THE 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 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest, ProQuest 10666209 Published by ProQuest LLC (2017). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106 - 1346 T b s i \YV5 C o o t , 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,