberation from it of formalde-
hyde.