Table Of ContentTHE STEREOISOMERS OF N ,N *»bls(a-PHEHYLETHyL)
FUMARAM1DE
by
Robert David Thompson
A thesis submitted in partial fulfillm ent of -the : re*.•' ; • V
quirements for the degree of Doctor of Philosophy* - •
in the Department of Chemistry in the : V v: V-'
Graduate College of the State - .
University of Iowa
June 1951
ProQuest Number: 10666209
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ACKNOWLEDGMENT
The author extends his most sincere gratitude
and appreciation to Dr# R* L# Shrlner for the suggestion
of this problem and his inspiring guidance throughout
the research* Thanhs are also due the Allied Chemical
and Dye Corporation for the fellowship grant under
which part of this work was carried out*
ill
TABLE OF CONTENTS
ACKNOWLEDGMENT. ......................... *.......... . i i
X« INTRODUCTION. .......................... 1
II. HISTORICAL........................ 2
A* Stereochemistry of Compound© Containing Two
Similar Asymmetric Carbon Atoms. ...............2
B* Stereoisomerism of Substituted Ftimaramides.. . . . . . . . #16
C. Synthetic Methods for Preparing N-Substituted
Fumaramides and the Properties of Diamides of
Dibasic Acids. .................... • .21
III. DISCUSSION OF RESULTS......................... .27
Part A. The Stereoisomers of NjN’^bisfa^Phenyl-*
eth y l} F u m a r a m i d e * .27
Part B. Discussion of Reactions and Observations
Made During Exper I mental Work......................... .36
The Reaction of Fumaryl Chloride (V) and dl-g-
Phenyl ethyl amine (VI .................. • ............ 36
a. Performing the reaction in an inert
solvent using a two mole excess of
the amine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 7
b* Carrying out the reaction by the
modified Schotten-Baumann procedure. . . . . . . . . 3 8
c* Carrying out the reaction in acetone
using potassium carbonate.. . . . . . . . . . . . . . . . . . 3 8
d. Performing the reaction in pyridine.. . . . . . . . . 3 9
The Reaction Between Fumaryl Chloride (V) and
Pyridine. ...................................... .39
Preparation of d-N,Nf-bis(a-Phenylethyi) Fumar-
^ amide (1 ).... .7 . ........... • .40
iv
TABLE OF CONTENTS (cont.}
Preparation of l^N^N^blsCa-Phenylethyl) Furaar**
(11)... .7 ................. *.........
amide 43
Attempted Synthesis of Methyl N**/^) a-Phenyl ethyl/
Fumaramate (IX) from Fumaryl ChTori d© ( V .#43
Preparation of Methyl N**^d}a^Phenylethyp Fumar*
azaate (IX) from Dime thyl^Fuma rate (VIX) » . . . . . . . . . . . . . 4 3
Preparation of m eso^N ^-bista-Phenylethyl}
Fumaramide {lVlTTT. ..........*.*..46
IV. EXPERIMENTAL##.................... .48
Fumaryl Chior Ide {V 48
Dimethyl Fumarate *......««i43
£l-#a»Phenyl ethyl amine (VI)........... #48
ci-*a~Phenyiethylamine (VII ).**.......... . ...........#.............•#49
jL*a~Phenylethylamin@ ( X . 49
dl~g~p-»B r omophe ny 1 e thy 1 am i ne ......................... . # . ...#50
Reaction of Fumaryl Chloride (V) and dl~q»Phenyl~
ethylamine (VI 50
a. In an Inert solvent using a two mole
excess of the amine. ........... ....SO
b. By the modified Schotten^Baumann
reaction. . . . . . . . . . . . . . . . . . . . . . .............*............ 5£
c# In acetone using potassiumc arbonate... . . . . . . 5 2
d. In pyridine solution.•* .••.•••••••..•••••.••.5 3
Reaction Between Fumaryl Chloride (V) and Pyrid in c..*#53
Separation of the di- and meso-NjN*-bis(g~?henyl~
)T7*
eth y l) FumaramideTlII) (IV * ......................................... 55
V
TABLE OF CONTENTS (cont*)
d-Nj^-bis(a~PhenyIethyl) Fumaramide (1 )••••••*••••*•• 50
j^NfNf-bis(a-Phenylethyl) Fumaramide (I!)*.**.............*••59
Characterisation of dl-N,Nf-bis(a*Phenylethyl)
Fumaramide (III)..* * .•••«•*«••••••••.•••*••*••*•••••*60
Characterisation and Synthesis of meso-N#Nf-
bis(a-Phenylethyl) Fumaramide (IV )..... * ** ............*62
Attempted Synthesis of Methyl N-JJjd) a* Phenyl -
ethyl} Pumaramate (IX)f rom Fumaryl Chloride (V)*....#63
Me thy1 N-fd)a-Pheny1 ethyl} Fumaramate (IX) from
Dimethyl Tumarate (VII}•••*.#*•••.••#.**•••*••*.••*•*64
mso-N»N*-bis(a*Phenylethy 1) Fumaramide (IV)•»••...*••65
Rotatory Powers of the and >l,-N,Nt-bis(a^Phenyl-
ethyl) Fum&ramides (I) (II) at Temperatures from
1• to 92°*. •.« ........... . . . . . . . . . . . . . . . . . ................... 66
Preparation of dl- and me so-N.N1-b is (g-p-Bromo-
phenyl ethyl} Fumaramide* * •••..* * •..•• .7 ............. •*67
V. SUMMARY* ...................................................................... * 70
VI. BIBL1OGRAPHY . ...................................................... ..71
BIOGRAPHY 74
1
1
INTRODUCTION
The general stereochemical isomerism of compounds
containing asymmetric atoms and also olefin linkage© has
been pointed out in several texts on stereoisomerism* A
properly substituted olefin exists in cl$*» and trans-
Isomers*
els trans
However, if the Regroups contain asymmetric
centers then additional isomers are possible* In the
special case where each Regroup contains one similar
asymmetric carbon atom* it has been pointed out that both
the —ci—s- and the tra" nsform s should exist in the 4M* * mIm* *.w*
and me so-isomers respectively* However, a ll of these
Isomers have not been realized experimentally*
The purpose of the present research problem was
to provide experimental basis for the d~, T-, and meso-
isomers of a trans*olefin* As a specific example, the
synthesis and proof of structure of the various possible
isom ersof N,Nt»bis(a*fcphenylethyl) fumaramide was
undertaken.
z
It
HISTORICAL
A# Stereochemistry of Compounds Containing Two Similar
Asymmetric Carbon Atoms
Stereochemistry (1) (2) is the study of those
chemical and physical phenomena which are believed to be
due to the relative position in space taken up by atoms
within a molecule. Early in the nineteenth century
investigators found that the plane of polarisation of
polarized light was rotated when passed through certain
media* A substance which possessed this property was
termed optically active* After considerable data had been
coIlected# the optically active substances were divided
into two classes: those which possessed the property only
when a solid, and those which retained It even when fused,
dissolved, or vaporized*
Pasteur {3} in 1660 laid the foundation of stereo-*
chemistry during his investigations on the tartaric acids*
He stated that the difference between the active ta rta ric
acids must be due to the asymmetric nonsuperimposable
character of their molecules. The f irs t suggestion as to
what this asymmetric character or arrangement might be was
made in 1874* In that year VanH Hoff (3) and LeBel (3)
3
simultaneously and independently submitted papers in which
the modern theory of stereochemistry was outlined* In
these papers the geometric isomers and the isomers of
optically active compounds were accounted for*
Chemists at f ir s t did not accept the theory of
Van*t Hoff and LeBel* It was either criticised or, in
general* received scant recognition* By 1687 the necessity
for explaining so many extremely puzzling relationships
had become so great that Wislicenus (3) took up this theory
again and was able to give successful explanations by
systematically applying the theory*
The conception, which Van1t Hoff and LeBel devised,
of the tetrahedral arrangement of the four groups attached
to a carbon atom is the basic assumption of the stereo-*
chemistry ©f the carbon compounds* A model of a compound
of the type Fig* 1, b uilt on the assumption of the
Fig* 1
tetrahedral arrangement will have no elements of symmetry}
such a compound is said to have an asymmetric configuration*
The carbon atom with four different groups attached is called
an asymmetric carbon atom*
The arrangement of the atoms is termed the con
figuration# Thus, if the configuration depicted in Fig# Z
is a rb itra rily labeled the d-a-phenylethylamine, then
Fig# 3 represents the l~eonfiguration# These figures
represent the two enantiomorphic optical antipodes of
NH,
CH
CeHs
d 1
Fig* Z Fig, 3
crphenyl ethyl amine# Their chemical behavior is the same
toward all symmetrical reagents, and their physical prop
erties are identical except the j|-.ro tates plane polarised
light in the dextro {right} direction and the I* rotates
ievo (le ft). An equimolecular mixture of the two Isomers
is optically Inactive! it is called the racemlc or d l-g-
phenyl e thy 1 amine #
Pasteur founded stereochemistry by studying the
tartaric acids, the classical example of a molecule con
taining two similar asymmetric carbon atoms# Such
substances exist in two enantiomorphlc optical antipodes,
