By SAMUEL P. SADTLER, Ph.D.
[Footnote: Introductory lecture, Course of 1883-84, Philadelphia College
of Pharmacy.]
The sciences of to-day present, as might be expected, a very different
aspect from the same branches of knowledge as they appeared fifty or
sixty years ago. It is not merely that the mass of observations in most
of these lines of study has enormously increased during this interval.
Were that all, the change could hardly be considered as an unmixed
benefit, because of the increased difficulty of assimilation of this
additional matter. Many would be the contradictions in the observations
and hopeless would be the task of bringing order out of such a chaos.
The advance in the several branches of knowledge has been largely one
resulting from improved methods of study, rather than one following
simply from diligence in the application of the old ways.
Let us turn to chemistry for our illustration of this. The chemistry of
the last century and the early decades of this was largely a descriptive
science, such as the natural history branches, zoology, and botany are
still in great part. Reasonably exact mineral analyses were made, it is
true, but the laws of chemical combination and the fundamental
conceptions of atoms and molecules had not been as yet generally
established. Now, this want of comprehensive views of chemical
reactions, their why and wherefore, was bad enough as it affected the
study of inorganic and metallic compounds, but what must have been the
conditions for studying the complex compounds of carbon, so widely
spread in the vegetable and animal kingdoms. Their number is so enormous
that, in the absence of any established relationships, not much more
than a mere enumeration was possible for the student of this branch of
chemistry. It is only within the last twenty years that chemists have
attained to any comprehensive views at all in the domain of organic
chemistry. It has been found possible to gradually range most carbon
compounds under two categories, either as marsh-gas or as benzol
derivatives, as fatty compounds or as aromatic compounds. To do this,
methods of analysis very different from those used in mineral chemistry
had to be applied. The mere finding out of percentage composition tells
us little or nothing about an organic compound. What the elements are
that compose the compound is not to be found out. That can be told
beforehand with almost absolute certainty. What is wanted is to know how
the atoms of carbon, hydrogen, oxygen, and nitrogen are linked together,
for, strange to say, these differences of groupings, which may be found
to exist between these three or four elements, endow the compounds with
radically different properties and serve us as a basis of
classification.
The development of this part of chemistry, therefore, required very
different methods of research. Instead of at once destroying a compound
in order to learn of what elements it was composed, we submit it to a
course of treatment with reagents, which take it apart very gradually,
or modify it in the production of some related substance. In this way,
we are enabled to establish its relations with well defined classes and
to put it in its proper place. Of equal importance with the analytical
method of study, however, is the synthetical. This method of research,
as applied to organic compounds, embodies in it the highest triumphs of
modern chemistry. It has been most fruitful of results, both theoretical
and practical. Within recent years, hundreds of the products of
vegetable and animal life have been built up from simpler compounds.
Thousands of valuable dye-colors and other compounds used in the arts
attest its practical value. It may, therefore, seem anomalous when I say
that one of the most important of all the classes of organic compounds
has not shared in this advance. The alkaloids, that most important class
from a medical and pharmaceutical point of view, have until quite
recently been defined in the books simply as "vegetable bases,
containing nitrogen." Whether they were marsh-gas or benzol derivatives
was not made out; how the four elements, carbon, hydrogen, oxygen, and
nitrogen, were grouped together in them was absolutely a thing unknown.
Chemists all admitted two things--first, that their constitution was
very complex, and, second, that the synthesis of any of the more
important medicinal alkaloids would be an eminently desirable thing to
effect from every point of view. Within the last five years, however,
quite considerable progress has been made in arriving at a clearer
understanding of these most important compounds, and I shall offer to
your attention this evening a brief statement of what has been done and
what seems likely to be accomplished in the near future.
It was early recognized that the alkaloids were complex amines or
ammonia derivatives. The more or less strongly marked basic character of
these bodies, the presence of nitrogen as an essential element, and,
above all, the analogy shown to ammonia in the way these bases united
with acids to form salts, not by replacement of the hydrogen of the
acid, but by direct addition of acid and base, pointed unmistakably to
this constitution. But with this granted, the simplest alkaloid
formulas, those of conine, C_{8}H_{17}N, and nicotine,
C_{10}H_{14}N_{2}, still showed that the amine molecule contained quite
complex groups of carbon and hydrogen atoms, and the great majority of
the alkaloids--the non-volatile ones--contained groups in which the
three elements, carbon, hydrogen, and oxygen, all entered. Hence the
difficulty in acquiring a knowledge of the molecular structure of those
alkaloids at all comparable with that attained in the case of other
organic compounds. Of course synthesis could not be applied until
analysis had revealed something of the molecular grouping of these
compounds, so the action of different classes of reagents was tried upon
the alkaloids. Before summarizing the results of this study of the
decomposition and alteration products of the alkaloids, a brief
reference to a related class of organic compounds will be of assistance
to those unfamiliar with recent researches in this field.
It is well known that in coal-tar is found a series of ammonia-like
bases, aniline or amido-benzol, toluidine or amido-toluol, and xylidine
or amido-xylol, which are utilized practically in the manufacture of the
so-called aniline dye-colors. It is perhaps not so well known that there
are other series of bases found there too. The first of these is the
pyridine series, including _pyridine_, C_{5}H_{5}N, _picoline_
(methyl-pyridine), C_{5}H_{4}N(CH_{3}), _lutidine_ (dimethyl-pyridine),
C_{5}H_{5}N(CH_{3})_{2}, and _collidine_ (trimethyl-pyridine),
C_{5}H_{2}N(CH_{3})_{3}. This series is also found in relatively larger
proportion in what is known as Dippel's oil, the product of the dry
distillation of bones.
The second series is the quinoline series, including _quinoline_,
C_{9}H_{7}N, _lepidine_ (methyl-quinoline), C_{10}H_{9}N, and
_cryptidine_ (dimethyl-quinoline), C_{11}H_{11}N. The two compounds
which give name to these series, pyridine, C_{5}H_{5}N, and quinoline,
C_{9}H_{7}N, respectively, bear to each other a relation analogous to
that existing between benzol, C_{6}H_{6}, and naphthalene, C_{10}H_{8};
and the theory generally accepted by those chemists who have been
occupying themselves with these bases and their derivatives is that
pyridine is simply benzol, in which an atom of nitrogen replaces the
triad group, CH, and quinoline, the naphthalene molecule with a similar
change. Indeed, Ladenberg has recently succeeded in obtaining benzol as
an alteration product from pyridine, in certain reactions. Moreover,
from methyl-pyridine, C_{5}H_{4}N(CH_{3}), would be derived an acid know
as pyridine-carboxylic acid, C_{5}H_{4}N(COOH), just as benzoic acid,
C_{6}H_{5}COOH, is derived from methyl-benzol, C_{6}H_{5}CH_{3}, and
from dimethyl-pyridine, C_{5}H_{3}N(CH_{3})_{2}, an acid known as
pyridine-dicarboxylic acid, C_{5}H_{3}N(COOH)_{2}, just as phthalic
acid, C_{6}H_{4}(COOH)_{2}, is derived from dimethyl-benzol,
C_{6}H_{4}(CH_{3})_{2}. The same thing applies to quinoline as compared
to naphthalene.
We may now look at the question of the decomposing effect of reagents
upon the alkaloids. The means which have proved most efficacious in
decomposing these bases are the action of oxidizing and reducing agents,
of bromine, of organic iodides, of concentrated acids and alkalies, and
of heat.
Taking up the volatile alkaloids, we find with regard to _conine_,
first, that the action of methyl iodide shows it to be a secondary
amine, that is, it restrains only one replaceable hydrogen atom of the
original ammonia molecule. Its formula is therefore C_{8}H_{16}NH. From
conine can be prepared methyl-conine, which also occurs in nature, and
dimethyl-conine. From this latter has been gotten a hydrocarbon,
C_{8}H_{14}, conylene, homologous with acetylene, C_{2}H_{2}. Conine, on
oxidation, yields chiefly butyric acid, but among the products of
oxidation has been found the pyridine carboxylic acid before referred
to. The formula of conine, C_{8}H_{17}N, shows it to be homologous with
piperidine, C_{5}H_{11}N, a derivative of piperine, the alkaloid of
pepper, to be spoken of later; and, just as piperidine is derived from
pyridine by the action of reducing agents, so conine is probably derived
from a propyl-pyridine. The artificial alkaloid paraconine, isomeric
with the natural conine, will be referred to later.
_Nicotine_, C_{10}H_{14}N_{2}, the next simplest in formula of the
alkaloids, is a tertiary base, that is, contains no replaceable hydrogen
atoms in its molecule. It shows very close relations to pyridine. When
nicotine vapor is passed through a red-hot tube, it yields essentially
collidine, and, with this, some pyridine, picoline, lutidine, and gases
such as hydrogen, marsh-gas, and ethylene. Heated with bromine water to
120°C. it decomposes into bromoform, carbon dioxide, nitrogen, and
pyridine. When its alcoholic solution is treated with ferricyanide of
potassium it is oxidized to dipyridine, C_{10}H_{10}N_{2}. Potassium
permanganate, chromic or nitric acid oxidises it to nicotinic acid,
C_{6}H_{5}NO_{2}, which is simply pyridine-carboxylic acid,
C_{5}H_{4}N(COOH), and which, distilled over quick-lime, yields
pyridine, C_{5}H_{5}N.
Turning now to the non-volatile and oxygenized bases, we take up first
the opium alkaloids. _Morphine_, C_{17}H_{19}NO_{3}, is a tertiary
amine, and appears to contain a hydroxyl group like phenols, to which
class of bodies it has some analogies, as is shown in its reaction with
ferric chloride. Its meythl ester, which can be formed from it, is
_codeine_, one of the accompanying alkaloids of opium. Besides the
methyl derivative, however, others are possible, and several have been
recently prepared, giving rise to a class of artificial alkaloids known
as _codeines_. Morphine, rapidly distilled over zinc dust, yields
phenanthren, trimethyl-amine, pyrrol, pyridine, quinoline, and other
bases. The action of strong hydrocholoric acid upon morphine changes it
into apomorphine, C_{17}H_{17}NO_{2}, by the withdrawal of a molecule of
water. Ferricyanide of potassium and caustic soda solution change
morphine into oxidimorphine, C_{34}H_{36}N_{2}O_{6}. When heated with
strong potassium hydrate, it yields methylamine.
_Narcotine_, another of the opium alkaloids, when heated with manganese
dioxide and sulphuric acid, is oxidized and splits apart into opianic
acid, C_{10}H_{10}O_{5}, and cotarnine, C_{12}H_{13}NO_{3}. This latter,
by careful oxidation, yields apophyllenic acid, C_{8}H_{7}NO_{4}, and
this, on heating with hydrochloric acid to 240° C., yields
pyridine-dicarboxylic acid, C_{5}H_{9}N(COOH)_{2}. The base cotarnine
also results from the prolonged heating of narcotine with water alone.
In this case, instead of opianic acid, its reduction product meconine,
C_{10}H_{10}O_{4}, is produced.
_Meconic acid_, C_{7}H_{4}O_{7}, which is found in opium in combination
with the different bases, has also been investigated. By acting upon
meconic acid with ammonia, comenamic acid is formed, and this latter,
when heated with zinc dust, yields pyridine.
If we go now to the cinchona alkaloids, we meet with exceedingly
interesting results. _Quinine_, C_{20}H_{24}N_{2}O_{2}, when carefully
oxidized with chromic acid or potassium permanganate, yields a series of
products. First is formed quitenine, C_{19}H_{22}N_{2}O_{4}, a weak
base, then quininic acid, C_{11}H_{9}NO_{3}, then the so-called
oxycinchomeronic acid, C_{8}H_{5}N0_{6}, and finally cinchomeronic acid,
C_{7}H_{6}NO_{4}. Now the two acids last mentioned are simple
substitution products of pyridine, oxycinchomeronic acid being a
pyridine-dicarboxylic acid, C_{5}H_{2}N(COOH)_{3}, and cinchomeronic
acid, a pyridine-dicarboxylic acid, C_{5}H_{3}N(COOH)_{2}. When
distilled with potassium hydrate, quinine yields quinoline and its
homologues. The alkaloid has been shown to be a tertiary base.
_Quinidine_ yields with chromic acid the same decomposition products as
quinine.
_Cinchonine_, C_{19}H_{22}N_{2}O, the second most important alkaloid of
these barks, when oxidized with potassium permanganate, yields cinchonic
acid, which is a quinoline-carboxylic acid, C_{9}H_{6}N(COOH),
cinchomeronic acid, which has just been stated to be a pyridine
dicarboxylic acid, and a pyridine tricarboxylic acid. When cinchonine is
treated with potassium hydrate, it is decomposed into quinoline and a
solid body, which on further treatment yields a liquid base,
C_{7}H_{9}N, which is probably lutidine. It has been found, moreover,
that both tetrahydroquinoline and dihydroquinoline, hydrogen addition
products of quinoline, are present. When cinchonine is distilled with
solid potassium hydrate, it yields pyrrol and bases of both the pyridine
and quinoline series.
_Cinchonidine_, when heated with potassium hydrate, yields quinoline
also, and with nitric acid the same products as cinchonine.
_Strychnine_ has been found to be a tertiary amine. When distilled with
potassium hydrate, quinoline is formed.
_Brucine_ is a tertiary diamine, that is, formed by substitution in a
double ammonia molecule. When distilled with potassium hydrate it yields
quinoline, lutidine, and two isomeric collidines.
The alkaloid _atropine_ has been quite thoroughly studied with results
of great interest. When heated with baryta-water or hydrochloric acid,
it takes up a molecule of water and is split into tropine,
C_{8}H_{15}NO, and tropic acid, C_{9}H_{10}O_{3}. This latter is
phenyl-oxypropionic acid. Tropine, when heated to 180°C. with
concentrated hydrochloric acid, splits off a molecule of water, and
yields tropidine, C_{8}H_{13}N, a liquid base, with an odor resembling
conine. When this tropidine is heated with an excess of bromine, it
yields dibrompyridine.
_Piperine_, the alkaloid of pepper, has also been well studied. When
boiled with alcoholic potash solution, it takes up a molecule of water
and splits apart into piperic acid, C_{12}H_{10}O_{4}, and piperidine,
C_{5}H_{11}N. This latter base has been shown to be a hydrogen addition
product of pyridine, C_{5}H_{5}N. When heated with concentrated
sulphuric acid, it is oxidized to pyridine. Piperidine hydrochlorate,
also, when heated with excess of bromine to 180° C., yields
dibrompyridine.
_Sinapine_, the alkaloid which exists as sulphocyanate in white mustard
seed, yields, under the same reaction as that applied to atropine and
piperine, quite different results. When boiled with baryta water,
sinapine decomposes into sinapic acid, C_{11}H_{12}O_{5}, and choline,
C_{5}H_{15}NO_{2}, the latter a well-known constituent of the bile, and
produced also in the decomposition of the lecithin of the brain and yolk
of egg.
_Cocaine_, the alkaloid of coca leaves, is decomposed by heating with
hydrochloric acid into methyl alcohol, benzoic acid, and a crystalline
base, ecgonine, C_{9}H_{15}NO_{3}.
_Caffeine_ and _theobromine_ have also quite different relations.
Caffeine, it will be remembered, is the methyl ester of theobromine, and
can be prepared from it. When caffeine is carefully oxidized with
chlorine, it yields dimethyl-alloxan and methyl-urea. Both theobromine
and caffeine are decomposed by heating to 240° C. in sealed tubes with
hydrochloric acid, identical products being obtained. These products are
carbon dioxide, formic acid, ammonia, methyl-amine, and sarcosine, the
last three being of course in combination with the excess of
hydrochloric acid. The artificial preparation of theobromine and
caffeine from xanthine, and guanine also show clearly their relations.
If, having completed our survey of what has been done in the way of
decomposing the alkaloids by the different classes of reagents, we
review the field, it will be seen that with all the alkaloids mentioned,
except the last four, a more or less immediate connection with the
pyridine and quinoline bases has been indicated. The conviction
accordingly forces itself upon us that, if we want to attack the problem
of building up any of these important alkaloids artificially, we must
turn to these bases as our starting point.
As already stated, both series occur in coal-tar and the pyridine series
also more abundantly in bone-oil. Pyridine, picoline, lutidine, and
collidine, the first four members of the pyridine series, have,
moreover, all been formed synthetically, although the processes are not
such as would yield the products as cheaply as they can be gotten from
Dippel's oil. Quinoline, the first member of the higher series, had been
made synthetically by several chemists, but by expensive and involved
methods, when Skraup, in 1881, effected its synthesis from nitrobenzol
and glycerin, or still better, a mixture of nitrobenzol and aniline with
glycerin. This process allows of its being made on a commercial scale if
desirable. Shortly after, by an application of the same principle,
Dobner and Miller effected the synthesis of lepidine, the second member
of the quinoline series.
At the same time that this general agreement to consider these bases as
the starting point in the endeavor to effect the synthesis of the
natural alkaloids had been arrived at by chemists, it was thought well
to look into the question whether these bases and their immediate
derivatives had any therapeutic value of their own.
Piperidine, the decomposition product of piperine, which we have shown
may be considered to be hexahydropyridine, was examined by Dr.
Kronecker, of Berlin, at the request of Prof. Hofmann, and was found to
have an action upon animals in many respects resembling that of conine.
Prof. Filehne, of Erlangen, who has studied a large number of these
pyridine and quinoline derivatives, found, moreover, that the
hydrochlorate of ethyl-piperidine had a physiological action quite
analogous to that of conine.
The physiological action of quinoline itself has been studied quite
extensively by Donath and others, and it was found that several of its
salts were quite valuable febrifuges, acting very like quinine, and
capable in cases of being used as a substitute for it. In general, the
hydrogen addition products were found to be more active than the simple
base, an observation entirely in accord with the theory formed by
Wischnegradsky, and by Konigs, as the result of the study of the
decomposition products of the alkaloids, viz., the alkaloids are in
general hydrogen addition products of pyridine and quinoline, or of the
two bases combined. Thus Prof. Filehne found that hydrochlorate of
tetrahydroquinoline was much more energetic in its action than
quinoline, but could not be used on account of a too powerful local
effect. The hydrochlorate of dimethyl-tetrahydroquinoline, which was
distinguished by its strong bitter taste, much resembling that of
quinine, had an effect like that of curare poison. The most decided
febrifuge action, however was found by Prof. Filehne to reside in the
hydrochlorate of oxyhydro-methyl-quinoline, introduced to public notice
by Prof. O. Fischer under the name of "Kairin," and in the acid sulphate
of tetrahydro-methylquinoline, introduced under the name of "Kairolin."
These compounds had a very surprising febrifuge action, without any
unpleasant after effects or local disturbances.
The most active workers in the field of synthetic formation of the
alkaloids have been Wischnegradsky, of St. Petersburg--who,
unfortunately for science, died at an untimely age in 1880--Königs and
Fischer, of Munich, and Ladenburg, of Kiel. The study of the
decomposition products of the cinchona alkaloids especially points quite
distinctly to the probable existence in quinine of a hydrogen addition
product of pyridine, in combination with a methyl-quinoline group. The
many experiments that are now being made to test this and other
questions that suggest themselves, will not long leave us in the dark.
Whether a practical commercial synthesis of quinine will follow is
another matter, but it is within the bounds of possibility, or perhaps
even of probability.
It must not be supposed that no syntheses of alkaloids have been
effected as yet. By heating butyl-aldehyde with alcoholic ammonia is
formed _paraconine_, an alkaloid isomeric with the natural conine, but
differing in physiological action. By the action of sodium upon pyridine
is produced a compound C_{10}H_{8}N_{2}, known as dipyridyl, and this,
under the influence of nascent hydrogen, takes up six atoms and becomes
_isonicotine_ C_{10}H_{14}N_{2}, a physiologically active alkaloid,
isomeric with the true nicotine. The formation of a series of alkaloids
under the name of _codeines_, by the substitution of other organic
radicals instead of methyl in the codeine reaction, has already been
alluded to. _Atropine_ can be formed by uniting tropine and tropic acid,
the two decomposition products already noted. The latter of these
products is already shown to be capable of synthetical formation, and
the other will no doubt be formed in the same way. The artificial
atropine is identical with the natural alkaloid. Ladenburg has also
formed a series of artificial alkaloids, called _tropeines_, by uniting
the base tropine with different organic acids, as in the case of the
compound of mandelic acid and tropine, known as _homatropine_, an
alkaloid of action similar to atropine, but possessing some decided
advantages in its use. _Piperine_ has also been made by the uniting of
piperidine and piperic acid, and, as piperidine has already been formed
from pyridine, we have here a true synthesis also. Both _theobromine_
and _caffeine_, its methyl derivative, have been made from xanthine,
which itself can be formed from guanine, a constituent of guano.
We may conclude from this reference to what has been done in the last
few years, that the reproach mentioned in first speaking of the
alkaloids as a class, that almost nothing was known of their
constitution, will not long remain, and that as their molecular
structure is laid bare in these studies now being made, keen-sighted
chemists will effect their artificial formation. When these most
valuable compounds can be made by exact methods, in a state of entire
purity, and at a cost much below that paid for the present extraction of
them from relatively rare plants, organic chemistry will have placed all
of us under obligations as great as those owing any branch of science,
no matter how practical we call it.--_Amer. Jour. of Pharmacy_.
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