Table Of ContentChemistry of The MITRAGYNA GENUS
With a supplementary section on:
The Zerewitinoff Estimation of
Active Hydrogen Atoms
and
Additional papers on:
Urea Alkyl Sulphates
Alkyl iso-Ureas
Chemistry of the Mitragyna Genus (Part !)•
T H E S I S
for the Degree of
Doctor of Philosophy
of the
University of Glasgow
by
Patrick A • Ongley, B.A*, M.Sc.(N«Z*).
October, 1950*
ProQuest Number: 13850817
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Acknowledgments.
0
I wish to acknowledge my Indebtedness to my
supervisors, Dr. G.M. Badger, and Professor J.W. Cook,
P.R.S., without whose assistance and encouragement this
work would never have been completed. I have also to
thank sincerely Dr. S.T.R* Stotherd Mitchell for advice
on the measurements of optical activity and ultra-violet
spectra; Dr. Irene M. McAlpine for advice on the Zere-
witinoff estimation of active hydrogen atoms; and Miss
R.H. Kennaway and Mr. J.M.L* Cameron for micro-analyses•
The plant materials were obtained through the courtesy of
Sir John Simonsen, F.R-S*, Director of the Colonial
Products Research Council, and of the Chief Conservator of
Forests, Nigeria, and the bulk extractions were carried
out by Messrs. Duncan Flockhart, Ltd., Edinburgh* Drs.
E. Dyer, W* Klyne, and L.J. Sargent, Professors D. Karrer
and L. Ruzicka, M. Raymond-Hamet and Mrs. E. Stedman were
most generous with gifts of material for investigation and
of authentic specimens. Finally, I must thank sincerely
my many friends, both in Glasgow and elsewhere, for their
unfailing encouragement and most helpful advice.
Table of Contents.
Page
Foreward
Xntroduotion
Botanical Classification • •• ••• 1
Historical ... ... ... 4
Mitraphylline ... ... 5
Mitragynine ... ... 6
Mitraversine ... ... 12
Mitraspecine ... ... 13
Formosanine ••• ••• 14
Hanadamine ... ... - 14
Isorhynchophylline ... ... 14
Gambirine ... ... 15
Rotundifoline ... ... 15
Mitragynol .... ... 16
Rh.ynchoph.yl line ... ... 16
Occurrence of Alkaloids in the Various Species of
Mitragyna and Ourouparia ... ... 18
Discussion ... ... ... 19
Isolation and Identification of Material 19
Quinovic Acid ... ... 19
• -Sitosterol ... ... 22
Alkaloids ... ... 23
Apparatus ... ... 23
Methods ... ... 23
Variability of Alkaloid Content of the Same
Material ... ... 24
The Alkaloids of M.cilia.ta ... 27
d and 1-Mitraphylline T.. ... 27
Properties of the Individual Alkaloids 29
Mitraphylline ... ... 29
Mitragynine ... ... 32
Mitraversine ... ... 33
Formosanine ... ... 34
Rotundifoline ... ... 34
Mitragynol ... ... 36
Rhynchophylline ... ... 50
General Chemistry • • • ..• 58
Specific Rotation ••• • •• 58
Ultra-Violet Spectra ... ... 59
Fluorescence ... ... 63
Colour Reactions ... ... 63
Function of the Nitrogen Atoms 72
Nature of the Oxygen Atoms 72
Ester Groups ... ... 74
Uncharacterised Oxygen Atoms 77
Active Hydrogen Atoms ... ... 81
Hydrogenation ... ... 84
Possible Skeletal Structure of the Alkaloids 84
Possible Heterocyclic Nuclei ••• 84
Pyridine _ ... ... 84
Quinoline and isoquinoline .•. 85
Indole ... • • • 85
Possible Skeletal Structures ... 86
Erythrine Alkaloids ... ... 86
Physostigma u ... ... 87
Ergot , ... ... 87
Calycanthe " ... ... 88
Evodia n ... ... 88
Strychnos u ... ... 89
Pseudocinchona n ... ... 89
Gelsemium n ... ... 92
92
lohimoeJ' " ... ... 92
Possible New Type of Skeletal Formula 93
Possible Future Work ... ... 94
Conclusion ... ... ... 97
Experimental ... * ... ... 98
Extraction and Purification of Products 98
Quinovic Acid ... ... 98
-Sitosterol ... ... 100
■3
Alkaloids ... ... 102
Apparatus ... ... 102
Trial Extractions ... ... 103
Extraction of Alkaloids from Various Plant
Materials ... ... 104
Page
Chemistry of Individual Alkaloids ... 109
Mit raphy lline • •• • • • 109
Mitragynine • • • • • • 123
Mitraversine 133
• • • • • •
Formosanine • • • • • • 134
Rotundifoline 137
Mitragynol • • • • • • 14 5
Rhynchophy11ine ... 157
Conclusion ... .. * 163
References 164
The Zerewitinoff Estimation of Active Hydrogen Atoms.
Introduction ••• • tt 172
Historical ... ... • • 173
•
Methods ... ... • 173
• •
Reagents ... ... • • 173
•
Solvents ... ... • • 174
♦
Temperatures ... ... • • 178
•
Results Obtained ... ... • • • 178
Discussion of Present Investigation ♦ • • 181
Methods ... ... ♦ • 181
•
Results ... ... • • • 182
Conclusion ... ... • • • 193
Experimental ... ... • • • 194
Method ... ... • • • 194
Reagents ... ... • • • 194
Apparatus ... ... • # • 195
Results ... ... • # i 196
References ... ... • • • 205
Summary.
Previous work on the Mitragyna alkaloids was largely
haphazard, and very little attempt had been made to correlate
the known properties. The first task in this investigation,
therefore, was to do this. The properties of mitragynine,
mitragynol, mitraphylline, rhynchophylline, and rotundi-
foline^ and of formosanine, from a species of the closely-
related genus Ourouparia, have now been more completely
examined.
Concerning the occurrence of the alkaloids, several
interesting results were encountered. There has been con
troversy as to whether or not mitrinermine from M. inermis
and “rhynchophylline,f from 0 .rhynchophylla are the same
alkaloid. It has now been shown conclusively that they
are the same. The hitherto unknown d-form of mitraphylline
has been found in the bark of M.rubrostipulacea, and in
M.ciliata, previously uninvestigated^ notundifoline has
been found in the leaves, and rhynchophylline in the bark.
," -sitosterol has been identified in the bark of M.inermis,
and quinovic acid in the bark and leaves of various
Mitragyna species.
As far as functional groups are concerned, it is now
known that the alkaloids contain no II-methyl groups, but are
methyl esters and often contain additional methoxyl groups.
Although neither mitraphylline nor rotundifoline gives
hydroxyl or keto derivatives, acetyl-rhynchophylline is known.
While neither mitragynine, mitraphylline, rotundifoline, nor
formosanine reacts with diazomethane, rhynchophylline does
to give a methyl derivative.
Mitragynol deserves special mention. This alkaloid,
because of its solubility In sodium hydroxide, formation of
azo dyes, and giving of several phenolic colour reactions,
seems to be phenolic, but several reactions are difficult to
explain on this hypothesis. Diazomethane, acetic and
propionic anhydrides, and acetyl chloride with mitragynol
all give the same reaction product, possibly the result of
isomerisation. Such isomerisation occurs in the hydrolysis
and re-esterification of ester alkaloids, e.g., other
Mitragyna alkaloids, and Yohimbe and Senecfro alkaloids.
Two known degradation products have been re-examined.
The base C^H^N resulting from the selenium degradation of
rotundifoline has been shown to be 3 :4-diethylpyridine , and
the neutral compound C10HgNO formed in the calcium oxide dis
tillation of rhynchophyllic acid and formerly considered a
carbostyril is shown by its spectrum to be an indole. The
various known properties of the compound suggest that it may
be a 2:3-dimethyl-hydroxy-indole.
From a detailed study of colour reactions and of
ultra-violet spectra, It is concluded that the alkaloids are
indolic. If this is so, and if they have the skeleton of
any known indolic alkaloid, it is possibly that of the
Pseudocinchona, but more probably that of the Yohimbe type.
Since at lower temperatures there was difficulty in
determining the number of active hydrogen atoms in the
various alkaloids, an investigation was made of the effect
of temperature on the determination of active hydrogen atoms. i
Examination of a range of 38 compounds each at the temperatures:
room 50-60°, 100°, and 160° in phenetole showed that at
elevated temperatures no abnormal values resulted. Low
values were met in fluorene compounds. A smaller range of
compounds, where low values had been either reported in the
literature or encountered in this investigation, was investi
gated also in butyl ether and in mixed solvents. In these
cases the expected values were obtained, if not at room
temperature, then at least at higher temperatures. Although
some hydrogen atoms, e.g., the second in an amino group, do
become active only at higher temperatures, it is felt that
many low values reported are due not to inactivity but either
to insolubility of reactant preventing complete reaction, or
insolubility of reaction product adsorbing the methane produc
In one case where this could happen, mechanical stirring
during the reaction led to the expected value being obtained.
1
Foreword.
The purpose of this investigation is the examination
of the chemistry of the genus Mitragyna and, to a minor
extent, of the closely related genus Qurouparia. After a
brief discussion of the botany of the plants concerned, it
is proposed to deal first with the known chemistry of the
Mitragyna and Qurouparia alkaloids, secondly with the iso
lation of the various products, both alkaloidal and non-
alkaloidal, thirdly with the new information obtained and
its correlation with that already known* Finally, an
attempt will be made to examine possible skeletal structures
for the alkaloids, and to indicate possible lines along which
future investigation might proceed. Since much of the
earlier work was unsystematic and even, in part, erroneous,
much of the present work has been concerned with the correc
tion of these errors, and with characterising more fully the
various alkaloids of the group.
Introduction.
Botanical Classification.
Three points in the botanical classification call
for comment:- first, an apparent confusion between the genera
Mitragyna and Mitragyne; secondly, the postulated identity of
M.diversifolia with M.rotundifoliaj and thirdly, the relation
ship of the genera Mitragyna and Qurouparia to the various
genera known to contain indole alkaloids. In some
