• TABLE OF CONTENTS
HIDE
 Title Page
 Dedication
 Acknowledgement
 Table of Contents
 List of Tables
 List of Figures
 Abstract
 Introduction
 Experimental
 Results and discussion
 Appendix: Selected 1H and 13C NMR...
 References
 Biographical sketch














Title: Bifunctional synzymes via alternating copolymerization
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Permanent Link: http://ufdc.ufl.edu/UF00099228/00001
 Material Information
Title: Bifunctional synzymes via alternating copolymerization
Physical Description: x, 136 leaves : ill. ; 28 cm.
Language: English
Creator: Vanderbilt, David Paul, 1954-
Copyright Date: 1982
 Subjects
Subject: Polymers and polymerization   ( lcsh )
Enzymes   ( lcsh )
Chemistry thesis Ph. D
Dissertations, Academic -- Chemistry -- UF
Genre: bibliography   ( marcgt )
non-fiction   ( marcgt )
 Notes
Statement of Responsibility: by David Paul Vanderbilt
Thesis: Thesis (Ph. D.)--University of Florida, 1982.
Bibliography: Bibliography: leaves 131-135.
General Note: Typescript.
General Note: Vita.
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Bibliographic ID: UF00099228
Volume ID: VID00001
Source Institution: University of Florida
Holding Location: University of Florida
Rights Management: All rights reserved by the source institution and holding location.
Resource Identifier: alephbibnum - 000365850
oclc - 09912027
notis - ACA4673

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Table of Contents
    Title Page
        Page i
    Dedication
        Page ii
    Acknowledgement
        Page iii
    Table of Contents
        Page iv
        Page v
    List of Tables
        Page vi
    List of Figures
        Page vii
        Page viii
    Abstract
        Page ix
        Page x
    Introduction
        Page 1
        Page 2
        Page 3
        Page 4
        Page 5
        Page 6
        Page 7
        Page 8
        Page 9
        Page 10
        Page 11
    Experimental
        Page 12
        Page 13
        Page 14
        Page 15
        Page 16
        Page 17
        Page 18
        Page 19
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        Page 56
        Page 57
        Page 58
        Page 59
    Results and discussion
        Page 60
        Page 61
        Page 62
        Page 63
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        Page 109
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        Page 111
        Page 112
    Appendix: Selected 1H and 13C NMR spectra
        Page 113
        Page 114
        Page 115
        Page 116
        Page 117
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        Page 130
    References
        Page 131
        Page 132
        Page 133
        Page 134
        Page 135
    Biographical sketch
        Page 136
        Page 137
        Page 138
        Page 139
Full Text












BIFUNCTIONAL SYNZYMES VIA
ALTERNATING COPOLYMERIZATION







BY

DAVID PAUL VANDERBILT





















A DISSERTATION PRESENTED TO THE GRADUATE COUNCIL OF
THE UNIVERSITY OF FLORIDA
IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE
DEGREE OF DOCTOR OF PHILOSOPHY

UNIVERSITY OF FLORIDA

1982



























To my parents:

John and Betty Vanderbilt

who made it all possible.

To my aunt and uncle:

John and Helene Taras

who instilled in me

an appreciation of chemistry.
















ACKNOWLEDGEMENTS

I would like to thank Dr. George B. Butler for the opportunity

to work under his tutelage for the past three years. His encourage-

ment and guidance is sincerely appreciated. I also thank the members

of my supervisory committee.

Special thanks are extended to Dr. Kurt G. Olson, Dr. Huey

Pledger, Jr., Dr. Roy King and Dr. Thomas Baugh for invaluable advice

and assistance. I also thank Ms. Patty Hickerson for the skillful

typing of this manuscript. I am especially indebted to my friends

outside of chemistry for keeping me sane.

Financial support for this work from the National Science Founda-

tion (Grant DMR 80-20206) is gratefully acknowledged.
















TABLE OF CONTENTS

PAGE

ACKNOWLEDGEMENTS . . . . . . . . ... . . . iii

LIST OF TABLES . . . . . . . ... . . . vi

LIST OF FIGURES. . . . . . . . . ... ...... vii

ABSTRACT . . . . . . . . ... . . . . . ix

CHAPTER

I. INTRODUCTION . . . . . . . ... . . 1

Kinetic Scheme for Esterolysis . . . . . . .. 1
Effective Binding. . . . . . . . ... ... 2
Chemistry at the Active Site-- Cooperativity . . . 4
Choice of Catalytic Functional Groups. . . . . . 7
Proposal of Research . . . . . . . . . 9

II. EXPERIMENTAL . . . . . . . . ... .. . . 12

General. . . . . . . . . . ..... 12
Solvents . . . . . . . ... . . . 13
Reagents . . . . . . . . . . . . 14
Maleimide and Maleamic Acid Synthesis .. . . . ... .14
Succinimides and Succinamic Acids. . . . . . ... 25
Vinyl Ethers . . . . . . . . . . . 28
Imidazole and Histamine Derivatives . . . . ... 31
Other Monomers . . . . . . . .... ..... 40
Homopolymers . . . . . . . . . . . 42
Copolymers . . . . . . . . . . . 46
Miscellaneous Reactions. . . . . . . . ... 54
Kinetic Measurements . . . . . . . ... 56

III. RESULTS AND DISCUSSION . . . . . . . ... 60

Imidazole --Maleimides . . . . . . . ... 62
Hydroxamic Acid -- Maleimides . . . . . . . 64
Carboxylic Acid --Maleimides . . . . . . . 67
Imidazole --Vinyl Ethers. .. . . . . . .69
Other Imidazole Monomers . . . . . . . ... 71










PAGE

Copolymerization of Maleimides with N-(B-Vinyloxyethyl)-
imidazole (28) . . . . . . . . . .. 75
Copolymerization of Fumaronitrile (45) and Diethyl-
fumarate (44) With N-(B-Vinyloxyethyl)imidazole (28) . 88
Copolymerization of Maleimide (16) With B-Vinyloxyethyl-
(imidazol-4ylmethyl)piperidinium Chloride (30). .... .90
Copolymerization of Maleimide (11) with 4-Allylimidazole
(38) . . . . . . . . . . . . 93
Homopolymers. . . . . . . . . . . . 93
Copolymerization of Propenylphenols With Maleic Anhy-
dride (47) and N-Ethylmaleimide (43). . . . . ... 98
Kinetic Studies With Imidazole, 50, and 53. .. .... .102
Kinetic Studies With Copolymers 59, 60, 62, 63 and 68
and Model Compound 26 . . . . . . . . .104
Conclusion .. . . . . . . . . .. . 112

APPENDIX: SELECTED 1H AND 13C NMR SPECTRA. . . . .. .. .114

REFERENCES. . . . . . . . . . . . 131

BIOGRAPHICAL SKETCH . . . . . . . .. . .136
















LIST OF TABLES


TABLE PAGE

I Functional Groups Involved in the Catalytic Action of
Some Hydrolytic Enzymes . . . . . . . . 8

II Hydrogenation of 4-Nitroimidazole (39). . . . ... 63

III Acylation of Histamine (20) with VOC-C1 . . . ... 73

IV Solubility of 53 in Salt Solutions. . . . . .. 84

V Copolymerization of B-Vinyloxyethyl(imidazol-4ylmethyl)-
piperidinium Chloride (30). . . . . . . ... 92

VI Copolymerization of 4-Allylimidazole (38) . . ... 94

VII Homopolymerization of N-(B-Vinyloxyethyl)imidazole (28) 97

VIII Properties of Copolymers 57 64. . . . . . ... 102

IX Esterolysis of PNPA with Imidazole, 50, and 53. .... .103

X Esterolysis of DNPB with 26, 59, 60, 62, 63 and 68. . 105















LIST OF FIGURES


FIGURE PAGE

1 Proton decoupled 13C NMR spectrum of copolymer 53 in
D20-HC1, 70C. . . . . . . . . ... ... 80

2 Off-resonance decoupled 13C NMR spectrum of copolymer
53 in D20-HC1, 600C. . . . . . . . . ... 82

3 Proton decoupled 13C NMR spectrum of copolymer 54 in
D20-HC1, 800C. . . . . . . . .... .89

4 Proton decoupled 13C NMR spectrum of copolymer 50 in
acetone-d6 . . . . . . . . . . ... 96

5 pH-rate profile for the esterolysis of DNPB using 59 0,
60 A and 62 [ as catalysts . . . . .... .107

6 Plot of nsp/C vs. C for copolymer 62, 0.02M Tris buffer,
p = 0.02 (KC1), pH = 9.5 .. . . . . . 110

7 pH-rate profile for the esterolysis of DNPB using 26 0
and 68 A as catalysts . . . . . . . . .111

8 1H NMR spectrum of N-(O-Vinyloxyethyl)imidazole (28)
in CDCI3 . . . . . . . . . ... 114

9 1H NMR spectrum of N-(6-Vinyloxyethyl)piperidine (29)
in CDC13 . . . . . . . . . . . .115

10 1H NMR spectrum of B-Vinyloxyethyl(imidazol-4ylmethyl)-
piperidinium Chloride (30) in D20. . . . . .. 116

11 1H NMR spectrum of N-[(Ethenyloxy)carbonyl]-H-imida-
zol-4-ethanamine (35) in CDC13 .. . ........117

12 1H NMR spectrum of 4-Allylimidazole (38) in CDC13 ..... .118

13 1H decoupled 13C NMR spectrum of Poly(N-Acetoxymale-
imide) (48) in CD3CN-(CHC12)2at 60 . . . . .119

14 1H decoupled 13C NMR spectrum of Poly(Phenyl N-Male-
imidyl Carbonate) (49) in CD3CN at 70C. . . .. .120


vii










FIGURE PAGE

15 1H decoupled 13C NMR spectrum of Poly[N-(4-Carbethoxy-
phenyl)maleimide] (51) in acetone-d6 at 500C. .... .121

16 1H NMR spectrum of N-(B-Vinyloxyethyl)imidazole-N-
Hydroxymaleimide alternating copolymer (53) in DMSO-
d6 at 1200C ... . . . ....... ... . 122

17 1H decoupled 13C NMR spectrum of N-(B-Vinyloxyethyl)-
imidazole-Diethylfumarate copolymer (56) in CDC13 . 123

18 H decoupled 13C NMR spectrum of Isoeugenol --Maleic
Anhydride copolymer (57) in acetone-d6 at 45"C. ... 124

19 1H decoupled 13C NMR spectrum of 2-Propenylphenol --
Maleic Anhydride copolymer (58) in DMSO-d6 at 1200C .125

20 H decoupled 13C NMR spectrum of Isoeugenol --N-[2-(4-
Imidazolyl)ethyl] maleimide copolymer (59) in DMSO-d6
at 1100C. . . . . . . . . . 126

21 1H decoupled 13C NMR spectrum of trans-Anethole--Maleic
Anhydride copolymer (61) in DMSO-d6 at 1100C. .... .127

22 1H decoupled 13C NMR spectrum of Isoeugenol --N-Ethyl-
maleimide copolymer (63) in DMSO-d6 at 1100C. .... .128

23 1H decoupled 13C NMR spectrum of 2-Propenylphenol --N-
Ethylmaleimide copolymer (64) in DMSO-d6 at 1100C . 129

24 1H decoupled 13C NMR spectrum of N-Acetoxymaleimide
cyclotrimer (65) in CD3CN at 700C . . . . .. 130
















Abstract of Dissertation Presented to the
Graduate Council of the University of Florida
in Partial Fulfillment of the Requirements for the
Degree of Doctor of Philosophy

BIFUNCTIONAL SYNZYMES VIA
ALTERNATING COPOLYMERIZATION

By

David Paul Vanderbilt

December 1982

Chairman: Dr. George B. Butler
Major Department: Chemistry

The synthesis, characterization and evaluation of bifunctional

synthetic enzymes (synzymes) via alternating copolymerization was

carried out. It was desired to obtain copolymers containing alternat-

ing placements of complementary functional groups to see if "coopera-

tivity" between the groups (in the hydrolysis of ester substrates)

could be greater than in a random copolymer containing the same groups.

To this end, the following bifunctional alternating copolymers

were synthesized: N-(B-vinyloxyethyl)imidazole-- N-hydroxymaleimide

(53), isoeugenol -- N-[2-(4-imidazolyl)ethyl] maleimide (59), and 2-

propenylphenol-- N-[2-(4-imidazolyl)ethyl] maleimide (60). These co-

polymers were evaluated as catalysts in the hydrolysis of p-nitrophenyl

acetate (PNPA) or 2,4-dinitrophenyl benzoate (DNPB). No cooperativity

between imidazole and hydroxamic acid or imidazole and phenol groups

was observed in the hydrolysis of activated esters, leaving unresolved










the premise that bifunctional alternating copolymers should make

better catalysts than bifunctional random copolymers.















CHAPTER I

INTRODUCTION

A great deal of attention has been given to the understanding of

the catalytic properties of enzymes.I Enzymes are globular proteins

(polyamino acids) which catalyze most of the chemical reactions in

living organisms. Recently, we have begun to understand the mecha-

nisms by which enzymes catalyze organic reactions in terms of the

transition state theory. As man's knowledge of enzyme mechanism has

grown, so too has his wish to synthesize artificial enzymes or "syn-

zymes." Synzymes have shown considerable utility as probes of enzyme

kinetics.2 These synthetic enzymes should emulate the desirable

characteristics of natural enzymes, i.e., show high selectivity and

high efficiency (rate enhancement) toward the substrate molecule. To

date, both characteristics have been incorporated into synthetic poly-

mers to some degree. As this work deals with the synthesis and eval-

uation of synzymes, a brief discussion of recent developments in the

field follows.

Kinetic Scheme for Esterolysis

Enzymes are capable of catalyzing a great variety of chemical

reactions; one of the most studied of these is the esterolysis (ester

hydrolysis) reaction. In general, the kinetic scheme for the hydroly-

sis of an activated ester by a catalyst can be represented as follows:2b









k
Cat + RCO2R' i Cat -RCO2R'

ka II
-1 I




k III kd
k I Cat-CR + OR kd- Cat + RCO2H

0 H20


where Cat is the catalyst, and RCO2R' is the ester substrate. Step I

represents an equilibrium between free catalyst and free substrate

and a catalyst-substrate complex or Michaelis complex. This step is

assumed to be rapid and reversible with non-covalent binding forces

holding the complex together. The actual hydrolysis steps then take

place via acylation of the catalyst (II) and subsequent deacylation

(IV). This pathway is believed to be important in the case where

the catalyst is a natural enzyme. Alternatively, acylation of the

catalyst may occur via a bimolecular reaction (III), in which no pre-

association of catalyst and substrate has taken place. This pathway

is followed in the case of small molecule catalysts and many synzymes.

Catalysis by a synzyme might follow both reaction pathways simultane-

ously.

Effective Binding

Effective binding between catalyst and substrate prior to the

acylation step plays a key role in providing high catalytic activity.

This pre-association step greatly increases the esterolysis rate by

increasing the concentration of substrate at the active site of the









catalyst. Furthermore, acylation can take place via an intramolecular

reaction (II) rather than by the much slower intermolecular pathway

(III). At least four types of binding forces have been identified in

the pre-association process: coulombic interactions, hydrophobic

interactions, hydrogen bond formation, and charge-transfer interac-

tions. The most important factor determining the catalyst's effec-

tiveness, however, is that the binding take place at a site which is

favorable for the subsequent acylation reaction to occur.

An example of coulombic interactions as the mode of polymer-sub-

strate binding has been demonstrated by Overberger and Maki.3 Poly[4

(5)-vinylimidazole-co-acrylic acid] (1), containing an excess of

acrylic acid units (53.7 mol%) and therefore having an excess of

anionic sites, hydrolyzed positively-charged 3-acetoxy-N-trimethyl-

anilinium iodide (ANTI) faster than neutral p-nitrophenyl acetate

(PNPA), which in turn was hydrolyzed faster than the negatively-

charged substrate 3-nitro-4-acetoxybenzoic acid (NABA).

0
y
x II
x OCCH


OH HN(CH3)3


1 ANTI

0 0
II II
OCCH COH
OCCH


NO2 NO2
PNPA NABA









This study also demonstrates a certain degree of selectivity shown by

the catalyst toward the substrate.

Favorable binding by hydrophobic interactions has been demon-

strated by Klotz and Stryker.4a They found that partially lauroylated

poly(ethylenimine) catalyzed the hydrolysis of PNPA at a faster rate

than did poly(ethylenimine) itself. Indeed, the most effective synzyme

studied to date is a dodecylated poly(ethylenimine) containing imida-

zole residues. This derivative was found to approach a-chymotrypsin in

catalytic activity.4b On the other hand, Overberger and Smith5 studied

the effect of varying the chain length of substrate (2) using poly(l-

butyl-5-vinylimidazole) (3) and poly(1-methyl-5-vinylimidazole) (4) as

catalysts.

CH3(CH2)nC02 ) 02H -Bu
_=> 071-Bu N N-Me
02N 2 3 4
n = 0, 5, 10, 16

It was found for both (3) and (4) that (2, n = 16) was hydrolyzed at a

faster rate than (2, n = 0).

Chemistry at the Active Site--Cooperativity

As we have seen above, in order to observe a significant rate en-

hancement in esterolysis reactions the substrate must first be bound

to the polymer near or at the active site. Only after complexation

has occurred do the actual hydrolysis steps take place. Synzyme es-

terolysis has been observed to proceed with or without a complexation

step. Studies with a-chymotrypsin (a serine proteinase consisting of

245 amino acid residues) have shown that a serine 0 anion is respon-

sible for catalytic acylation of substrate.1












/0 0
o .... H-N N...H-0-- -H....N N-H
S j== \ /" -0-(Ser 195)

Asp(102) His(57) Ser(195)

The serine hydroxyl group is activated for the acylation reaction
by the scheme shown above, dubbed a "charge relay system," in which

the imidazole moiety plays an integral role in lowering the activation

energy for catalysis. A variety of cooperative effects among the

functional groups responsible for catalytic action is common in natu-

ral enzymes. The synthetic chemist has also sought to take advantage

of cooperativity in order to produce more efficient synzymes. A good

example of bifunctional cooperation utilizing a molecular relay system

was demonstrated by Kunitake and Okahata. These workers found that

the rate of hydrolysis of PNPA was 1000 times faster using a terpoly-

mer N-phenylacrylohydroxamate : 4(5)-vinylimidazole : acrylamide (5)

compared with N-phenylacrylohydroxamate : acrylamide copolymer (6) as

catalysts.


Ph' 'OH









The acylation step was demonstrated to occur primarily via the

hydroxamate anion, which is known to be a highly nucleophilic species.

It is also known that decomposition of an acylhydroxamate is a slow

process; the fact that S is a much better catalyst than 6 implies that

imidazole is catalyzing deacylation of the acylhydroxamate intermedi-

ate either acting as a nucleophile or general base.

Another example of a bifunctional catalyst exhibiting coopera-

tivity is a 1:1.95 copolymer of 4(5)-vinylimidazole and p-vinylphenol

(7).7a This copolymer was 63 times as efficient as imidazole for the
hydrolysis of ANTI at pH 9.1, and 10.6 times as effective as imidazole

vs. PNPA at the same pH. Phenol, poly(p-vinylphenol), poly[4(5)-

vinylimidazole] and a 1:0.48 copolymer of 4(5)-vinylimidazole and p-

methoxystyrene gave no significant rate enhancement under the same

conditions.


1.95




N-i OH
H
7

This great rate enhancement was attributed to cooperativity be-

tween imidazole and phenolate ion, which might involve (i) phenol

anion acting as a general base assisting the decomposition of the

tetrahedral intermediate and/or (ii) the phenol anion activating a

neutral imidazole for nucleophilic attack on the substrate. Coopera-

tive interactions have been demonstrated in small molecules by Bender

et al.7b












N" N-C-U-H 0 0 CH

OR HN N C=O

OR


i ii

Polymer Configuration

Catalytic properties of polymers are influenced to a large extent

by the configuration (conformation) of the polymer in solution. Vinyl

polymers are rather flexible as compared with enzymes, i.e., they

usually lack specific secondary and unique tertiary structure. As a

result, synthetic polymers lack the specific binding pocket which is

typical of enzymes. Therefore, the catalytic efficiency of synzymes

will depend to a large extent on the pH, ionic strength and composi-

tion of the medium, distance of the catalytic group from the polymer

backbone, degree of dissociation of catalytic groups, and many other

considerations.

Choice of Catalytic Functional Groups

As we have seen above, combinations of cooperative and/or com-

plementary functional groups are necessary to achieve high catalytic

efficiency. Catalysis by hydrolytic enzymes is of the nucleophilic

and acid-base type. Table I contains a list of functional groups

which are directly involved in the catalytic action of some hydrolytic

enzymes.















TABLE I

Functional Groups Involved in the 2
Catalytic Action of Some Hydrolytic Enzymesa

Enzyme Functional Group


Serine protease

Chymotrypsin
Trypsin
a-Lytic protease
Elastase
Subtilisin


-OH(Ser),

N
H


(His), -COOH (Asp)


-SH(Cys), N (His)


N
/ (His), N H (His, protonated)

H H
-COOH (Glu), -CO0 (Asp)


-- 0 OH (Tyr), Zn2+


Papain


Ribonuclease


Lysozyme


Carboxypeptidase










Proposal of Research

As was stated previously, synthetic vinyl macromolecules con-

taining bi- or multi-functionalities have been studied in other

laboratories and have shown enzyme-like catalytic activity. These

studies have shown a cooperativity between the functionalities lead-

ing to a rate enhancement for esterolysis reactions. However, up to

this time, functionalities have been introduced into copolymers in

random fashion. This ensures a degree of cooperation between the

functionalities which is dependent on the degree of alternation (i)

or upon the conformation of the polymer chain (ii) as depicted below.






A A B A A B B









-B




It appeared to us that the degree of cooperativity between func-

tional groups could be maximized by preparing regular alternating co-

polymers. This would assure that each functional group of a given

type would be flanked on either side by a functional group of the

complementary type.









Fundamental to this proposed research is the selection of monomer
pairs which undergo regular alternating copolymerization under free-
radical conditions. This type of copolymerization is generally thought
to result from the formation of a 1:1 charge-transfer complex between
electron-rich (donor) and electron-deficient (acceptor) monomer pairs.
Some examples of monomer pairs which give regularly alternating co-
polymers include styrene -- N-phenylmaleimide,8 2-chloroethyl vinyl
ether-- maleic anhydride,9 styrene-- maleic anhydride,10 2-allyl
phenol --maleic anhydride,11 and 2-allylphenol -- N-phenylmaleimide.11
In these laboratories, the alternating copolymerization of N-phenyl-
maleimide and 2-chloroethylvinyl ether has been studied extensively
by Olson.12


O+ n



Cl 0 Cl




It was concluded in this study that the predominant propagation
mechanism is homopolymerization of a 1:1 donor-acceptor complex. An
excellent review of the role of the charge-transfer complex in alter-
nating copolymerization can be found in this work.12
Our goal of producing bifunctional synzymes via alternating co-
polymerization could be approached by at least two methods. The first
method, which we believed would result in fully functionalized copoly-
mer, is the direct polymerization of monomer pairs containing the









desired functional groups (or the desired functional groups in masked

or protected forms).


+ n
A B



The second method involves derivatization of a pre-existing alternat-

ing copolymer. This method suffers from the fact that polymers can be

difficult to functionalize completely and resultant difficulties asso-

ciated with characterization of a partially functionalized polymer.


-- n B
A X A X A B




We have approached the problem via both methods. Our initial

efforts were aimed at direct polymerization of appropriately substi-

tuted monomer pairs. Difficulty was encountered effecting copolymeri-

zation due to side reactions caused by one of the unprotected func-

tionalities. Hence, derivatization of a pre-existing alternating

copolymer was also attempted.















CHAPTER II

EXPERIMENTAL

General

Melting points were determined on a Thomas-Hoover Capillary

Melting Point Apparatus or a Fisher-Johns Melting Point Apparatus

and are given in degrees celsius (uncorrected). Pressures are ex-

pressed in millimeters (mm) of mercury. Elemental analyses were

performed by Atlantic Microlabs, Inc., Atlanta, Georgia, and

Schwarzkopf Microanalytical Laboratories, Inc., Woodside, New York.

Proton nuclear magnetic resonance (NMR) spectra (60 MHz) were

recorded on Varian A-60A or Jeol JNM-PMX-60 instruments. Carbon-13

NMR (25 MHz) and 100 MHz proton NMR spectra were recorded on a Jeol-

JNM-FX-100 spectrometer. Chemical shifts are expressed in parts per

million (ppm) on the 6 scale downfield from tetramethylsilane (TMS)

or sodium 2,2-dimethyl-2-silapentane-5-sulfonate (DSS) unless other-

wise indicated. In cases where no internal reference was added,

spectra were calibrated via a characteristic signal of the deuterated

solvent used.13 The solvent used and calibration information are

given in parentheses for each spectrum reported. Multiplicities of

proton and off-resonance decoupled carbon resonances are designated

as singlet (s), doublet (d), triplet (t), quartet (q), multiple (m),

or broad (br).









Infrared (IR) spectra were recorded on a Perkin-Elmer 281 spec-

trophotometer. Absorbances are expressed in wavenumbers (cm- ) using

polystyrene (1601 cm-1) calibration. Solid samples were run as a KBr

pellet; liquid samples were analyzed neat as a thin film between NaCl

plates. Absorption bands are assigned the classifications: weak (w),

medium (m), strong (s), very strong (vs), broad (br), and shoulder (sh).

Low resolution mass spectra (LRMS) and high resolution mass spec-

tra (HRMS) were recorded on an Associated Electronic Industries (AEI)

Model MS-30 spectrometer.

Number average molecular weights (Mn) of polymers were determined

by vapor pressure osmometry (VPO) on a Wescan 233 Molecular Weight

Apparatus. Benzil was used as a calibration standard.

Intrinsic viscosities were measured with a Ubbelohde viscometer

(dilution viscometer).

Gel Permeation Chromatography (GPC) of polymers was carried out

on a Waters Associates- Liquid Chromatograph using glycerated porous

glass columns and both ultraviolet (UV) and differential refracto-

meter detectors.

Compound headings appear with the common name(s) listed first,

followed by the systematic name as found in Chemical Abstracts (CA).

CA registry numbers of known compounds are given in brackets.

Solvents

Deuterated NMR solvents were obtained from the Aldrich Chemical

Co. and Merck and Co., Inc. All solvents used for general applica-

tions were of Reagent grade or ACS grade quality. For special appli-

cations, solvents were distilled. Reference to a distilled solvent









in this chapter indicates that the solvent was purified in the manner

described below.14 Methanol was distilled from Mg(OCH3)2. Tetrahy-

drofuran (THF) was distilled from CaH2. Dimethylsulfoxide (DMSO) and

N,N-dimethylformamide (DMF) were allowed to stand over KOH and were

distilled from CaO. Dioxane was refluxed with aqueous HC1, dried over

KOH and distilled from sodium metal. Ethanol-free chloroform (CHC13)

was obtained by extraction of reagent grade CHC13 with conc. H2SO4 and

water, followed by distillation from P4H10. Dichloromethane (CH2C12)

was distilled from P4H10. Acetone was distilled from Nal.

Reagents

Starting materials and reagents were obtained from the following

suppliers: Aldrich Chemical Co., Fisher Scientific Co., Mallinckrodt,

Inc., Eastman Kodak Co., and Polysciences, Inc.

Maleimide and Maleamic Acid Synthesis

3,6-Endoxo-1,2,3,6-tetrahydrophthalic Anhydride/3a,4,7,7a-Tetrahydro-
4,7-epoxyisobenzofuran-1,3-dione [5426-0905] (8)

The following procedure was modified from the procedure of Narita

et al.15 To a 1 L three-necked round-bottomed flask equipped with a

mechanical stirrer and reflux condenser was added 109.2 g (1.604 mol)

of freshly distilled furan and 200 mL of benzene. The solution was

cooled via an external ice bath to 0-5C, after which 157.3 g (1.604

mol) of maleic anhydride was added portionwise. The ice bath was re-

moved after refluxing had slowed, and the mixture was stirred at room

temperature for 24 h. Additional benzene was added to facilitate

stirring. The mixture was filtered and dried in vacuo to give 235.9 g

(88.5%) of white crystalline product (8), mp 115-1160C (dec) [litera-

ture mp 118C (dec)].16









H NMR (DMSO-d6, TMS): 3.32 (s, 2H), 5.35 (s, 2H), 6.57 (s, 2H).

1C NMR (DMSO-d6, 39.5): 49.10, 81.75, 136.90, 171.53.

IR (KBr): 3195 (w), 3162 (w), 3136 (w), 3102 (w), 2995 (w), 1860

(s), 1787 (vs, br), 1640 (w), 1595 (w), 1567 (w), 1380 (w),

1321 (m, sh), 1310 (m), 1282 (m), 1242 (m, sh), 1230 (s), 1218

(s), 1193 (m), 1145 (m), 1086 (s), 1020 (s), 1000 (m), 950 (s),
920 (s), 903 (s), 878 (s), 848 (s), 820 (m), 798 (m), 731 (m),

689 (m), 672 (m), 633 (m), 620 (w).

N-Hydroxy-3,6-epoxy-1,2,3,6-tetrahydrophthalimide/3a,4,7,7a-Tetrahy-
dro-2-hydroxy-4,7-epoxy-1H-isoindole-1,3(2H)-dione [5596-17-8]
(9)
The following procedure was obtained from Narita et al.15 To a

1 L round-bottomed flask equipped with a mechanical stirrer and a

250 mL addition funnel was added 75.3 g (1.083 mol) of hydroxylamine

hydrochloride (dried in a vacuum oven at 600C overnight) and 400 mL

of freshly distilled methanol. After dissolution, the flask was

cooled to 0-5C. The addition funnel was charged with a solution of

60.8 g (1.083 mol) of potassium hydroxide in 150 mL of freshly dis-

tilled methanol and the solution added dropwise with vigorous stir-

ring. After addition, the mixture was stirred an additional 0.5 h,

and subsequently suction-filtered into a second 1 L three-necked

round-bottomed flask fitted with a mechanical stirrer and reflux con-

denser. To the stirring hydroxylamine solution was added portionwise

180 g (1.083 mol) of 3,6-endoxo-1,2,3,6-tetrahydrophthalic anhydride

(8). The mixture was refluxed for 8 h and then allowed to stir for

13 h at room temperature. The flask was cooled in an ice bath, and








the precipitate was filtered and dried in vacuo to yield 128.6 g

(65.5%) of white solid (9), mp 189-195C (dec) [literature mp 187-

188C (dec)].15

1H NMR (DMSO-d6, TMS): 2.86 (s, 2H), 5.13 (s, 2H), 6.53 (s, 2H).

1C NMR (DMSO-d6, 39.5): 43.91, 80.00, 136.24, 172.50.

IR (KBr): 3300 (s, br), 3095 (w), 3085 (w), 3050 (w), 3022 (m),

2998 (m), 1787 (s), 1730 (vs, br), 1567 (w), 1437 (s), 1338

(w), 1305 (m), 1283 (m), 1264 (m), 1240 (s), 1227 (m, sh), 1207

(m), 1196 (m), 1150 (s), 1089 (s), 1070 (m), 1010 (m), 951 (m),
916 (m), 881 (s), 846 (m), 823 (m), 803 (m), 792 (m), 720 (s),

644 (s).

N-Acetoxy-3,6-epoxy-1,2,3,6-tetrahydrophthalimide/2-(Acetyloxy)-3a,
4,7,7a-tetrahydro-4,7-epoxy-1H-isoindole-1,3(2H)-dione [32463-
66-4] (10)


To a 250 mL three-necked round-bottomed flask fitted with a me-

chanical stirrer and reflux condenser was added 47.7 g (0.263 mol)

of 9 and 135 mL of acetic anhydride. The stirred mixture was

heated to 89-900C via an oil bath and maintained at this temperature

for 3 h. The resulting solution was cooled to room temperature and

placed in a refrigerator overnight. The precipitate was filtered

and washed with cold benzene. A second crop of crystals was obtained

by concentration of the combined mother liquors in vacuo, followed by

precipitation into water. The combined products were recrystallized

from benzene and dried in vacuo to afford 34.14 g of white crystals.

An additional 10.17 g fraction was obtained from concentration of the

benzene mother liquor (75.4%), mp 139-143C (dec) [literature mp 137-

1380C (dec)].15









H NMR (CDC13, TMS): 2.30 (s, 3H), 2.87 (s, 2H), 5.27 (s, 2H), 6.47
(s, 2H).
C NMR (DMSO-d6, 39.5): 17.08, 44.03, 79.85, 136.02, 165.46, 169.26.

IR (KBr): 3095 (w), 3020 (w, sh), 2998 (m), 1810 (s), 1783 (s), 1735

(s), 1430 (w), 1375 (s), 1350 (m), 1284 (m), 1272 (m), 1230 (s),
1218 (s, sh), 1192 (s), 1168 (s), 1139 (s), 1092 (s), 1060 (s),
1012 (m), 992 (m), 985 (m), 915 (m), 878 (s), 845 (m, sh), 836

(m), 817 (m), 800 (s), 739 (m), 710 (m), 693 (m), 637 (m), 629 (m).
N-Acetoxymaleimide/l-(Acetyloxy)-1H-pyrrole-2,5-dione (11)

To a 100 mL one-necked round-bottomed flask was added 49.47 g of
10 and a Telfon-coated stir bar. A short path vacuum distillation

head was fitted to the flask, and the pressure of the system was re-
duced to 25 mm. The flask was heated slowly to approximately 180'C.
Decomposition of the solid occurred before 140C and was accompanied

by the evolution of furan. The product was then distilled, bp 140-
146C (24 mm Hg), and collected by cooling the receiving flask. Two
recrystallizations from CC14 gave 28.36 g (82.5%) of white crystal-
line product (11), mp 70.5-71.5C (literature mp 70.5-71.5C).15
1H NMR (CDC13, TMS): 2.32 (s, 3H), 6.70 (s, 2H).

(DMSO-d6, TMS): 2.38 (s, 3H), 7.18 (s, 2H).
C NMR (CDC13, TMS): 17.33, 132.44, 164.22, 166.80.

(DMSO-d6, 39.5): 17.03, 133.08, 165.05, 167.49.
IR (KBr): 3080 (w), 3057 (m), 3048 (m), 3003 (w), 2950 (w), 2880 (w),
1818 (s), 1782 (s), 1740 (vs), 1577 (w), 1432 (w), 1380 (s),
1341 (w), 1317 (w), 1177 (s), 1123 (s), 1048 (s), 1007 (w), 820

(s), 778 (m), 670 (s).








Elemental Analysis: Calcd. for C6H5N03: C, 46.46; H, 3.25; N, 9.03.

Found: C, 46.49; H, 3.28, N, 9.04.

Phenyl N-(3,6-Epoxy-1,2,3,6-tetrahydrophthalimidyl) Carbonate/3a,4,
7,7a-Tetrahydro-2-[(phenoxycarbonyl)oxy]-4,7-epoxy-iH-isoindole-
1,3(2H)-dione [60361-88-8] (12)


The following procedure was adopted from Akiyama et al.17 To a

500 mL three-necked round-bottomed flask fitted with a mechanical

stirrer and addition funnel was added 76.4 g (0.422 mol) of 9 and 210

mL of freshly distilled DMF. The flask was cooled to 0-50C via an

external ice bath, and 58.8 mL (0.422 mol) of dry triethylamine was

added. The addition funnel was charged with 66.03 g (0.422 mol) of

phenyl chloroformate which was added to the stirred solution over a

1 h period. The ice bath was removed and the mixture allowed to stir

an additional 3 h. Triethylamine hydrochloride was filtered out and

the filtrate precipitated into 2 L of water. Additional product was

obtained by dissolving the filtered Et3N-HCl in 1 L of water. Both

precipitates were suction filtered and dried in vacuo giving 126.3 g

of crude product. Recrystallization from isopropanol afforded 71.4 g

(56.3%) of white needles, mp 137-1390C (literature mp 135-136C).17
1H NMR (CDCI3, TMS): 2.88 (s, 2H), 5.32 (s, 2H), 6.48 (s, 2H), 7.20-

7.45 (m, 5H).
1C NMR (CDCI3, T'4S): 44.25, 80.47, 120.28, 126.96, 129.74, 136.22,

149.97, 150.70, 168.29.

IR (KBr): 3095 (w), 3075 (w), 3060 (m), 3022 (w), 3003 (w), 1817 (s),

1790 (s), 1740 (vs), 1600 (w), 1585 (m), 1485 (m), 1460 (m), 1360

(m), 1310 (m), 1272 (s), 1230 (vs, br), 1148 (s), 1092 (s), 1068








(s), 1019 (m), 1005 (m, sh), 998 (m), 973 (m), 954 (m), 917 (m),
882 (s), 850 (m), 817 (m), 803 (m), 788 (m), 774 (m), 753 (m),

730 (m), 713 (m), 686 (m), 660 (w), 629 (m), 622 (m).

Phenyl N-Maleimidyl Carbonate/l-[(Phenoxycarbonyl)oxy]-1H-pyrrole-2,
5-dione [60361-89-9] (13)

Into a 250 mL Erlenmeyer flask was placed 38.68 g (0.128 mol) of

12, 0.428 g (2.57 mmol) of 4-tert-butylcatechol, 70 mL of bromobenzene,

and a few boiling chips. The mixture was heated on a hot plate at

such a rate as to allow bromobenzene vapors to condense in the neck

of the flask (~160C inside the flask) for 1.5 h. Bromobenzene was

then removed in vacuo and the resulting solid recrystallized from cy-

clohexane and dried in vacuo giving 24.51 g (81.8%) of maleimide (13)
as a pale-yellow solid, mp 99-102.50C (literature mp 98-990C).17 A

quantity of 13 was sublimed at 1 mm (1000C) affording white crystals,

mp 101-104C.
1H NMR (CDC13, TMS): 6.77 (s, 2H), 7.20-7.45 (m, 5H).

1C NMR (CDC13, TMS): 120.33, 127.06, 129.84, 132.62, 150.75, 163.47.

IR (KBr): 3160 (w), 3100 (m), 3070 (w), 1818 (s), 1783 (s), 1740 (vs),

1587 (m), 1578 (m), 1492 (m), 1482 (m), 1456 (w), 1375 (m), 1220

(vs), 1162 (m), 1155 (m), 1126 (s), 1050 (m), 1023 (m), 1004 (m),
974 (m), 910 (w), 860 (w), 815 (s), 778 (w), 765 (m), 752 (m),

743 (n), 715 (m), 685 (m), 667 (s), 638 (m).

N-Hydroxymaleimide/1-Hydroxy-1H-pyrrole-2,5-dione [4814-74-8] (14)

N-Hydroxymaleimide was prepared via the procedure of Akiyama et

al.17 Thus, to a 100 mL three-necked round-bottomed flask fitted

with a reflux condenser and magnetic stir bar was added 7.358 g









(0.0316 mol) of 13 and 40 mL of freshly distilled methanol. The solu-

tion was refluxed for 2 h, after which the methanol was removed in

vacuo. The residual oil was triturated with a solution of 7:5 hexanes:

benzene, and the resulting solid was recrystallized from toluene and

dried in vacuo to give 1.55 g (43.4%) of an off-white crystalline

solid (14), mp 126-1300C (literature mp 125-126C).17 Spectral prop-

erties were in agreement with those of an authentic sample kindly sup-

plied by Dr. M. Akiyama.

1H NMR (acetone-d6, TMS): 6.76 (s, 2H), 9.20 (br, 1H).

(DMSO-d6, TMS): 6.92 (s, 2H), 10.29 (br, 1H).

C NMR (acetone-d6, TMS): 125.50, 160.05.

(DMSO-d6, 39.5): 131.91, 167.00.

IR (KBr): 3150 (m, br), 3100 (m), 2950 (w), 2850 (w), 1785 (m), 1730

(vs), 1572 (w), 1488 (m), 1306 (w), 1230 (w), 1175 (s), 1130 (m),

1047 (m), 1041 (m), 822 (s), 773 (w), 735 (m), 670 (s).

N-(4-Carbethoxyphenyl)maleanilic Acid/(Z)-4-[(3-Carboxy-1-oxo-2-pro-
penyl)amino]benzoic acid, 1-ethyl ester [53616-17-4] (15)

To a 500 mL Erlenmeyer flask was added 24.4 g (0.148 mol) of

ethyl p-aminobenzoate and 250 mL of chloroform. The stirred solution

was cooled in an ice bath, and 14.5 g (0.148 mol) of maleic anhydride

was added portionwise. After 1 h, the mixture was warmed to room temp-

erature and stirred overnight. The white precipitate was filtered,

washed with CHCl3, and dried in vacuo, affording 38.1 g (98%) of male-

anilic acid (15). A portion of the product was recrystallized from

CH3CN, mp 190-1920C.








1H NMR (DMSO-d6, 2.49): 1.28 (t, 3H), 4.25 (q, 2H), 6.41 (AB q, 2H),

7.84 (AB q, 4H), 10.62 (s, 1H).
C NMR (DMSO-d6, 39.5): 14.20, 60.51, 118.89, 124.74, 130.30, 131.71,

143.07, 163.78, 165.34, 166.95.

IR (KBr): 3300 (m), 3205 (m), 3110 (m), 2975 (w), 1710 (s), 1635 (m),

1610 (m), 1580 (s), 1540 (s), 1470 (m), 1415 (w), 1405 (m), 1365

(m), 1330 (m), 1310 (m), 1270 (s), 1225 (w), 1175 (m), 1120 (m),
1105 (m), 1025 (m), 1010 (w), 970 (m), 900 (w), 865 (m), 850 (m),

770 (m), 695 (w), 680 (w), 610 (m).
N-(4-Carbethoxyphenyl)maleimide/[4-(2,5-Dihydro-2,5-dioxo-1H-pyrrol-
1-yl)benzoic acid, ethyl ester] [14794-06-1] (16)

To a 500 mL one-necked round-bottomed flask was added 38.1 g

(0.145 mol) of 15, 1.2 g (0.015 mol) of anhydrous sodium acetate, and

100 mL of acetic anhydride. A magnetic stir bar was added, and a re-

flux condenser was fitted. The stirring mixture was brought to 900C

over a 1.0 h period, and then allowed to cool to room temperature.

The resulting solution was precipitated into 1.5 L of ice-water and

allowed to stir overnight. The yellow solid was collected by filtra-

tion, recrystallized from ethanol-water, and dried in vacuo, giving

29.57 g (83.4%) of yellow plates, mp 112-1130C (literature mp 1130C).18
H NMR (CDCl3, TMS): 1.38 (t, 3H), 4.37 (q, 2H), 6.84 (s, 2H), 7.80

(AB q, 4H).
13C NMR (CDC13, 77.0): 13.94, 60.77, 124.86, 129.00, 129.93, 133.97,

135.10, 165.26, 168.63.
IR (KBr): 3470 (w), 3090 (w), 2995 (w), 2900 (w), 1718 (vs), 1710

(vs), 1603 (m), 1507 (m), 1472 (w), 1442 (w), 1405 (m, sh), 1395








(s), 1382 (s), 1365 (m, sh), 1307 (m, sh), 1282 (s), 1213 (w),
1175 (m), 1142 (m), 1128 (m), 1108 (m), 1068 (w), 1022 (m),
948 (w), 853 (m), 830 (m), 764 (m), 699 (m), 684 (m), 638 (w).
N-Hydroxymaleamic Acid [4296-73-5] (17)
N-Hydroxymaleamic acid (17) was prepared from the addition of
hydroxylamine [from 61.5 g (0.885 mol) of hydroxylamine hydrochloride
neutralized with one equivalent of sodium methoxide in methanol] to
a solution of 86.8 g (0.885 mol) of maleic anhydride in distilled
dioxane at 00C. After warming to room temperature and stirring for
1 h, the product was filtered and dried in vacuo, affording 69.3 g
(60%) of 17, mp 126-1290C (dec) [literature mp 122-128C (dec)].19
1H NMR (DMSO-d6, TMS): 6.30 (s, 2H).
1C NMR (DMSO-d6; 39.5): 129.22, 132.98, 162.17, 165.93.

IR (KBr): 3500-2600 (br, s), 3180 (s), 1695 (m), 1630 (s), 1540 (br,
vs), 1400 (s), 1310 (m), 1230 (br, s), 1080 (m), 1065 (s), 990

(m), 980 (m), 915 (m), 847 (m), 800 (m), 730 (m), 630 (m).
N-Carbethoxymaleimide/2,5-Dihydro-2,5-dioxo-1H-pyrrole-l-carboxylic
acid, ethyl ester [55750-49-7] (18)

This maleimide was prepared by the method of Keller and Rudinger2
in 44% yield, mp 55-570C (literature mp 58-59C).20
1H NMR (CDC13, TMS): 1.42 (t, 3H), 4.45 (q, 2H), 6.84 (s, 2H).

IR (KBr): 3180 (w), 3100 (m), 2985 (m), 1795 (s), 1770 (vs), 1710 (m),
1595 (m), 1475 (m), 1445 (m), 1398 (m), 1370 (m), 1330 (s), 1265
(s), 1130 (m), 1102 (m), 1053 (m), 1035 (m), 995 (m), 850 (m),
765 (m), 755 (m), 690 (m), 635 (m).








N-[2-(4-Imidazolyl)ethyl]maleamic Acid/(Z)-4-([2-(1H-Imidazol-4-yl)
ethyl]amino)-4-oxo-2-butenoic Acid (19)

In an Erlenmeyer flask was combined 0.437 g (3.93 mmol) of hista-

mine (20), 0.367 g (3.74 mmol) of maleic anhydride and 20 mL of chloro-
form (ethanol-free). The mixture was stirred for 20 h; the solid fil-

tered and dried in vacuo, affording 0.672 g (86%) of 19, which slowly
decomposed above 1200C.
1H NMR (D20, DSS): 2.95 (m, 2H), 3.52 (m, 2H), 6.13 (AB q, 2H), 7.26

(s, 1H), 8.53 (s, 1H).
IR (KBr): 3600-2400 (br, m), 3230 (w), 3135 (w), 3060 (w), 1655 (m),

1625 (s), 1570 (br, s), 1450 (w), 1430 (w), 1398 (w), 1365 (w),
1313 (w), 1270 (m), 1208 (w), 1185 (m), 1100 (br, m), 1065 (w),
975 (m), 902 (w), 855 (br, m), 815 (m), 730 (w), 715 (m), 638

(m), 610 (m).
N-(2-Thiazolyl)maleamic Acid/(Z)-4-Oxo-4-(2-thiazolylamino)-2-bute-
noic Acid [19789-91-4] (21)

Into an Erlenmeyer flask was placed 0.922 g (9.21 mmol) of 2-
aminothiazole (recrystallized from cyclohexane), 0.902 g (9.20 mmol)

of maleic anhydride and 40 mL of acetone. The mixture was stirred
for 45 h at room temperature. The solid was filtered, washed with

acetone and dried in vacuo, affording 1.308 g (72%) of yellow powder

(21), mp 151-1530C (dec).
H NMR (DMSO-d6, 2.49): 6.46 (s, 2H), 7.37 (AB q, 2H).
1C NMR (DMSO-d6, 39.5): 113.97, 128.20, 132.54, 137.90, 157.64,

162.56, 167.14.








IR (KBr): 3090 (w), 3000-2200 (br, m), 1655 (m), 1618 (m), 1565 (br,
s), 1435 (m), 1398 (m), 1322 (m), 1270 (s), 1205 (m), 1172 (m),
1060 (m), 905 (m), 850 (m), 775 (m), 725 (m), 705 (m), 650 (m),
620 (m).
N-(4-Carboxyphenyl)maleanilic Acid/4-[(3-Carboxy-l-oxo-2-propenyl)
amino]benzoic Acid [36847-92-4] (22)

This compound was previously synthesized in these laboratories21
from p-aminobenzoic acid and maleic anhydride, mp 2340C (dec).
H NMR (DMSO-d6, TMS): 6.19 (AB q, 2H), 7.72 (AB q, 4H),10.48 (br, 1H)

IR (KBr): 3350-2010 (br, m), 3310 (m), 3210 (w), 3000 (w), 2840 (br,
w), 2665 (w), 2540 (w), 2240 (w), 1705 (s), 1690 (s), 1625 (m),
1580 (s), 1540 (vs), 1420 (m), 1405 (m), 1325 (m), 1310 (m),
1290 (s), 1265 (m), 1220 (w), 1175 (m), 1120 (w), 1012 (w), 970
(m), 940 (w), 900 (w), 860 (m), 845 (m), 770 (m), 690 (m), 670
(m), 608 (m).
4-[(3-Carboxy-l-oxo-2-propenyl)amino]benzeneacetic Acid (23)
This compound was previously synthesized in these laboratories21
from p-aminophenylacetic acid and maleic anhydride, and was used with-
out further purification.
H NMR (DMSO-d6, TMS): 3.57 (s, 2H), 6.41 (AB q, 2H), 7.41 (AB q,
4H), 10.43 (br, 1H).
IR (KBr): 3280 (s), 3190 (w), 3050 (m), 2720 (w), 2620 (w), 2390 (w),
2240 (w), 1715 (s), 1685 (s), 1615 (s), 1570 (s), 1535 (vs),
1510 (s), 1425 (m), 1400 (m), 1320 (m), 1300 (m), 1265 (m), 1220
(m), 1200 (w), 1180 (m), 1050 (m), 980 (m), 925 (m), 900 (m),
860 (m), 840 (m), 812 (m), 790 (m), 775 (m), 720 (m), 670 (w),
630 (m), 610 (m).








N-[2-(4-Imidazolyl)ethyl]-3,6-endoxo-l,2,3,6-tetrahydrophthalic Acid
(24)

To a 50 mL Erlenmeyer flask was added 2.505 g (0.0136 mol) of

histamine dihydrochloride and 15 mL of water. To the stirred solu-

tion was carefully added 2.286 g (0.0272 mol) of NaHCO3.

Into another flask was placed 2.263 g (0.0136 mol) of 8 and 22

mL of acetone. The solution of free-base (20) in water was slowly

added to the acetone solution with rapid stirring. Addition of addi-

tional acetone (200 mL) was necessary to make the flask contents homo-

geneous. After stirring 1 h, the liquid phase was decanted off, and

the remaining oily precipitate stirred over fresh acetone. The re-

sulting fine white solid was collected and dried in vacuo to give

4.898 g of 24, apparently contaminated by NaC1. The solid gradually

decomposed upon heating to 1350C.

H NMR (D20, DSS): 2.73 (s, 2H), 2.67-3.63 (m, 4H), 5.07 (d, 2H),

6.43 (m, 2H), 7.12 (m, 1H), 8.48 (d, 1H).

IR (KBr): 3660-2730 (m, br), 3240 (m), 3120 (m), 1715 (w), 1650 (s),

1625 (s), 1555 (s), 1430 (m), 1395 (s), 1310 (w), 1270 (m), 1245

(w), 1218 (m), 1183 (w), 1167 (w), 1092 (w), 1060 (w), 1028 (w),

1000 (w), 982 (w), 972 (w), 930 (w), 900 (m), 838 (m), 820 (m),

808 (w), 752 (w), 730 (m), 702 (m), 627 (m),

Succinimides and Succinamic Acids

N-[2-(4-Imidazolyl)ethyl]succinamic Acid/4-([2-(1H-Imidazol-4-yl)
ethyl]amino)-4-oxo-2-butanoic Acid (25)

To an Erlenmeyer flask containing a solution of 0.248 g (2.48

mmol) of succinic anhydride in 5 mL of acetone was added dropwise a








solution of 0.275 g (2.47 mmol) of histamine in 3.5 mL of water, and

the solution was stirred overnight. Absolute ethanol and acetone

were added, and the precipitate was collected and dried in vacuo,

giving 0.239 g (45.8%) of white solid, mp 159-159.50C.
H NMR (DMSO-d6, 2.49): 2.37 (m, 4H), 2.63 (m, 2H), 3.26 (m, 2H),

6.84 (s, 1H), 7.68 (s, 1H), 7.98 (t, 1H).
1C NMR (DMSO-d6, 39.5): 26.68, 29.75, 30.44, 38.87, 117.19, 134.00,

134.73, 171.34, 174.41.

IR (KBr): 3240 (w), 3155 (m), 3100 (m), 3000 (m), 2940 (m), 2855 (m),

1635 (vs), 1610 (s), 1570 (s), 1450 (w), 1420 (s), 1352 (s),

1285 (w), 1205 (s), 1140 (m), 1110 (m), 1065 (w), 1035 (w), 975

(w), 940 (w), 905 (w), 865 (m), 820 (m, br), 770 (m), 720 (m),

640 (m).

N-[2-(4-Imidazolyl)ethyl]succinimide/1-[2-(lH-Imidazol-4-yl)ethyl]-
2,5-pyrrolidinedione (26)

A 25 mL three-necked round-bottomed flask fitted with a stir bar,

condenser, and gas inlet tube was assembled hot and was cooled by flush-

ing the apparatus with Ar. To the cool flask was introduced 0.734 g

(7.34 mmol) of succinic anhydride and 2 mL of distilled DMF. To the

stirred solution was added via syringe a solution of 0.820 g (7.38

mmol) of histamine (20) in 3 mL of DMF. A white solid formed which
dissolved when the mixture was heated. The solution was refluxed for

2.5 h and allowed to cool. DMF was removed in vacuo, leaving a brown

solid which was recrystallized from CHCl3, mp 164-165C.

H NMR (DMSO-d6, 2.49): 2.58 (s, 4H), 2.67 (m, 2H), 3.56 (m, 2H),

6.83 (s, 1H), 7.57 (s, 1H), 8.87 (br, 1H).








C NMR (DMSO-d6, 39.5): 24.83, 28.00, 38.04, 116.36, 133.86, 134.88,

177.57.
IR (KBr): 3440 (w), 3120 (w), 3080 (w), 3035 (w), 2990 (w), 2940 (2),

2830 (m), 2750 (w), 2640 (m), 1765 (m), 1690 (vs), 1575 (m),

1485 (m), 1450 (m), 1438 (m), 1433 (m), 1405 (s), 1330 (s), 1318

(m), 1289 (m), 1260 (w), 1248 (s), 1230 (m), 1150 (s), 1090 (m),
1055 (m), 1030 (w), 1000 (sh, m), 990 (m), 950 (m), 910 (br, m),

840 (m), 825 (m), 798 (m), 772 (m), 660 (m), 630 (m), 608 (w).
N-Acetoxysuccinimide [14464-29-0] (27)

To a dry 250 mL three-necked round-bottomed flask fitted with a
mechanical stirrer, N2 inlet tube and septum cap was added 3.0 g

(0.026 mol) of N-hydroxysuccinimide, 100 mL of anhydrous ether, and

20 mL of distilled THF. Dry pyridine (2.06 g, 0.026 mol) was added

under N2, and the flask was cooled to 0-50C. To the stirred solution

was added dropwise via syringe 1.5 mL (0.0265 mol) of acetyl chloride.

The mixture was stirred for 0.5 h at 00 and then at room temperature

for 1 h. The flask contents were transferred to a separatory funnel

and extracted with 1 N HC1. The organic layer was dried over anhy-

drous MgSO4, the solvent removed in vacuo, and the residue triturated

with hexanes to give white solid. The solid was recrystallized from
benzene-hexanes, filtered, and dried in vacuo to afford 1.496 g (36%)

of needles (27), mp 131-133.5C (literature mp 132-133C).22
1H NMR (CDC13, TMS): 2.33 (s, 3H), 2.82 (s, 2H).

C NMR (CDC13, TMS): 17.50, 25.59, 165.71, 169.41.

IR (KBr): 2990 (w), 2940 (w), 1822 (s), 1795 (s), 1745 (vs), 1430

(m), 1380 (s), 1360 (sh, m), 1298 (w), 1255 (m), 1220 (s), 1170









(s), 1160 (sh, s), 1075 (sh, m), 1060 (s), 1045 (m), 1005 (w),

990 (w), 832 (s), 810 (m), 765 (m), 650 (m).

Vinyl Ethers
N-(B-Vinyloxyethyl)imidazole/l-[2-(Ethenyloxy)ethyl] -1H-imidazole (28)

The general procedure for N-alkylation of imidazole described by

Fournari et al.23 was used. To a nitrogen-flushed 500 mL three-necked

round-bottomed flask fitted with a mechanical stirrer, condenser, and

addition funnel was added 100 mL of freshly distilled THF and 13.2 g

(0.339 mol) of potassium metal. The addition funnel was charged with

a solution of 25.37 g (0.373 mol) of imidazole in 150 mL of THF, which

was added over a 1.5 h period. Refluxing the rapidly stirred mixture

for 2 h consumed all visible potassium. A solution of 40 mL (0.39

mol) of 2-chloroethyl vinyl ether (CEVE) and 20 mL of THF was added

over 1 h, and reflux was maintained an additional 17 h. Precipitated

KC1 was removed by filtration, and the solvent evaporated in vacuo.

The resulting oil was dried over CaH2 and distilled (131.5-134C, 4.0

mm), affording 31.2 g of pale-yellow oil. 1H NMR indicated the pre-

sence of imidazole (-25%). The oil was dissolved in THF and stirred

over NaH overnight. The precipitate was filtered, and the filtrate

concentrated in vacuo and dried over CaH2. Short-path distillation

gave 21.86 g (46.7%) of pure 28, bp 90-92C (0.5 mm),as a colorless

oil. The product was stored over CaH2 at room temperature.

1H NMR (CDC13, TMS): 3.74-4.40 (m, 6H), 6.38 (X of ABX, 1H), 6.98

(m, 2H), 7.47 (s, 1H).

(DMSO-d6, TMS): 3.83-4.47 (m, 4H), 6.46 (X of ABX, 1H), 6.93

(t, 1H), 7.15 (t, 1H), 7.60 (s, 1H).









C NMR (CDC13, 77.0): 44.93, 65.96, 86.48, 118.35, 128.08, 136.36,

149.89.

IR (neat, NaCl): 3115 (m), 2940 (m), 2880 (m), 1620 (br, s), 1506

(s), 1465 (m), 1440 (m), 1365 (s), 1325 (s), 1285 (s), 1230 (s),
1195 (br, s), 1150 (sh, m), 1110 (s), 1092 (sh, s), 1078 (s),

1038 (s), 1028 (sh, m), 990 (m), 963 (sh, s), 952 (s), 915 (m),

906 (s), 820 (br, s), 740 (br, s), 662 (s), 622 (s).

LRMS (m/e, rel. intensity): 138 (M1, 19.2), 137 (11.9), 109 (19.4),

108 (96.4), 95 (14.0), 94 (10.0), 86 (19.7), 84 (32.7), 82

(20.0), 81 (100).
HRMS: m/e 138.07744 (calcd. for C7H10N20 = 138.07931).

Elemental Analysis: Calcd. for C7H10N20: C, 60.85; H, 7.29; N, 20.27.

Found: C, 60.85; H, 7.32; N, 20.28.

N-(B-Vinyloxyethyl)piperidine/1-[2-(Ethenyloxy)ethyll-piperidine
[702-06-71 (29)

This vinyl ether was synthesized via the method of Goette.24
Thus, to a 250 mL three-necked round-bottomed flask fitted with a

magnetic stir bar, condenser, and addition funnel was added 42.5 g

(0.506 mol) of NaHCO3, 25 mL of water and 25 mL (0.253 mol) of piperi-

dine. The addition funnel was charged with 77 mL (0.759 mol) of CEVE

and the contents added over a 1.5 h period to the gently refluxing
mixture. Reflux was maintained for 17 h after addition was complete.
Ether was added to the cool flask, and the organic phase was dried

over NaOH for several days. Ether and excess CEVE were removed under

reduced pressure. The residue was distilled under vacuum, affording








35.2 g (87.0%) of colorless oil (29), bp 75-76.50C (10 mm) [litera-

ture bp 72.3-730C (7.5 mm)].24
H NMR (CDC13, TMS): 1.23-1.88 (m, 4H), 2.22-2.80 (m, 4H), 3.72-4.37

(m, 4H), 6.51 (X of ABX, 1H).
C NMR (CDC13, 77.0): 23.73, 25.34, 54.39, 57.26, 64.82, 85.58,

151.18.

IR (neat, NaCI): 3120 (w), 3080 (w), 3050 (w), 2940 (s), 2855 (m),

2780 (m), 2750 (m), 1635 (m), 1610 (s), 1478 (m), 1455 (m),

1442 (m), 1383 (w), 1352 (m), 1320 (s), 1305 (m), 1280 (m), 1262

(m), 1200 (s), 1160 (m), 1126 (m), 1090 (m), 1080 (m), 1040 (m),
1023 (w), 1000 (m), 984 (m), 962 (m), 945 (w), 862 (m), 810 (s),

780 (w), 760 (w), 700 (w).
B-Vinyloxyethyl(imidazol-4ylmethyl)piperidinium Chloride (30)

The method reported by Tonellato25 was employed. To a 50 mL

one-necked round-bottomed flask containing a stir bar was added 1.338 g

(8.74 mmol) of 4-(chloromethyl)imidazole hydrochloride (31) and 10 mL

of anhydrous methanol. To the stirred solution at room temperature

was added 2.771 g (17.8 mmol) of 29 in one portion, and the solution

was stirred for 0.5 h. Approximately 1 g of Na2CO3 was added, the
mixture stirred for 5 min, and filtered. The filtrate was reduced in

volume on a rotary evaporator and suction filtered again. Slow addi-

tion of the filtrate into ether gave an oily precipitate, which was
taken up in 10 mL of anhydrous methanol, again stirred over ~1 g of

Na2CO3, filtered, and the filtrate reduced in vacuo. The viscous oil

was triturated with acetonitrile, suction filtered and reduced in

volume. Precipitation into ether gave an oily residue. This process









(treatment with Na2CO3, etc.) was repeated 2 additional times to en-

sure complete removal of 29 as its free base. Final drying of the

oily precipitate in vacuo overnight afforded 1.998 g (84%, crude) of

hydroscopic solid (30). Proton NMR revealed the presence of ether

as a major contaminant.

H NMR (D20, DSS): 1.50-2.17 (m, 6H), 3.25-3.69 (m, 6H), 4.17-4.53

(m, 4H), 4.63 (s, 2H), 6.60 (X of ABX, 1H), 7.52 (s, 1H), 7.86

(s, 1H).

1C NMR (D20, DSS): 22.17, 23.15, 58.87, 59.95, 61.80, 63.94, 91.33,

124.57, 129.11, 140.02, 153.18.

IR (KBr): 3600-2500 (br, s), 1625 (s), 1558 (w), 1495 (sh, m), 1465

(m), 1435 (sh, m), 1370 (m), 1325 (m), 1295 (w), 1195 (s), 1090

(m), 1028 (m), 977 (m), 942 (w), 897 (m), 865 (m), 830 (m), 796

(m), 663 (m), 626 (s).

Imidazole and Histamine Derivatives

Histamine/lH-Imidazole-4-ethanamine [51-45-6] (20)

Free base (20) was prepared from histamine dihydrochloride by

three methods.

Method A. The procedure of Tabor and Mosettig26 was used.

A 2% solution of histamine dihydrochloride in 95% ethanol was

slowly trickled through a column of Amberlite IRA-400 ion exchange

resin. The percolate was reduced to an oil on a rotary evaporator,

and distilled under vacuum, bp 134-1350C (0.075 mm) [literature bp

209-210C (18 mm)],27 affording a colorless to pale-yellow viscous

oil. Distilled yields were generally poor and the purity and boiling

point of the product variable.









'H NMR (DMSO-d6, TMS): 2.42-3.00 (m, 4H), 4.97 (br, 3H), 6.77 (s,

1H), 7.54 (s, 1H).

Method B. To a 50 mL Erlenmeyer flask was added 5.638 g (0.03063

mol) of histamine dihydrochloride and -10 mL of H20. To the stirred

solution was added in small increments 5.146 g (0.06125 mol) of NaHCO3,

and the flask was allowed to stand overnight. Solvent was removed in

vacuo, and the resultant colorless oil was triturated with absolute

ethanol. The precipitate was filtered out, and the filtrate reduced

in volume in vacuo. Short-path distillation of the resultant oil

afforded 1.597 g (46.9%) of 20 as a viscous oil, bp 140-143C (1.0 mm).

Spectral properties of this material were identical to those of 20

made by Method A.

Method C. To an Erlenmeyer flask containing 6.728 g (0.0365 mol)

of histamine dihydrochloride dissolved in 10 mL of H20 was added

18.25 mL (0.0730 mol) of 4 N NaOH solution. The solution was stirred

for 0.5 h, and the solvent was removed in vacuo. The resultant thick

oil was triturated with 95% ethanol, filtered, and the filtrate re-

duced to an oil in vacuo. The oil was distilled in a Kugelrohr appa-

ratus (0.050 mm, ~1600C), affording 3.245 g (80%) of a colorless oil,

which crystallized on standing, mp 85-880C (literature mp 83-84C).27

4-(Hydroxymethyl)imidazole Hydrochloride/1H-Imidazole-4-methanol
[32673-41-9] (32)

This material was prepared by the method of Totter and Darby.28

To a 1 L three-necked round-bottomed flask fitted with a mechanical

stirrer and reflux condenser was added 250 mL of benzene, 125 mL of

water and 50 mL (0.6 mol) of 37% HC1. The mixture was brought to 80C








via an oil bath, and 50.0 g (0.153 mol) of 4-(hydroxymethyl)imidazole

picrate was added in one portion. Stirring was continued until all

the solid had dissolved, at which time heating was discontinued and

the flask allowed to cool. The aqueous phase was extracted 5 times

with 150 mL portions of benzene, stirred over ~2 g of Norit-A and con-

centrated in vacuo. Recrystallization from absolute ethanol gave

15.45 g (69.3%) of yellow crystals, mp 105-1090C (literature mp 107-

1090C).28 A second recrystallization from absolute ethanol gave

14.25 g of pale-yellow crystals, mp 107-1100C.
1H NMR (D20, DSS): 5.00 (br, 2H), 7.52 (br, 1H), 8.79 (br, 1H).

1C NMR (020, DSS): 56.00, 119.26, 134.95, 136.37.

IR (KBr): 3500-2500 (br, s), 1615 (s), 1520 (w), 1458 (s), 1450 (sh,

s), 1420 (s), 1362 (m), 1290 (m), 1258 (m), 1252 (m), 1210 (m),

1140 (s), 1070 (s), 1032 (s), 974 (m), 920 (m), 870 (m), 828 (sh,

s), 813 (s), 745 (m), 620 (s).

4-(Chloromethyl)imidazole Hydrochloride/4-(Chloromethyl)-1H-imidazole
Hydrochloride [31036-72-3] (31)

The procedure of Turner et al.29 was employed. To a 100 mL three-

necked round-bottomed flask equipped with a mechanical stirrer, con-

denser, drying tube, and addition funnel was added 14.25 g (0.106

mol) of 32 and 10 mL of benzene. The addition funnel was charged with

11 mL (0.15 mol) of thionyl chloride and 20 mL of benzene, .nd the

solution was added to the rapidly stirred suspension over a 1 h period.

The mixture was refluxed for 2 h, and then allowed to stand at room

temperature overnight. The solid product was suction filtered, washed

with benzene and dried in vacuo. Recrystallization from acetonitrile-









absolute ethanol afforded 11.50 g (71.0%) of off-white crystals, mp

141-144C (literature mp 144C).30
13C NMR (ethanol-d1, 17.2): 33.23, 117.94, 130.03, 134.56.

IR (KBr): 3500-2500 (s, br), 3140 (m), 1615 (m), 1460 (m), 1430 (m),

1290 (m), 1265 (w), 1168 (w), 1147 (m), 1076 (w), 1062 (m), 978

(m), 922 (m), 900 (m), 853 (m), 808 (m), 765 (w), 720 (m), 675

(w), 620 (s).
Dichlorobis(l-[2-(ethenyloxy)ethyl]-1H-imidazole-N3)zinc (33)

The method of Eilbeck et al.31 was employed. In a 25 mL Erlen-
meyer flask was weighed 0.198 g (1.45 mmol) of ZnCl, and 4 mL of ab-

solute ethanol was added. To the stirred solution was added 0.803 g

(5.81 mmol) of 28, the transfer aided by 2 mL of ethanol. The solu-

tion was stirred for 1 h, at which time anhydrous ether was added

dropwise until the solution became turbid. On standing, a colorless

oil precipitated from solution. Enough absolute ethanol was added to

redissolve the precipitate, and the flask was allowed to stand for 12
days. Upon addition of ether, a white crystalline mass precipitated

from solution. The solid was collected, washed with ether, and dried

in vacuo, affording 0.535 g (89%) of 33, mp 78.5-800C.

IR (KBr): 3115 (m), 3040 (w), 2925 (w), 2875 (w), 1635 (sh, m), 1620

(s), 1525 (m), 1442 (w), 1397 (w), 1365 (w), 1322 (m), 1240 (m),
1232 (m), 1187 (s), 1112 (m), 1097 (s), 1033 (m), 992 (m), 952

(m), 850 (m), 830 (m), 760 (m), 668 (m), 653 (m), 630 (m).
Elemental Analysis: Calcd. for C14H20N402.ZnC12: C, 40.75; H, 4.89;

N, 13.58; C1, 17.18. Found: C, 40.72; H. 4.91; N, 13.51; C1,
17.09.








Dichlorobis(1-methyl-1H-imidazole-N3)zinc-(T-4) [23570-24-3] (34)

N-methylimidazole-ZnCl2 complex was prepared in an analogous man-

ner to 33. Thus, the reaction of 0.294 g (2.16 mmol) of ZnC12 and

1.088 g (13.25 mmol) of N-methylimidazole in 15 mL of 95% ethanol gave,

after precipitation with ether, 0.512 g (79%) of fine-white solid (34),

mp 205-208C (literature mp 2090C).32

IR (KBr): 3150 (w), 3125 (s), 1695 (w), 1635 (w), 1588 (w), 1535 (m),

1520 (m), 1425 (m), 1287 (m), 1235 (s), 1105 (s), 1092 (s), 1025

(w), 955 (m), 847 (m), 775 (m), 740 (m), 668 (m), 653 (s), 620

(m), 615 (m).

Elemental Analysis: Calcd. for C8H12N4'ZnC12: C, 31.98; H, 4.02; N,

18.64; Cl, 23.60. Found: C, 32.03; H, 4.07; N, 18.59; Cl, 23.59.

N-[(Ethenyloxy)carbonyl)]-1H-imidazole-4-ethanamine (35) and 7,8-Dihy-
dro-5-oxo-imidazo[l,5-c]pyrimidine (36)

To a 100 mL three-necked round-bottomed flask containing a stir

bar and an addition funnel was added 5.522 g (0.030 mol) of histamine

dihydrochloride, 10 mL of water, and 13 mL of dioxane. To the stirred

mixture was added in portions 7.562 g (0.090 mol) of NaHCO3. The

flask was cooled to 00, and a solution of 3.19 g (0.030 mol) of vinyl

chloroformate in 12 mL of dioxane was added over 25 min. The mixture

was stirred an additional 0.5 h and then warmed to room temperature.

NaCI was filtered, and the filtrate was reduced in volume in vacuo.

The resulting oil was chromatographed on a basic alumina column (3:2

CHC13:methanol eluting solvent). One large fraction was collected;

removal of solvent in vacuo gave 2.361 g of yellow oil. 1H NMR indi-

cated the desired mono acylated product (35) was present. The oil was









rechromatographed on a silica gel column (4% methanol:CHCl3 eluting

solvent). Two products were isolated, 35, 0.108 g (2%), mp 88-890C

and 36, 0.260 g (6.3%), mp 219-221C (dec).

35
H NMR (CDC13, TMS): 2.83 (t, 2H), 3.51 (m, 2H), 4.37-4.79 (AB of

ABX, 2H), 5.67 (br, 1H), 6.83 (d, 1H), 7.16 (X of ABX, 1H), 7.57

(d, 1H), 9.19 (br, 1H).
1C NMR (acetone-d6, 29.8): 28.05, 41.69, 94.13, 116.46, 135.71,

136.87, 143.15, 154.18.

(CDC13, TMS): 27.49, 41.04, 95.28, 115.90, 135.00, 136.12,

142.22, 153.91.

IR (KBr): 3220 (m), 3005 (w), 2965 (w), 2940 (w), 1708 (s), 1647 (m),

1570 (m), 1550 (m), 1485 (w), 1450 (m), 1425 (w), 1362 (w), 1310

(m), 1295 (m), 1277 (m), 1260 (m), 1222 (m), 1190 (w), 1158 (m),

1082 (m), 1040 (m), 983 (m), 974 (m), 952 (m), 860 (m), 820 (m),
785 (m), 764 (w), 735 (w), 700 (w), 617 (m).

LRMS (m/e, rel. intensity): 181 (M+, 0.1), 138 (5.9), 137 (30.6),

82 (10.2), 81 (100).

HRMS: m/e 181.0828 (calcd. for C8H11N302 = 181.0851).

Elemental Analysis: Calcd. for CsH11N302: C, 53.03; H, 6.12; N,

23.19. Found: C, 53.09; H, 6.14; N, 23.20.

36
1 NMR (DMSO-d6, 2.49): 2.84 (t, 2H), 3.26-3.42 (m, 2H), 6.77 (d,

1H), 8.04 (d, 1H), 8.17 (br, 1H).
1C NMR (DMSO-d6, 39.5): 19.27, 38.72, 124.64, 127.33, 134.00, 148.38.









IR (KBr): 3220 (br, m), 3115 (s), 2960 (w), 2940 (w), 2920 (w), 2890

(m), 1735 (sh, s), 1710 (s), 1580 (w), 1473 (m), 1455 (m), 1430

(m), 1410 (s), 1360 (w), 1342 (m), 1327 (m), 1310 (w), 1297 (w),
1258 (w), 1232 (w), 1210 (s), 1180 (m), 1150 (m), 1080 (m), 1060

(m), 1045 (m), 930 (m), 865 (w), 833 (m), 755 (m), 680 (m),650 (m).
LRMS (m/e, rel. intensity): 138 (2.5), 137 (M+, 26.5), 81 (100).

HRMS: m/e 137.05836 (calcd. for C6H7N30 = 137.05891).

Elemental Analysis: Calcd. for C6H7N30: C, 52.55; H, 5.14; N, 30.64.

Found: C, 52.51; H, 5.17; N, 30.65.

N,1-[(Diethenyloxy)carbonyl]-1H-imidazole-4-ethanamine (37)

To a 200 mL three-necked round-bottomed flask equipped with an

addition funnel was added 0.97 g (8.7 mmol) of 20 and 50 mL of ethanol-

free CHCl3. The solution was cooled to 00C, and 1.2 mL (8.6 mmol) of

dry triethylamine was added. The addition funnel was charged with

0.88 g (8.3 mmol) of vinyl chloroformate and 50 mL of CHC13, and the

contents were added over a 2.5 h period. The flask was allowed to

reach room temperature, and water was added. The organic phase was

twice extracted with 50 mL portions of water and dried over anhydrous

MgSO4. Removal of solvent in vacuo gave a white solid which was re-

crystallized from cyclohexane, filtered, and dried in vacuo, afford-

ing 0.40 g (38% based on vinyl chloroformate) of 37, mp 99-1000C.

H NMR (CDCI3, TMS): 2.79 (t, 2H), 3.55 (m, 2H), 4.36-5.24 (2 AB of

2 ABX, 4H), 5.40 (br, 1H), 7.09-7.39 (2 X of 2 ABX, 2H), 7.26

(d, 1H), 8.13 (d, 1H).
C NMR (CDCI3, 77.0): 27.73, 39.96, 94.79, 100.35, 113.65, 136.95,

140.85, 141.67, 141.97, 145.77, 153.42.









IR (KBr): 3240 (m), 3145 (w), 3050 (m), 2940 (w), 1775 (s), 1735 (s),

1640 (m), 1587 (m), 1560 (m), 1488 (m), 1453 (w), 1440 (w), 1406

(s), 1370 (m), 1327 (m), 1295 (m), 1265 (s), 1247 (s), 1215 (m),
1197 (m), 1173 (m), 1138 (m), 1108 (m), 1055 (m), 1010 (m), 982

(m), 965 (w), 952 (m), 943 (m), 880 (m), 847 (m), 838 (m), 752

(m), 730 (m), 680 (w), 668 (w).
LRMS (m/e, rel. intensity): 253 (0.3), 252 (0.7), 251 (M+, 0.8), 210

(2.0), 209 (5.2), 208 (40.0), 207 (8.7), 164 (21.3), 152 (26.9),
151 (38.9), 138 (34.0), 137 (13.0), 95 (24.7), 81 (100).
HRMS: m/e 251.0899 (calcd. for C11H13N304 = 251.0906).

Elemental Analysis: Calcd. for C11H13N304: C, 52.59; H, 5.22; N,

16.73. Found: C, 52.58; H, 5.31; N, 17.21.

4-Allylimidazole/4-(2-Propenyl)-1H-imidazole [50995-98-7] (38)

A 250 mL three-necked round-bottomed flask, mechanical stirring
rod, condenser, and addition funnel were assembled while hot and

cooled by flushing with N2. To the flask was added 3.408 g (0.140

mol) of Mg turnings; the addition funnel was charged with 100 mL of

freshly distilled THF and 10 mL (0.142 mol) of vinyl bromide. Reac-

tion was initiated by addition of a solution of a drop of ethylene
bromide in 10 mL of THF. The vinyl bromide solution was then added

at a rate which maintained a gentle reflux. When formation of Grignard
reagent was complete, the solution was cooled to 0OC via an external
ice bath. To the flask was added 4.289 g (0.0280 mol) of 31 in -15

equal portions over a 2.5 h period. The rapidly stirred mixture was
maintained at 00C for an additional 0.5 h, then allowed to warm to

room temperature and was quenched by careful addition of 20 mL of









saturated NH4Br. Additional water was added to dissolve the pre-
cipitated salts, and the organic layer was separated. The aqueous

layer was extracted with 2-150 mL portions of CHC13, and the combined
organic fractions were dried over anhydrous MgSO4. Solvent was re-

moved in vacuo, giving dark-yellow oil. This oil was chromatographed

on a column of silica gel using a mixture of CHC13:CH30H (95:5) as
eluting solvent. Fractions were combined which gave an Rf 0.30 by
TLC [silica gel, CHC13:CH30H (95.5)]. Removal of solvent in vacuo

afforded 1.372 g (45%) of pale-yellow oil (38) having identical 1H
NMR properties as reported by Begg et al.
1H NMR (CDC13, TMS): 3.30-3.45 (m, 2H), 5.00-5.20 (m, 2H), 5.79-6.20

(m, 1H), 6.81 (d, 1H), 7.60 (d, 1H), 11.05 (br, 1H).
C NMR (CDCI3, TMS): 31.39, 116.14, 117.31, 134.76, 135.25, 135.78.

IR (neat, NaC1): 3500-2300 (br, s), 3080 (m), 3015 (w), 2985 (m),

2850 (br, m), 2740 (w), 2640 (w), 1640 (m), 1588 (m), 1570 (m),
1473 (br, m), 1430 (m), 1323 (w), 1298 (m), 1262 (m), 1230 (m),
1195 (w), 1160 (w), 1105 (m), 1088 (m), 990 (s), 940 (m), 915

(s), 820 (m), 750 (m), 662 (m), 625 (m).
LRMS (m/e, rel. intensity): 109 (6.6), 108 (M+, 68.4), 107 (100),
82 (20.7), 81 (85.5), 80 (86.2), 54 (26.8), 53 (40.9).
HRMS: m/e 108.06875 (calcd. for C6HgN2 = 108.06875).
4-Nitroimidazole/4-Nitro-1H-imidazole [3034-38-6] (39)
This material was prepared in accordance with the method of
Stambaugh and Manthei34 in 31% yield, mp 308-3090C (literature mp
308-310C).34
1H NMR (DMSO-d6, 2.49): 7.83 (d, 1H), 8.29 (d, 1H).









Other Monomers
2-Propenylphenol/(E) and (Z)-2-(1-Propenyl)-phenol [6380-21-8] (40)

This monomer was synthesized via the isomerization of 2-allyl-
phenol as reported by Tarbell.35 The product consisted of both E and

Z isomers (87%), bp 115-1230C (17 mm), [literature bp 110-115C (15-

16 mm)].35
H NMR (CDC13, TMS): 1.69 and 1.86 (2 d of d, 3H), 5.34 (br, 1H),

5.85-7.34 (m, 6H).
1C NMR (CDC13, 77.0): 14.42, 18.71, 115.11, 115.70, 120.33, 120.86,

123.93, 125.25, 127.20, 127.83, 127.98, 128.47, 129.73, 130.86,

152.15.

IR (neat, NaCl): 3540-3300 (br, s), 3060 (m), 3035 (m), 2960 (m),

2935 (m), 2910 (m), 2875 (w), 1850 (m), 1730 (w), 1655 (w), 1605

(m), 1580 (m), 1495 (s), 1483 (s), 1450 (s), 1330 (br, m), 1282

(m), 1225 (br, s), 1172 (s), 1150 (m), 1105 (m), 1080 (m), 1037

(m), 965 (s), 945 (sh, m), 840 (m), 790 (m), 750 (s), 717 (m),
610 (m).
Isoeugenol/2-Methoxy-4-(1-propenyl)-phenol [97-54-1] (41)

Isoeugenol was obtained from the Aldrich Chemical Co. and was
distilled before use, bp 138.5-140.5C (9 mm), [literature bp 1400C

(12 mm)].27
1H NMR (CDCI3, TMS): 1.82 (d, 3H), 3.80 (s, 3H), 5.72 (s, 1H), 5.76-

6.38 (m, 2H), 6.81 (s, 3H).
C NMR (CDC13, TMS): 18.27, 55.80, 108.05, 114.44, 119.31, 123.31,

130.81, 144.80, 146.65.








IR (neat, NaCl): 3540-3400 (s, br), 3015 (m), 2960 (m), 2935 (m),

2910 (m), 2880 (w), 2845 (m), 2730 (w), 1590 (m), 1510 (vs),
1462 (s), 1450 (s), 1423 (s), 1370 (m), 1260 (br, s), 1230 (s),
1205 (s), 1153 (s), 1120 (s), 1030 (s), 960 (m), 920 (w), 905

(w), 855 (m), 820 (m), 802 (m), 783 (m), 755 (w), 732 (w).
trans-Anethole/(E)-l-Methoxy-4-(l-propenyl)-benzene [4180-23-8] (42)
This material was purchased from the Aldrich Chemical Co. and
was used without further purification.
H NMR (CDC13, TMS): 1.82 (d, 3H), 3.73 (s, 3H), 5.92-6.42 (m, 2H),

7.01 (ABq, 4H).
1C NMR (CDC13, 77.0): 18.32, 55.12, 113.85, 123.30, 126.86, 130.37,

130.81, 158.64.
IR (neat, NaC1): 3029 (m), 3000 (m), 2955 (m), 2930 (m), 2910 (m),
2880 (w), 2835 (w), 2730 (w), 1650 (w), 1605 (s), 1575 (m), 1505

(vs), 1462 (br, m), 1440 (m), 1415 (w), 1375 (w), 1305 (m), 1280
(m), 1245 (s), 1210 (w), 1175 (m), 1110 (m), 1035 (s), 962 (m),
940 (m), 837 (m), 785 (m), 755 (m), 710 (w).
N-Ethylmaleimide/1-Ethyl-1H-pyrrole-2,5-dione [128-53-0] (43)

This monomer was purchased from the Aldrich Chemical Co. (Gold
Lable) and was used without further purification.
Diethylfumarate/(E)-2-Butenedioic acid, diethyl ester [623-91-6] (44)
Diethylfumarate (44) was obtained from the Bordon Chemical Co.
and was distilled from CaH2 under reduced pressure, bp 83.5-840C (4.3
mm) [literature bp 75C (5 mm)].36
H NMR (CDCl3, TMS): 1.33 (t, 3H), 4.28 (q, 2H), 6.82 (s, 2H).









Fumaronitrile/(E)-2-Butenedinitrile [764-42-1] (45)

This monomer was purchased from the Aldrich Chemical Co. Re-

crystallization of 45 from benzene gave white needles, mp 94-96.5C

(literature mp 95-970C).37

H NMR (CDC13, TMS): 6.29 (s, 2H).

N-Vinylimidazole/1-Ethenyl-1H-imidazole [1072-63-5] (46)

This monomer was purchased from Polysciences, Inc. and distilled

from CaH2 before use, bp 89-90C (17 mm).
H NMR (CDC13, TMS): 4.77-5.33 (AB of ABX, 2H), 6.89 (X of ABX, 1H),

7.07 (s, 1H), 7.18 (s, 1H), 7.66 (s, 1H).
1C NMR (acetone-d6, 29.8): 101.15, 116.55, 130.10, 130.30, 137.02.

Maleic Anhydride/2,5-Furandione [108-31-6] (47)

Maleic anhydride was obtained from Fisher Scientific Co. and was

sublimed at atmospheric pressure (800C) prior to use, mp 50.5-53C

(literature mp 52.80C).27

Homopolymers
Poly(N-Acetoxymaleimide) (48)

To a heavy-walled polymerization tube was added 2.021 g (0.0130

mol) of 11, 0.0211 g (0.128 mmol) of AIBN, and 25 mL of freshly dis-

tilled CH2C12. After all the solid had dissolved, the tube was de-

gassed (3 freeze-pump-thaw cycles) and sealed at -10-5 mm. Polymeri-

zation was carried out in a constant temperature bath (610C) for 66 h.

The tube was opened and the contents precipitated into ether. The

solid was collected, redissolved in dioxane and reprecipitated into

ether. The solid was again collected and dried in a vacuum oven

(1000C) overnight to afford 1.614 g (80% conversion) of pink powder (48).









H NMR (DMSO-d6, TMS): 2.34 (br-s, 3H), 3.45, 4.13 (br, 2H).

13C NMR (CD3CN-C12CHCHCI2, 600C, 1.30): 17.43, 42.19, 165.74, 169.05,

170.95.

IR (KBr): 2940 (w), 1820 (s), 1790 (s), 1730 (vs), 1625 (w), 1430

(w), 1373 (m), 1220 (s), 1160 (s), 1055 (m), 1000 (w), 820 (m),
725 (w), 640 (m).

Elemental Analysis: Calcd. for C6H5N04: C, 46.46; H, 3.25; N, 9.03.

Found: C, 45.74; H, 3.38; N, 8.88.

VPO (acetone): Mn = 3850 g/mol.

Poly(Phenyl N-Maleimidyl Carbonate) (49)
To a heavy-walled polymerization tube was added 3.143 g (0.01348

mol) of 13, 0.0250 g (0.152 mmol) of AIBN, and 6 mL of distilled ace-

tone. The tube was transferred to a high-vacuum line, degassed in
the usual manner and sealed at -105 mm. The polymerization was car-

ried out in a constant temperature bath (600C) for 89 h. The tube was

opened, and the solution was slowly added dropwise to a beaker of vig-

orously stirred ether. The precipitate was collected and dried in

vacuo giving 2.755 g (87% conversion) of pale-green solid (49).
1H NMR (CD3CN, 1.93): 3.99 (br, 2H), 7.32 (br, 5H).

1C NMR (CD3CN, 70C, 1.30): 42.92, 121.39, 128.50, 131.18, 150.63,

151.95, 169.49.

IR (KBr): 3060 (w), 2940 (w), 1825 (s), 1795 (s), 1735 (vs), 1600

(w), 1588 (m), 1490 (m), 1457 (m), 1375 (m), 1290 (m), 1225 (br,
vs), 1160 (m), 1115 (w), 1070 (s), 1020 (m), 1005 (m), 960 (m),

905 (w), 840 (w), 775 (m), 750 (m), 682 (m), 630 (m).









Elemental Analysis: Calcd. for C11H7N05: C, 56.66; H, 3.03; N, 6.01.

Found: C, 55.44; H, 3.11; N, 6.17.

Poly(N-Hydroxymaleimide) (50) from 48

To a 50 mL Erlenmeyer flask containing a stir bar was added 1.0 g

(0.0144 mol) of hydroxylamine hydrochloride and 20 mL of freshly dis-

tilled methanol. To the stirred solution was added 3.9 mL (0.0144

mol) of 3.7M sodium methoxide. After 0.5 h, the mixture was suction

filtered. To the filtrate was added a solution of 48 in CD3CN and

C12CHCHC12 (NMR sample -150 mg), the transfer aided by rinsing the

tube with acetone. The resulting mixture (pink ppt.) was stirred for

48 h, and the solvents were then removed in vacuo. Trituration of

the resulting solid with water gave pink solid which was suction fil-

tered and dried in vacuo.

C NMR (acetone-d6, 29.80): 42.03, 172.75.

IR (KBr): 3640-2300 (br, m), 3470 (br, m), 2920 (w), 2800 (w), 1785

(m), 1700 (br, vs), 1620 (m), 1470 (br, m), 1385 (w), 1340 (w),

1230 (s), 1120 (m), 1070 (m), 728 (m), 645 (m).

Poly(N-Hydroxymaleimide) (50) from 49

To a 50 mL round-bottomed flask containing a stir bar was added

1.411 g (6.05 mmnol of repeat units) of 49 and 20 mL of methanol. A

reflux condenser was attached, and the mixture was refluxed for 20 h.

The cooled solution was precipitated into 200 mL of benzene-pentane

(2:1). The solid was reprecipitated from acetone into ether, fil-

tered, and dried in vacuo, giving 0.605 g (88%) of tan powder (50).

The product decomposed above 2650C. The IR spectrum of this material

was identical to that of 50 derived from 48.









Elemental Analysis: Calcd. for C4H3N03: C, 42.49; H, 2.67; N, 12.39.

Found: C, 43.75; H, 3.40; N, 11.94.

Poly[N-(4-Carbethoxyphenyl)maleimidel (51)

To a heavy-walled polymerization tube was added 3.423 g (0.01396

mol) of 16, 0.0270 g (0.164 mmol) of AIBN, and 10 mL of freshly dis-

tilled DMF. When all the solid had dissolved, the tube was degassed

(3 freeze-pump-thaw cycles) and sealed at -10-5 mm. Polymerization

was carried out in an oil bath (750C) for 44 h. The tube was opened,

and most of the DMF was removed in vacuo. The resulting oil was dis-

solved in 5 mL of acetone and precipitated into ether. The solid was

reprecipitated from acetone into ether, collected, and dried in vacuo

to give 2.102 g (61% conversion) of pink solid (51).

1H NMR (acetone-d6, 500C, TMS): 1.36 (br, 3H), 4.33, 4.40 (br, 4H),

7.47, 8.08 (br, 4H).

C NMR (acetone-d6, 500C, 29.8): 14.55, 41.74, 45.64, 61.77, 127.47,

130.74, 136.44, 165.83, 175.82.

IR (KBr): 2985 (m), 2940 (w), 2910 (w), 1785 (sh, m), 1715 (vs),

1610 (m), 1510 (m), 1470 (w), 1445 (w), 1415 (sh, m), 1385 (s),

1280 (s), 1185 (s), 1110 (s), 1020 (m), 855 (m), 768 (m), 740

(m), 695 (m), 640 (m).

Elemental Analysis: Calcd. for C13H11N04: C, 63.67; H, 4.52; N, 5.71.

Found: C, 63.13; H, 4.67; N, 6.05.

Poly[N-(B-Vinyloxyethyl)imidazole](52)

All attempts to obtain homopolymer (52) of moderate molecular

weight and in good yield were unsuccessful. Low yields of oligomers

were generally obtained. Polymerization reaction conditions are de-

scribed in Chapter III, p. 97.









Copolymers
N-(B-Vinyloxyethyl)imidazole N-Hydroxymaleimide Alternating Copoly-
mer (53)

To a 100 mL round-bottomed flask was added 2.325 g (0.0168 mol)

of 28 and 39.95 mL (0.0168 mol) of 0.4 N HC1. Most of the water was

removed on a rotary evaporator at room temperature. The resultant

viscous oil was transferred to a heavy-walled polymerization tube

aided by a few mL of deionized water. Into a 5 mL volumetric flask

was placed 2.223 g (0.0143 mol) of 11, and the flask was diluted to

the mark with distilled THF. This solution was added to the polymeri-

zation tube (previously cooled to -780C), and the volumetric flask was

rinsed with 3 mL of THF. Finally, 0.0847 g (0.313 mmol) of K2S208 and

0.1237 g (0.315 mmol) of Fe (NH4)2(SO4)2.6H20 were added. The final

volume of solution was 22 mL. The tube was then degassed on a high-

vacuum line (3 freeze-pump-thaw cycles) and sealed at -10-5 mm. The

tube was placed in a 30.0C water bath for 91 h. The tube was opened

and the contents precipitated into CH3CN. The acetonitrile was de-

canted off, and the oily precipitate was taken up in 40 mL of 1 N HC1

and dialized (2000 MW retention) against deionized water for several

days. The precipitated solid was suction filtered and dried in vacuo

to afford 0.844 g (20% conversion) of light-brown solid (53).
H NMR: See Appendix, p. 122.

13C NMR: See Chapter III, p. 80.

IR (KBr): 3600-3320 (br, m), 3140 (m), 2940 (w), 1780 (m), 1705 (vs),

1575 (w), 1440 (w), 1400 (w), 1355 (w), 1290 (w), 1230 (s), 1105

(s), 1080 (s), 835 (w), 760 (w), 665 (w), 625 (w).









Elemental Analysis: Calcd. for C11H13N304: C, 52.59; H, 5.21; N,

16.73. Found: C, 49.78; H, 4.97; N, 14.68; S, 0.53.

VPO (DMSO): Mn = 488 g/mol.

Intrinsic Viscosity (0.1 N HC1, 30.0C): [n] = 0.112 dL/g.

Dichlorobis(1-[2-(ethenyloxy)ethyl]-1H-imidazole-N3) zinc-- N-Acetoxy-
maleimide Alternating Copolymer (54)

To a heavy-walled polymerization tube was added a solution of

0.327 g (2.40 mmol) of ZnC12 in 6 mL of distilled THF, followed by a

solution of 0.630 g (4.56 mmol) of 28 in THF (3 mL). To this solution

was added 0.703 g (4.53 mmol) of 11, 0.0075 g (0.046 mmol) of AIBN,

and 6 mL of THF. The solution was degassed on a vacuum line and
sealed at -10- mm. Polymerization was carried out at 700C for 3.5 h.

The white precipitate was filtered, washed with THF and dried in vacuo.

The material was extracted (Soxhelet) with THF for 3 days and dried in

vacuo, affording 1.110 g (67.5% conversion) of white solid (54) which

decomposed above 2200C.
13C NMR: See Chapter III, p. 89.

IR (KBr): 3640-3340 (br, m), 3135 (m), 2940 (m), 2880 (w), 1818 (s),

1785 (s), 1730 (vs), 1650 (br, w), 1522 (m), 1440 (m), 1370 (m),

1290 (w), 1220 (s), 1165 (s), 1110 (s), 1095 (s), 1065 (m), 950

(m), 830 (m), 755 (m), 655 (m), 625 (w).
Elemental Analysis: Calcd. for C26H30N6010'ZnCl2: C, 43.20; H, 4.18;

N, 11.63; C1, 9.81. Found: C, 42.35; H, 4.18; N, 10.98; C1,

9.22.
Intrinsic Viscosity (DMSO, 30.0C): [n] = 0.043 dL/g.









N-(B-Vinyloxyethyl)imidazole-- Fumaronitrile Copolymer (55)

To a heavy-walled glass polymerization tube was added 1.878 g

(0.0136 mol) of 28, 1.116 g (0.0143 mol) of 45, 0.0466 g (0.284 mmol)

of AIBN, and 25 mL of distilled CH2Cl2. The tube was transferred to

a high-vacuum line, degassed via several freeze-pump-thaw cycles and

sealed at 410-5 mm. The polymerization was carried out at 600C for

44 h, resulting in red solution containing an oily dark precipitate.

The tube contents were poured into ether. The oily precipitate was

taken up in acetone-methanol and precipitated into chloroform. The

solid was reprecipitated from acetone into carbon tetrachloride and

dried in vacuo (room temperature) overnight, affording 0.367 g of

mustard-brown powder. The mother liquors (from precipitations) were

combined and reduced in volume on a rotary evaporator. Precipitation

into chloroform gave an additional 0.525 g of dark-brown powder.

IR (KBr): 3150 (m), 2970 (m), 2940 (m), 2250 (m), 2200 (s), 2140 (m),

1620 (s), 1545 (m), 1440 (m), 1420 (m), 1355 (w), 1330 (m), 1290

(m), 1170 (m), 1080 (m), 1035 (w), 830 (m), 750 (m), 665 (m),

625 (m).

Elemental Analysis: Calcd. for C11H12N40: C, 61.10; H, 5.59; N,

25.91. Found: C, 60.53; H, 4.38; N, 28.62.

N-(B-Vinyloxyethyl)imidazole-- Diethylfumarate Copolymer (56)

To a polymerization tube was added 1.202 g (8.70 mmol) of 28,

1.199 g (6.96 mmol) of 44, 0.0114 g (0.0694 mmol) of AIBN and 25 mL

of distilled acetone. The tube contents were degassed (4 freeze-

pump-thaw cycles) and the tube sealed at 10-5 mm. Polymerization

was carried out at 600C for 90 h. The acetone solution was









precipitated into cold ether, and the gummy precipitate was dried in

a vacuum oven (50C, 48 h) to give 0.262 g of brittle solid (56).

1C NMR: See Appendix, p. 123.

IR (KBr): 3110 (w), 2980 (m), 2940 (m), 2905 (w), 2870 (w), 1730 (vs),

1595 (m), 1505 (m), 1465 (m), 1445 (m), 1370 (m), 1230 (br, s),

1175 (s), 1160 (s), 1095 (m), 1075 (m), 1025 (s), 905 (w), 855

(m), 815 (w), 740 (m), 660 (m), 620 (w).
Elemental Analysis: Calcd. for C15H22N205: C, 58.05; H, 7.14; N,

9.03. Found: C, 56.82; H, 7.11; N, 6.23.

Isoeugenol --Maleic Anhydride Copolymer (57)

To a dry heavy-walled polymerization tube was added 2.758 g

(0.0168 mol) of 41 and a solution of 1.652 g (0.0168 mol) of 47 and
0.0555 g (0.338 mmol) of AIBN in 10 mL of distilled acetone. The

solution immediately turned yellow in color. The tube contents were

degassed on a high-vacuum line and the tube sealed at -10-5 mm. Poly-

merization was carried out at 600C for 72 h. The viscous acetone

solution was added dropwise to a beaker of rigorously stirred CH2C12,

the precipitate filtered and dried in vacuo affording 2.725 g (62%

conversion) of white solid (57).
1C NMR: See Appendix, p. 124.

IR (KBr): 3580-3300 (m), 2965 (w), 2940 (w), 1855 (m), 1775 (vs),

1605 (m), 1515 (s), 1460 (m), 1430 (m), 1370 (m), 1275 (s), 1235

(s), 1215 (sh, s), 1155 (m), 1130 (m), 1080 (m), 1030 (m), 920

(s), 825 (m), 785 (w), 735 (w), 645 (w).
Elemental Analysis: Calcd. for C14H1405: C, 64.12; H, 5.38. Found:

C, 63.47; H, 5.61.









VPO (acetone): = 6950 g/mol.

Intrinsic Viscosity (acetone, 30.00C): [n] = 0.183 dL/g.

2-Propenylphenol -- Maleic Anhydride Copolymer (58)

To a dry heavy-walled polymerization tube was added 2.331 g

(0.0174 mol) of 40 and a solution of 1.703 g (0.0174 mol) of 47 and

0.0542 g (0.330 mmol) of AIBN in 10 mL of distilled acetone. The

solution became yellow, and the color persisted throughout polymeri-

zation. The tube contents were degassed and the tube sealed at ~10-5

mm. Polymerization was carried out at 600C for 44 h. The viscous

acetone solution was added dropwise to a beaker of vigorously stirred

CH2C12. The precipitate was filtered and dried in vacuo, affording

3.510 g (87% conversion) of white solid (58).

C NMR: See Appendix, p. 125.

IR (KBr): 3660-2500 (m, br), 1855 (m), 1770 (s, br), 1610 (m), 1585

(m), 1485 (m), 1455 (m), 1365 (m, br), 1225 (s), 1150 (s, br),

920 (m, br), 755 (s).

Elemental Analysis: Calcd. for C13H1204: C, 67.24; H, 5.21. Found:

C, 63.94; H, 5.69.
VPO (acetone): ~n = 21,200 g/mol.

Intrinsic Viscosity (acetone, 30.00C): [n] = 0.231 dL/g.

Isoeugenol -- N-[2-(4-Imidazolyl)ethyl]maleimide Copolymer (59)

A 25 mL three-necked round-bottomed flask fitted with a stir bar,

condenser, and gas inlet tube was assembled hot and cooled via flush-

ing with Ar. To the flask was introduced 0.3463 g (1.32 mmol of re-

peating units) of 57 and ~2 mL of distilled DMF. To this solution was

added 0.1707 g (1.54 mmol) of 20 in 0.5 mL of DMF. A white









precipitate was observed. The mixture was refluxed for 6 h and al-

lowed to cool. The viscous solution was added dropwise to a beaker

of rapidly stirred CHC13; the precipitate was filtered and dried in

vacuo. The product was subjected to Soxhelet extraction with CHC13

for 48 h and dried in vacuo, affording 0.473 g of off-white solid (59).

C NMR: See Appendix, p. 126.

IR (KBr): 3550-2500 (br, m), 3140 (m), 1765 (m), 1690 (s), 1615 (m),

1595 (m), 1510 (m), 1445 (m), 1400 (m), 1360 (m), 1270 (m), 1225

(br, m), 1160 (m), 1130 (m), 1080 (w), 1025 (m), 900 (br, w),

820 (m), 785 (m), 650 (w), 620 (m).

Elemental Analysis: Calcd. for C19H21N304: C, 64.21; H, 5.96; N,

11.82. Found: C, 58.75; H, 5.66; N, 10.68.

2-Propenylphenol--N-[2-(4-Imidazolyl)ethyl]maleirmide Copolymer (60)

Copolymer 60 was prepared from 58 by the same method as copoly-

mer 59 Thus, 0.383 g (1.65 mmol of repeat units) of 58 was com-

bined with 0.198 g (1.78 mmol) of 20 in refluxing DMF to give 0.470 g

of off-white product (60).


IR (KBr): 3650-2500 (br, m), 2960 (m), 1765 (m), 1690 (s), 1590 (m),

1483 (m), 1450 (m), 1400 (m), 1360 (m), 1255 (m), 1220 (m), 1160

(m), 1100 (m), 980 (w), 935 (w), 830 (w), 755 (m), 660 (w), 615

(w).
Elemental Analysis: Calcd. for C18H19N303: C, 66.45; H, 5.89; N,

12.91. Found: C, 62.00; H, 5.56; N, 10.55.









trans-Anethole-- Maleic Anhydride Copolymer (61)

To a polymerization tube was added 1.630 g (0.0166 mol) of 47,

0.0534 g (0.325 mmol) of AIBN, 2.464 g (0.0166 mol) of 42, and 10 mL

of distilled acetone. The tube contents were degassed in the usual

manner and sealed at -10- mm. Polymerization was carried out for

20 h at 600C. The gelatinous mass was dissolved in DMF and precipi-

tated into ether. The precipitate was filtered and dried in a vacuum

oven (900C, 1 mm) for 48 h, affording 2.065 g (50% conversion) of

white solid (61).
1C NMR: See Appendix, p. 127.

IR (KBr): 2960 (m), 2940 (m), 2840 (w), 1860 (m), 1780 (vs), 1610

(m), 1580 (w), 1510 (s), 1465 (m), 1440 (m), 1390 (w), 1335 (m),
1305 (m), 1255 (s), 1180 (s), 1080 (m), 1030 (m), 920 (s), 830

(m), 815 (sh, m), 738 (m).
Elemental Analysis: Calcd. for C14H1404: C, 68.28; H. 5.73. Found:

C, 68.11; H, 5.77.

trans-Anethole -- N-[2-(4-Imidazolyl)ethyl]maleimide Copolymer (62)

Copolymer 62 was prepared from 61 by the same method as copoly-
mers 59 and 60. Thus, 0.422 g (1.71 mmol of repeat units) of 61 was

combined with 0.200 g (1.80 mmol) of 20 in refluxing DMF to give 0.402

g of off-white product (62).


IR (KBr): 3440-2800 (br, m), 2940 (m), 2840 (m), 1770 (m), 1695 (s),
1610 (m), 1580 (w), 1510 (s), 1460 (sh, m), 1440 (m), 1400 (m),

1355 (m), 1300 (w), 1250 (m), 1180 (m), 1160 (m), 1105 (w), 1085

(w), 1030 (m), 975 (w), 930 (w), 830 (m), 730 (w), 660 (w), 615
(m).









Isoeugenol-- N-Ethylmaleimide Copolymer (63)

To a polymerization tube was added 1.5315 g (0.0122 mol) of 43,

0.0397 g (0.242 mmol) of AIBN, 2.010 g (0.0122 mol) of 41, and 10 mL

of distilled acetone. The tube contents were degassed and the tube

sealed at -10-5 mm. Polymerization was carried out at 600C for 38 h.

The acetone solution was added dropwise to a vigorously stirred beaker

of ether. The precipitate was filtered and dried in vacuo, affording

3.117 g (88% conversion) of white solid (63).
13C NMR: See Appendix, p. 128.

IR (KBr): 3680-3100 (br, m), 2970 (m), 2940 (m), 2880 (w), 2840 (w),

1770 (m), 1690 (vs), 1600 (m), 1510 (s), 1450 (m), 1405 (s),

1375 (m), 1350 (m), 1270 (m), 1225 (s), 1130 (m), 1030 (m), 940

(w), 895 (w), 860 (w), 810 (m), 790 (m), 770 (w), 730 (w), 650

(m).
Elemental Analysis: Calcd. for C16H19N04: C, 66.42; H, 6.62; N, 4.84.

Found: C, 65.66; H, 6.64; N, 5.03.

VPO (acetone): Mn = 25,200.

Intrinsic Viscosity (acetone, 30.00C): [n] = 0.276 dL/g.

2-Propenylphenol -- N-Ethylmaleimide Copolymer (64)

To a polymerization tube was added 1.8594 g (0.01486 mol) of 43,

0.0485 g (0.295 mmol) of AIBN, 1.994 g (0.01486 mol) of 40, and 10 mL

of distilled acetone. The tube contents were degassed in the usual

manner and the tube sealed (-10-5 mm). Polymerization was carried out

at 60C for 38 h. The acetone solution was added dropwise to ethyl

ether, the precipitate filtered and dried in vacuo, affording 1.286 g

(33% conversion) of white solid (64).








13C NMR: See Appendix, p. 129.

IR (KBr): 3660-3100 (br, m), 2975 (m), 2940 (m), 2880 (w), 1770 (m),

1695 (vs), 1605 (m), 1500 (m), 1485 (m), 1450 (s), 1405 (s),

1378 (m), 1350 (s), 1225 (s), 1135 (m), 1095 (m), 1040 (w), 935

(m), 850 (w), 830 (w), 810 (m), 755 (m), 680 (w).
Elemental Analysis: Calcd. for C15H17N03: C, 69.48; H, 6.61; N, 5.40.

Found: C, 67.01; H, 6.51; N, 6.25.
Intrinsic Viscosity (acetone, 30.00C): [n] = 0.083 dL/g.

Miscellaneous Reactions
Reaction of N-Acetoxymaleimide (11) and N-(B-Vinyloxyethyl)imidazole
(28). Preparation of N-Acetoxymaleimide Cyclotrimer (65)

To a 50 mL Erlenmeyer flask was added 4.038 g (0.0260 mol) of 11
and 10 mL of CH2Cl2. To this colorless solution was added a solution

of 0.0180 g (0.130 mmol) of 28 in 1 mL of CH2C12. Immediately a red

color became apparent which intensified with time. The flask was

allowed to stand at room temperature for 165 h. The dark-red solu-

tion was added dropwise to a beaker of vigorously stirred ether. The

precipitate was filtered and dried in vacuo at 100C to afford 0.66 g

(16.3%) of purple powder (65).
H NMR (CD3CN, TMS): 2.29 (br, ~3H), 3.00-4.60 (br-m, ~2H).
13C NMR: See Appendix, p. 130.

IR (KBr): 2945 (w), 1820 (s), 1790 (s), 1740 (vs), 1430 (w), 1375

(m), 1225 (s), 1160 (s), 1065 (m), 1005 (w), 820 (m), 670 (w),
645 (w).
Elemental Analysis: Calcd. for (C6H5N04)3: C, 46.46; H, 3.25; N,

9.03. Found: C, 46.40; H, 3.24; N, 9.03.









LRMS (m/e, rel. intensity): 465 (m 0.1), 423 (0.4), 113 (0.4), 60

(19.3), 45 (24.4), 44 (61.8), 43 (100).

VPO (acetone): Mn = 488 g/mol

Reaction of Maleic Anhydride (47) and N-(8-Vinyloxyethyl)imidazole (28)

To a 125 mL Erlenmeyer flask was added 0.967 g (7.00 mmol) of 28
and 20 mL of CH2Cl2. To this colorless solution was added 0.687 g

(7.00 mmol) of 47. The solution immediately turned yellow in color

and eventually became brown. The flask was allowed to stand for 11

days. The solution was decanted, leaving a black precipitate which

was removed from the flask and stirred with 100 mL of acetone for 3 h.

The solid was filtered and dried in vacuo, affording 0.897 g of brown

powder.

IR (KBr): 3650-2320 (br, m), 3140 (m), 2950 (w), 1770 (s), 1720 (br,

s), 1620 (m), 1580 (m), 1555 (m), 1445 (w), 1380 (br, m), 1220

(br, m), 1190 (m), 1135 (m), 1085 (m), 1035 (m), 935 (m), 830

(m), 750 (m), 665 (w), 625 (m).
Reaction of N-Hydroxymaleimide (14) and N-(B-Vinyloxyethyl)imidazole
(28)

To a 50 mL Erlenmeyer flask was added 0.326 g (2.88 mmol) of 14

and 10 mL of distilled acetone. To this pale yellow solution was

added 0.406 g (2.94 mmol) of 28. The solution immediately assumed a

darker yellow color, and a precipitate began to form. After stirring

for 20 h, the precipitate was filtered, washed with acetone and dried

in vacuo, affording 0.421 g of yellow solid which decomposed upon

heating to 1800C.









IR (KBr): 3140 (w), 3100 (w), 2940 (w), 1785 (m), 1695 (br, s), 1615

(m), 1570 (w), 1555 (w), 1540 (w), 1415 (w), 1360 (w), 1320 (w),

1235 (br, m), 1190 (m), 1080 (m), 955 (w), 830 (w), 740 (w),

690 (m).

Elemental Analysis: Calcd. for (C4H3NO3)3-C7H10N200H20: C, 46.06; H,

4.27; N, 14.14. Found: C, 45.92; H, 4.21, N, 13.96.

Kinetic Measurements

Equipment and Materials

Pseudo first-order kinetics were measured on Cary 17-D or Perkin-

Elmer 330 spectrophotometers. Temperature control was provided by a

Lauda K-2/R (40.0 0.20C) or a Haake A80 (25.0 0.20C) constant

temperature apparatus. A Corning-125 pH meter fitted with a Ag/AgCl

pH electrode was used to measure the pH of solutions before and after

the reaction with substrate. p-Nitrophenyl acetate (PNPA) was obtained

from the Aldrich Chemical Co. and was recrystallized from cyclohexane

before use, mp 77-78C (literature mp 81-820C).38 2,4-Dinitrophenyl

benzoate (DNPB) was kindly supplied by Ms. Ann Mobley.39 Deionized

water was distilled in glass before use. DMSO and THF were purified

as previously described. Tris(hydroxymethyl)aminomethane (Tris) was

obtained from Fisher Chemical Co. and was used without further purifi-

cation.

Kinetic measurements were carried out under two sets of condi-

tions: Method A for the catalysts imidazole, 50, and 53, and Method

B for catalysts 26, 59, 60, 62, 63 and 68.

Buffer Solutions

In Method A, two stock buffer solutions were prepared, 0.1M Tris









and 0.1M Tris-HC1, both having an ionic strength (y) of 0.1 (KC1).

The first solution was prepared by adding 12.114 g (0.100 mol) of Tris

and 7.455 g (0.100 mol) of KC1 to a 1 L volumetric flask and diluting

to the mark with distilled water. Tris*HCI was prepared by adding an

ampule of 0.1 N HC1 (Acculute), 12.114 g (0.100 mol) of Tris and 7.455 g

(0.100 mol) of KC1 to a 1 L volumetric flask and diluting to the mark

with distilled water. These two solutions were combined to give a

buffer solution of the desired pH. Thus a 2:1 volume ratio of Tris-

HCl:Tris gave a pH of 7.86 and a 3:1 ratio of Tris-HCl:Tris gave a pH

of 7.68 at 250C.

In Method B, two 80% DMSO:H20 (v/v) stock solutions were prepared,

both 0.02M in Tris or Tris-HC1, i = 0.02 (KC1). The first solution

was prepared by adding 1.2114 g (0.010 mol) of Tris, 0.7455 g (0.010

mol) of KC1, and 100 mL of distilled water to a 500 mL volumetric

flask and diluting to the mark with distilled DMSO. The second solu-

tion was prepared in the same manner, substituting 100 mL of 0.1N HC1

(aq) for 100 mL of distilled water. Again, the solutions were com-

bined to give buffer solution of the desired pH. Thus, a 4:1 volume

ratio of Tris-HC1:Tris gave a pH of 8.9.

Substrate Solutions

In Method A, a stock solution of PNPA (2.69 x 10 M) in aceto-

nitrile was used. In Method B, stock solutions of PNPA (1.60 x 10-3M)

in DMSO and DNPB (1.60 x 10-3M) in THF were employed.

Catalyst Solutions

In both Methods A and B, catalyst solutions were prepared accord-

ing to the concentration of functional groups. Due to difficulty in









determining the exact composition of copolymers, it was assumed that

the copolymers studied were strictly 1:1 alternating copolymers. The

contribution to the molecular weight by endgroups was also neglected

in all polymer catalysts. Thus, stock solutions of all copolymer

catalysts studied in Method B were -5.33 x 10-3N in repeat units dis-

solved in 0.02M Tris buffer of the desired pH.

Kinetic Method

The following paragraph describes the kinetic method using the

Cary 17-D spectrophotometer. The same procedure was used in conjunc-

tion with the Perkin-Elmer 330 spectrophotometer with the exception

that each sample cell required a corresponding reference cell. To

each of 6 -one cm path length quartz cells was added 3.0 mL of buffer

solution via pipet. To 4 of the cuvettes was added 150 pl of catalyst

solution via micropipet; to the other 2 cuvettes was added 150 i1 of

buffer solution. To one of the latter cuvettes was added 50 pl of

substrate solvent (CH3CN, DMSO, or THF), and it was placed in the

reference beam of the spectrophotometer. The remaining 5 cuvettes

were placed in the sample compartment to equilibrate thermally. The

sample cuvettes were then each charged with 50 pi of substrate solu-

tion, agitated by inverting the sample holder, and replaced in the

sample compartment. The release of p-nitrophenolate ion (Method A -

400 nm, Method B 416 nm) or 2,4-dinitrophenolate ion (Method B -

370 nm) was observed at constant wavelength at constant time intervals.

The reaction was followed for at least 10 half-lives as judged by

the constancy of the absorbance readings (A_). A plot of In (A~-At)

vs time (t) was constructed, and the negative slope of the best






59


straight line as determined by the least squares program of a Texas

Instruments TI-55-II calculator gave the desired rate constants

(kmeas). As kmeas is the sum of the catalyzed (kobs) and uncatalyzed
(kblank) rate constants, it was necessary to subtract kblank from

k means to obtain kobs. Furthermore, the second-order rate constant

(kcat) was calculated from the relation kcat = kobs/[catalyst]. In

the case of slow reactions where A_ was not obtained in a reasonable

time, kmeas was determined by the method of Kezdy and Swinbourne,

which is described in a monograph by Espenson.41















CHAPTER III

RESULTS AND DISCUSSION

As was stated in Chapter I, alternating copolymers containing

pendant groups which would exhibit cooperative behavior in the hydrol-

ysis of an ester substrate were sought. It was decided to utilize

substituted vinyl ether and maleimide monomer pairs in order to achieve

the desired alternation of pendant functional groups, as this combina-

tion of monomers is known to give regularly alternating copolymers

under free-radical initiation conditions.1 The selection of catalyt-

ically active functional groups was made possible by the work of

Kunitake et al.6'4244 In these studies, it was shown that the hydrox-

amic acid group is an excellent acylation catalyst for activated ester

substrates. However, decomposition of an acylhydroxamate is a slow

process. In order to obtain a useful catalyst, i.e., one with effi-

cient turnover of the catalytic group, the deacylation rate must be

comparable to the acylation rate. Kunitake and Okahata6 found that

introduction of an imidazole group into the polymer will accelerate

the deacylation process. It was concluded that the imidazole group

assists deacylation of the acylhydroxamate intermediate either by

acting as a general base or as a nucleophilic catalyst as depicted

below.





61




0 H 0
4N O-0-H,_: H N H +. H
Ph OCH3 Ph O-
0 + CH COOH

or




O 0
N \ 1-- 4 H N CH3 X+.>H
Ph OCCH Ph 0 0
11 3
0


H2O


CH3COOH + N 0 N H

Ph OH



With this information in mind, the synthesis of maleimide and

vinyl ether monomers substituted with imidazole and hydroxamic acid

functionalities was initiated. Initial effort was directed at attach-

ing an imidazole group to a maleimide; however, due to the base sensi-

tive nature of maleimides,45 it was decided that the hydroxamic acid-
maleimide combination would be more comparable. This logic dictated
that the complementary vinyl ether monomer should contain an imidazole

group. In the next section are described several strategies to carry


out this objective.









Imidazole --Maleimides
Our initial attempt to prepare an imidazole maleimide is out-
lined schematically below.


02N H2N
N HNO N H
r{\ ^ -, -- _"._ n
H2SO4 2
H H H
39

47

0 0 0 H 0
-H20 /


H H



34
Imidazole was nitrated via a literature procedure34 to afford 4-
nitroimidazole (39). We envisioned obtaining the desired N-(4-imida-
zolyl ) maleimide via reaction of 4-aminoimidazole with maleic anhy-
dride (47) followed by dehydration of the resulting maleamic acid.
This attempt was thwarted by the inability to obtain 4-aminoimidazole
from reduction of 39. Indeed, 4-aminoimidazole is very unstable and
has been isolated only as dihydrochloride and sesquipicrate salts.46
Our attempts to convert 39 to 4-aminoimidazole are outlined in Table II.
In lieu of 4-aminoimidazole, the reactions of histamine (20) and
2-aminothiazole with maleic anhydride were carried out. Although the
maleamic acids were obtained in reasonable yield, attempts to effect










TABLE II

Hydrogenation of 4-Nitroimidazole (39)


Reaction Conditions Work Up Comments


H2/5% Pd on C DMSO solution diluted black tar obtained
DMSO/1 atm. with ether, treated
with anhy. HC1

H2/10% Pd on C DMSO solution diluted black tar obtained
DMSO/-4 atm. with benzene, treated
with anhy. HC1

Fe/HC147 benzene solution black tar obtained
benzene treated with anhy. HC1

3% Na(Hg)48 added Hg(OAc)246 gray solid obtained
methanol



dehydration to the corresponding maleimides by the method of Searle49

were unsuccessful.


H2N N

20





H2N + 47
2-


+ 47


0
OH


0 S









Another strategy to synthesize N-[2-(4-imidazolyl)ethyl]malei-
mide is outlined below.


0 0
H

H H
8 0


SI-H20
0 0 0

0 ~HN H







Reaction of the furan-maleic anhydride Diels-Alder adduct (8) with
20 afforded compound 24 in good yield. Dehydration of this succinamic
acid derivative was also unsuccessful using the Ac20/NaOAc49 and N,N-
dicyclohexylcarbodiimide (DCC)/DMF50 procedures.
Hydroxamic Acid --Maleimides
The simplest hydroxamic acid --maleimide is N-hydroxymaleimide
(14). The acidity of hydroxamic acids is comparable to the acidity of
carboxylic acids;51 thus, one would expect hydroxamic acid groups in-
corporated into a polymer to be significantly ionized in neutral or
basic media. As N-hydroxysuccinimide has a pka of -6.0,52 it was be-
lieved copolymerization of 14 would fulfill the hydroxamic acid re-
quirement.









Ivanov et al.53 reported the synthesis of 14, and we attempted to

duplicate this synthesis as outlined below:




OH
0 0 NH OH I 14


47 17 ON
C N-OH

66

Treatment of maleic anhydride (47) with hydroxylamine afforded

N-hydroxymaleamic acid (17) in 60% yield. We attempted dehydration

of 17 using the Ac20/NaOAc49 and P20 /DMF50 methods, but were unable

to isolate 14. Narita et al.50 had also studied the dehydration of

17 using the following reagents: P205, SOC12, Ac20, p-toluenesulfonic

acid, DCC, and acetyl chloride in pyridine. Reaction of 17 with P205

in DMF gave N-hydroxyisomaleimide (66) and not 14 as reported by

Ivanov et al. Neither 14 or 66 was obtained by Narita et al. using

the other above mentioned dehydration reagents.

In another publication by Narita et al.15 was described the syn-

thesis of N-acetoxymaleimide (11). We felt this monomer would better

suit our needs than 14 itself. It has been observed by Kunitake

et a.43 that polymerization of monomers containing unprotected hydrox-

amic acid groups is difficult, because the hydroxamic acid group is

tautomeric with the nitrone structure, and nitrones are efficient

free-radical trapping agents.










/OH OH 0
-C-N = -C=N
R R

hydroxamic acid nitrone

Therefore, it seemed advisable to use a maleimide containing a
protected hydroxamic acid group for polymerizations. Protected male-

imide (11) was synthesized via the steps outlined below. The yields
indicated are those obtained in this laboratory.

0 0

+ 0 +- OH 88%

47 8
NH20H
MeOH
0 0 75%

d)-OAc Ac20 -OH 65%

10 0 9 0



25 mm 82%
82%
N
OAc
11
The reverse Diels-Alder reaction of N-substituted maleimide
adducts of furan is a powerful method for synthesis of N-substituted
maleimides which cannot be obtained from the direct dehydration of the
corresponding maleamic acids. Indeed, isomaleimide formation was not

a side reaction in this synthesis.









The preparation of N-hydroxymaleimide (14) itself was described

in two publications by Akiyama et al.17,54 This synthesis also em-

ployed the furan-maleic anhydride Diels-Alder adduct as a means to

obtain maleimide (13), the methanolysis of which gave 14. The reac-

tion scheme along with yields obtained in this laboratory is outlined

below.




0 0 0 0

-OH OCOCl
OY-oH -00COCOCOPh 56%
DMF, EtN h 56%

9 0 12


bromo-
benzene
0 1600C

OH MeH -OCOPh
0-H -H-- I-0 OPh-
0 43% 0 82%

14 13



Carboxylic Acid --Maleimides

The carboxylic acid group has been incorporated into synzymes55,56

and also plays a key role in the "charge-relay system" of the natural

enzyme chymotrypsin.57 We attempted the synthesis of carboxylic acid

containing maleimide monomers for two reasons: evaluation of bifunc-

tional synzymes containing the carboxylic acid residue, and conversion
58
of the carboxylic acid group via its N-hydroxysuccinimide ester5 to a

hydroxamic acid group.







The direct dehydration of maleanilic acids 22 and 23 were unsuc-
cessfully carried out using the following reagents: Ac20/NaOAc,49
DCC/DMF,50 DCC/CH2C2 59 and refluxing xylene.60 On the other hand,
maleanilic acid 15 was cleanly dehydrated to maleimide 16 in 83% yield
using Ac20/NaOAc.



0 0 0 1 O 00
OH NH 0 H H H

0 0 0 0
CO2H CH2CO2H CO2Et CO2Et
22 23 15 16


Clearly, the presence of the second carboxyl group in 22 and 23
is in some way responsible for the inability to effect dehydration.
Other workers61 have reported on the inability to dehydrate amino acid-
maleamic acids, and the synthesis of maleoylamino acids by modification
of maleimide itself has only recently been reported.20'62 Using this
former procedure, N-carbethoxymaleimide (18) was synthesized in 44%
yield.



C C02C2Et
0 Et O, 0C o0
H C02Et








Imidazole -- Vinyl Ethers
Although imidazole substituted vinyl ethers have not been re-
ported in the literature, we were able to synthesize these compounds
in some cases via modification of standard procedures. Our first
attempt involved the vinyl transetherification reaction as reported
by Watanabe and Conlon.63

or N

cat. Hg(OAc)2 ( )
H H


Thus, 2-benzimidazole methanol was treated with an excess of ethyl
vinyl ether or n-butyl vinyl ether at reflux in the presence of a
catalytic amount of mercuric acetate. 1H NMR analysis of the reaction
mixtures (upon removal of excess vinyl ether) indicated that no reac-
tion had taken place. A possible explanation for the failure of the
desired reaction to work was the observation that 2-benzimidazole
methanol was largely insoluble in both ethyl vinyl ether and n-butyl
vinyl ether.
A different approach to this class of compound was more fruitful.


1) K, THF
0 2)
H CDMSO
28

Alkylation of the potassium salt of imidazole with 2-chloroethyl vinyl
ether (CEVE) in DMSO afforded desired N-(B-vinyloxyethyl)imidazole (28)








as a colorless oil in 46% yield. Vinyl ether (28) was also synthesized
via the sodium salt (NaH) of imidazole, albeit in lower yield (25-30%).
Although 28 is a tertiary (N-substituted) imidazole, it was believed
that the position of substitution would not significantly hinder this
compound's ability to catalyze deacylation of the acylhydroxamate in-
termediate in esterolysis reactions.42
A 4(5)-substituted imidazole --vinyl ether, B-vinyloxyethyl(imida-
zol-4ylmethyl)piperidinium chloride (30), was synthesized, and its
ability to copolymerize with maleimide (16) was studied.


Cl-

Cla N I MeOH
Cl 1 -HC1 + 2 H
H N


31 29 30

Reaction of N-(B-vinyloxyethyl)piperidine (29) and 4-(chloromethyl)-
imidazole hydrochloride (31) gave 30 in yields of 70-80%. Vinyl ether
30 proved very difficult to purify, requiring repeated treatment with
Na2CO3 in methanol and precipitation into ethyl ether to remove excess
29 as its free base. Furthermore, 30 was isolated as a gummy hygro-
scopic solid, and attempts to isolate 30 as its hydrochloride salt re-
sulted in rapid hydrolysis of the vinyl ether group. Vinyl ether 30
was consequently used for copolymerization studies in free base form.
Despite prolonged drying in vacuo, a major contaminant in 30 was
ethyl ether as determined from 1H NMR.








Another attempt at preparation of a 4(5)-substituted imidazole--

vinyl ether is outlined below.




1) Mg, THF V N
SO C1 72) 31

H
67

The covalently bound chlorine atom in 31 is extremely labile to nucleo-

philes as reported by Turner et al.29 It was postulated that vinyl

ether 67 could be obtained by slowly adding 31 to a solution of 2-

chloroethylmagnesium chloride. The free base of 31 is not stable,

presumably due to self-condensation, which necessitated the use of 31.

However, CEVE reacted with Mg turnings in THF to give an insoluble

Grignard reagent. Addition of 31 resulted in no 67 being formed.

Other Imidazole Monomers

A search for other imidazole containing monomers which might

alternately copolymerize with N-substituted maleimides was conducted.

Convinced that the reaction of a Grignard reagent with 31 as described

above should work, the reaction of vinylmagnesium bromide with 31

afforded 4-allylimidazole (38) in 45% yield.


1) Mg, THF
SBr 2) 31 /









This compound had previously been synthesized and characterized by

Begg etal.33 from the pyrolysis of N-allylimidazole, giving approxi-

mately equal amounts of 2- and 4-allylimidazole. Our synthesis thus

represents a new and regiospecific method of obtaining 38. In view of

the report that allylphenols and N-substituted maleimides copolymerize

in alternate fashion,11 copolymerization studies with 38 were carried

out.

It was postulated that N-substituted maleimides might also alter-

nately copolymerize with vinyloxycarbonyl-substituted imidazoles, due

to similarities in structure between vinyl ethers, vinyl esters, and

vinyl carbamates. An empirical comparison of monomer reactivities can

be found in the Q-e scheme introduced by Alfrey and Price.64 The e

value, which is a measure of monomer polarity, is positive for elec-

tron-deficient olefins such as N-phenylmaleimide (e = +3.24) and nega-

tive for electron-rich olefins such as CEVE (e = -1.58), vinyl acetate

(e = -0.88), and vinyl N,N-diethylcarbamate (e = -1.10).65 The reac-

tion of histamine (20) and vinylchloroformate (VOC-C1) was therefore

studied.

The reaction of 20 and VOC-Cl was carried out in organic solvents

in the presence of an organic base over a range of temperatures.




VOC-C1 0 0
solvent, RN 6-38%
20 -_430 15C 3 H 76-38%

37









In each case, the major isolable product was a diacylated hista-

mine as evidenced by mass spectrometry (M = 251), 1H NMR (presence

of 2 ABX patterns), and 13C NMR (11 resonances). In the IR spectrum,

carbonyl stretching frequencies were observed at 1775 and 1735 cm-1

There are three sites on 20 which might be acylated, N N and

N 66




H


Difficulty was encountered in determining the sites of substitution.

Structure 37 was tentatively assigned as the Na, NT isomer, although

the N", N' and N", Na structures cannot be ruled out. The IR carbonyl

stretching frequencies were especially disturbing in view of the car-

bonyl stretch (1710 cm- ) observed for the monoacylated histamine (35).

In Table III is reported the conditions and yields obtained in the

reaction of 20 with VOC-C1.

TABLE III
Acylation of Histamine (20) with VOC-C1

20(equiv) VOC-C1 (equiv) Solvent Base (equiv) T (C) %Yield 37a

1.0 1.0 dioxane Et3N (1.0) 12-14 6.2

1.0 0.95 CHC13b Et3N (0.95) 0-5 38

1.0 0.95 CHC13 0 22

1.0 0.95 CHC3b Et3N (0.95) -43 33

1.0 0.95 CHCI3 pyridine (XS) -43
a yield based on VOC-C1
bethanol-free CHC13









When the reaction of 20 and VOC-C1 was carried out under aqueous

conditions, the monoacylated histamine 35 was obtained in low yield.


3.0 equiv.NaHCO3 0-
202HC1 H-dioxane NH
VOC-C1, 00C N
2%
35
H
Evidence for structure assignment is based on mass spectrometry (M =

181), 1H NMR (broad one proton signals at 5.67 and 9.19 ppm), and 13C
NMR (8 resonances). When 35 was heated above its melting point, a

reaction involving displacement of a vinyloxy group took place.


H 0 2 S 2
N-"N\ N



36 zapotidine

This compound was assigned structure 36 on the basis of mass spectro-

metry (M+ = 137), 1H NMR (loss of vinyl signals), and 13C NMR (6 reso-

nances). Furthermore, H-2 (the proton flanked by both nitrogen atoms

of the imidazole ring) appears further downfield (8.04 ppm) than usual.

Comparison with the 1H NMR spectrum of zapotidine (H-2 = 8.42 ppm)

confirms that the downfield resonance of H-2 can be attributed to the

deshielding effect of the carbonyl group.67 No copolymerization stud-

ies were conducted with 35 due to difficulties in obtaining sufficient

quantities to work with. It was also suspected that 35 rearranged to

36 while being chromatographed on silica gel.









Copolymerization of Maleimides with N-(B-Vinyloxyethyl )imidazole (28)

Addition of 28 to a CH2C 2 solution of 11 resulted in the imme-

diate appearance of a blood-red color which intensified with time. No

color change occurred when CEVE was added to a solution of 11. The

red color was also apparent in solutions of N-vinylimidazole (46)--

11 and N-methylimidazole-- 11, suggesting that the imidazole group was

responsible for the red coloration. After appreciable reaction times,

the red solutions were precipitated into hexanes or ether-giving pale-

red solids in each case. Evaporation of the filtrate in vacuo gave an

oil whose 1H NMR spectrum revealed a preponderance of N-substituted

imidazole over 11. The red solids appeared to be the same substance

as judged from their IR spectra (1820, 1790, 1740, 1225, 1160 cm-')

and appeared to be the homopolymer of 11. The belief that N-substi-

tuted imidazoles were catalyzing homopolymerization of 11 was demon-

strated by carrying out the reaction using 0.5 mol% of 28.



OAc

0
0 0 0.005 equiv. 28. AcO- 16%

1 0
S3 N0
0
OAc
11 65

Further insight as to the structure of 65 was gained by determin-

ing the molecular weight by VPO (fn = 488). This information revealed

that 65 was most likely a trimer of 11.









A search of the literature revealed that this reaction had been

reported previously, and the major product was a maleimide cyclotri-

mer.68 Wagner-Jauregg and Ahmed69 invoked a zwitterionic mechanism

to account for the observed product.






R1 R R R
N.
0 0-




+ 2 x iR

0


0 R R
0 0


R0 R


0 R 0
R

Furthermore, in addition to the desired Michael adduct, 1-25% of male-

imide cyclotrimer was formed when imidazole was reacted with N-substi-

tuted maleimides in stoichiometric amounts.68











=Lmaleimide
H + 0 0 R cyclotrimer

R 0N



Although this information was disconcerting as far as our copoly-

merization strategy was concerned, we nevertheless attempted the co-

polymerization of 11 and 28 using AIBN as initiator. Not surprizing-

ly, only homopolymers of 11 were obtained. Direct copolymerization

of maleimides 13 and 14 with 28 were also unsuccessful.

Recognizing that the cyclotrimerization reaction was responsible

for the inability to obtain alternating copolymer, ways were sought to

circumvent this side reaction. It was reasoned that reaction of 28

with a Lewis acid would effectively retard the imidazole residue's

ability to catalyze cyclotrimerization.



PG N-PG

28

AIBN



n n

-PG









The ideal protecting group (PG) would coordinate strongly enough with

the imidazole moiety to preclude cyclotrimerization yet be easily re-

moved following copolymerization. The hydrochloride salt of 28 might

afford adequate protection, however when 28 was treated with anhydrous

HC1 in ether or THF solution, oligomerization of 28 occurred with con-

comitant cleavage of the vinyl ether.




n OH
anhyd. HC1 or C1
28 -
S THF or Et20



+ C
N
H


Reaction of 28 with chlorotrimethylsilane (Me3SiC1) in THF might

also be expected to provide protection.


Me3SiCI N
28 Me3SF ) "N- SiMe3
THF
C1


In these experiments, either 28 or 46 was allowed to react with 1.0

equivalent of Me3SiC1 in THF in a polymerization tube under N2. A

solution of 11 or 13 and AIBN in THF was subsequently added. The

appearance of a pink color probably indicated that the N-Si bond was

too labile to afford adequate protection. Homopolymers of 11 and 13

were obtained in low yields.









Vinyl ether 28 and maleimide 11 were successfully copolymerized

when 28 was pretreated with 1.0 equivalent of aqueous HC1. Maleimide

11 was added in acetone or THF solution to give a homogeneous mixture.

Polymerization was initiated via redox conditions, K2S208 and an Fe(II)

salt.


n
28 + 11 1.0 equiv. HC1 (aq)
H 0-THF
K2208,,Fe(NH4)2(SO4)2-6H20 0 -20%
30C, 90 h
0- N


53 H
The copolymer was purified by precipitating the reaction mixture into

acetone (to remove maleimide homopolymer), redissolving the oily pre-

cipitate in aqueous HC1 and dialyzing this solution against deionized

water. Copolymer 53 precipitated from solution during dialysis. The

IR spectrum of 53 indicated the presence of both monomers, carbonyl

stretching frequencies at 1780 and 1705 cm-1 (indicating that the N-

acetoxy group had been hydrolyzed) and C-O-C ether stretch at 1105

cm-1 The carbonyl absorbances for 53 are identical to those reported

for N-hydroxymaleimide --styrene copolymer.70 Evidence for alterna-

tion can be found in 13C NMR spectrum of 53 (Figure 1). In the carb-

onyl region appear 3 peaks in area ratios of ~2:1:1. This is consist-

ent with an alternating copolymer with a homogeneous sequence distribu-

tion whose stereochemistry at the succinimide unit is exclusively cis

or trans and whose carbonyls can "see" relative stereochemistry two

bonds distant. Carbon 10 can be assigned as the upfield doublet










E
CL







.J



o









0
S r-
i

o
O









0
Co


































u
0L
Cn













Ci




















Ss-
U
C




0

CL
0









4 -










u-
U-








0 j









reflecting random relative stereochemistry between C-2andC-3. Carbon

11 then appears as a singlet as a result of its inability to "see"

relative stereochemistry three bonds distant. The carbonyl region of

53 is analogous to the carbonyl region of N-phenylmaleimide --2-chloro

ethyl vinyl ether alternating copolymer as reported by Olson.12 In-

deed, a more complete explanation of this reasoning can be found in

this work.12

The assignment given carbonyl carbons 10 and 11 can also be ra-

tionalized by empirical chemical shift parameters first reported by

Grant and Paul.71 Substituents other than protons which are situated

a or B to a carbon of interest cause a downfield shift (-9 ppm) rela-

tive to a similar compound without substitution. Substituents other

than protons which are situated y to a carbon of interest cause an

upfield shift (~2 ppm). Examination of the copolymer structure re-

veals that carbons 10 and 11 have equal numbers of a and 3 substituents.

Carbonyl 10, however, has an addition y substituent by virtue of

branching at C-2. Therefore, C-10 should appear further upfield than

C-11.

The resonances between 120 and 140 ppm were assigned to the car-

bons of the imidazole ring. The signal appearing furthest downfield

was assigned to C-9, while no distinction could be made between C-7

and C-8.

The resonances between 70 and 80 ppm are typical for carbon atoms

alpha to an oxygen atom. Differentiation between C-2 and C-5 could be

made after examination of an off-resonance spectrum (Figure 2). The

signal furthest upfield appeared as a triplet (C-5) and the downfield






















C-)

CD




CD


.0
U3
rL
0
O










Co

Q.-


C-
U

-1 -


E

-


a


Ji
Co









signal as a doublet (C-2). Carbon-6 also appeared as a triplet in the

off-resonance 1C spectrum.

Further evidence for alternation can be obtained from the chemi-

cal shifts of the succinimide backbone carbons, C-3 and C-4. In the

1C NMR spectrum of N-hydroxymaleimide homopolymer (50), the backbone

carbons appear as a broad singlet centered at -42 ppm. In copolymer

53 the succinimide backbone carbons appear as two signals at -39 and

-48 ppm. Carbon-4 was assigned to the upfield signal on the basis of

having one additional y substituent vs. C-3. In addition, C-3 has one

additional 6 substituent than does C-4. The broad hump appearing be-

tween C-3 and C-4 at -42 ppm is probably attributable to the methine

carbons of homomaleimide sequences. The methylene backbone carbon

atom (C-1) was assigned to the signal appearing furthest upfield.

Copolymer 53 possesses very interesting solubility characteris-

tics. As isolated, 53 is virtually insoluble in all common organic

solvents, although it will dissolve in DMSO at elevated temperatures.

Interestingly, 53 is water soluble at pH <3.6 and pH >7.1 but insoluble

between these limits. This solution behavior led us to believe that

53 is a polyampholyte.





n n n


N N 0 N N
I II-
OH 0 0

H H
H H










Solubility is attained when the copolymer is protonated or deprotonated

giving rise to net positive or negative charges. Under these condi-

tions, 53 might be expected to behave as a polyelectrolyte. At the

isoelectric point, however, the attraction between oppositely charged

side chains should result in tight coiling, hence a lack of solubility.

In this case, an increase in the ionic strength of the medium should

lead to expansion of the chains and impart water solubility. Such be-

havior has been noted for poly(vinyl imidazolium sulphobetaine) (PVISB)

by Salamone et al.72

The solubility of 53 in various salt solutions is shown in Table

IV. It can be seen that certain salts are more effective than others

with respect to dissolving power. Interestingly, both sat. LiC1 and

sat. LiBr completely dissolve 53, while 5.0 M LiC1 only partially dis-

solves 53. It is also not clear why 53 is soluble in sat. Nal, par-

tially soluble in sat. NaC1, and apparently insoluble in sat. NaBr.

TABLE IV

Solubility of 53 in Salt Solutions

Anion ....
Cation ion C1 Br I BF4

.+ sat. +
Li+ sat. + sat. +
5.0M P

Na sat. P sat. sat. +
3.0M P

K sat. P sat. sat. -

sat. = saturated solution
+ = soluble
= insoluble
P = partially soluble










Salamone et al.72 found that large cations, e.g. K and large anions,

e.g. C104 were more effective solubilizing ions than were smaller

ions. Minimum salt concentrations were of the order of 0.03-0.52M

for PVISB, while saturated salt solutions were necessary to impart

solubility to 53.

Determination of the molecular weight of 53 proved difficult, and

the results were ambiguous. VPO analysis in DMSO at 1000C gave M n

500 g/mol. It is believed that this number represents a minimum value

as 53 was observed to decompose under similar conditions in the NMR

probe. As VPO is a colligative technique, the presence of decomposi-

tion fragments would result in a lower Mn than expected. A maximum

molecular weight value was calculated from end group analysis (elemen-

tal analysis for S). Presumably the initiating species in the redox

system employed is the sulfate radical anion.73

52082- + Fe+2 S042- + s04 + Fe+3


Assuming the incorporation of one sulfate group per polymer chain,

from calculation of an empirical formula a molecular weight of s 6000

g/mol was derived.

The intrinsic viscosity [n] of 53 was determined in 0.1N HC1 at

30.0C to be 0.112 dL/g. Although this value cannot be directly re-

lated to molecular weight, it is an indication of the hydrodynamic

volume of 53. Of course the size of the polymer chains should vary

with the pH of the medium, and one would expect a change in [n] de-

pendent on the degree of ionization of imidazole groups.









Gel permeation chromatography of 53 revealed two components in a

3:1 area ratio, the larger component having the shorter retention

volume. The presence of two components precluded accurate molecular

weight determination, as the individual viscosities could not be de-

termined independently. It was suspected that the minor component was

attributable to N-hydroxymaleimide homopolymer (50), which we were un-

able to separate from 53.

In another set of experiments, 28 was mixed with ZnCl2 in THF

before addition of AIBN and 11. In this case, a white-THF insoluble

powder was obtained after only a few hours at 60C. The IR spectrum

of this material indicated that both 11 and 28 had been incorporated

as evidenced by carbonyl stretching frequencies at 1818, 1785 and 1730
-1
cm and C-O-C ether stretch at 1110 and 1095 cm-. The incorporation

of ZnC12 into this material was inferred by elemental analysis for C1

(9.22%). Elemental analysis was reasonably consistent with a struc-

ture containing two equivalents of 28 and two equivalents of 11 per

equivalent of ZnCl2.

Reaction of 28 with four equivalents of ZnC12 in ethanol gave,

after dilution with ether, an 89% yield of 33, mp 78.5-80C.


4.0 equiv. ZnC12 ZnC

-2
28 EtOH < 0 ZnC2

33


The stoichiometry of this complex was determined from elemental analy-

sis and is consistent with N-alkylimidazole -- ZnCl2 complexes studied

by Welleman et al.32 On the basis of the structure of 33 and the









elemental analysis data for the ZnCl2 copolymer, the latter's repeat-

ing unit was assigned structure (54).


54

This crosslinked structure accounts for the insolubility of 54 in
common organic solvents. However, 54 dissolves in warm DMSO (~600C),

presumably giving a DMSO-ZnC274 complex and free copolymer. The [n]
of a DMSO solution of 54 at 30.00C was equal to 0.043 dL/g. Copolymer
54 is also soluble in water at pH >13 (NaOH) and pH <3.5 (HC1).


\ *Cl









The proton decoupled 13C NMR spectrum of 54 is shown in Figure 3.

Similarities to the 13C NMR spectrum of 53 (Figure 1) are apparent,

and the assignment of carbon atoms is the same as in 53. Two addi-

tional peaks one in the carbonyl region and one at -22 ppm can

probably be assigned to acetic acid (from hydrolysis of the N-acetoxy

group). The resonance at -42 ppm most likely indicates the presence

of homomaleimide sequences.

Copolymerization of Fumaronitrile (45) and
Diethylfumarate (44) With N-(3-Vinyloxyethyl)imidazole (28)

In view of the fact that 28 would not cleanly copolymerize with

11 or 13, it was decided to attempt copolymerization of 28 with fuma-

ronitrile (45) and diethylfumarate (44). As both latter monomers are

electron deficient, 45 (e = +2.73)65 and 44 (e = +2.26),65 it was be-

lieved copolymerization with vinyl ether (28) might afford alternating

copolymers. Indeed, alternating copolymers have been obtained from

copolymerization of both 45 and 44 with N-vinylcarbazole (e =-1.29).65

It was envisioned that hydroxamic acid groups could be introduced

following copolymerization via transformation of the nitrile and es-

ter groups.

Copolymerizations of 28 with 44 and 45 were carried out in solu-

tion at 600C using AIBN as initiator. Low yields of low molecular

weight copolymers were obtained in each case. The 1H NMR spectrum of

56 indicated that the copolymer was rich in diethylfumarate (-2.3:1)

as determined by comparing the integration of methyl protons to imida-

zole protons. These data are supported by elemental analysis for ni-

trogen, the value obtained being -2.8% lower than expected for a 1:1
















Q.











0
o

0 D









0
co

---











- '-








0


4-
0






.-
O
O













4U
0
u
4,





0









S..
1 U
N0




+-
01
s-
0











14















Sacetone
28 + 44
AIBN
600C, 90 h







CH2C12
28 + 45 A
60C, 44 h
60C, 44 h


CO2Et
m
fn CO2Et




N
0 56
NC




CN




55


copolymer. Copolymer 55 was suspected of being rich in fumaronitrile

on the basis of nitrogen analysis, found to be -2.7% higher than ex-

pected for a 1:1 alternating copolymer. Since alternating copolymers

were not obtained in either case, no attempt was made to transform

either the nitrile or ester group to a hydroxamic acid group.

Copolymerization of Maleimide (16) With
B-Vinyloxyethyl(imidazol-4ylmethyl)piperidinium Chloride (30)

After it had been established that copolymer (53) was not an

efficient catalyst, new catalysts were sought. It was proposed that

a better catalyst could be obtained by changing the nature of the hy-

droxamic acid group and by varying the position of substitution on

the imidazole ring. Our strategy involved copolymerizing a 4(5)-

imidazole-substituted vinyl ether with an ester-maleimide and convert-

ing the ester group to a hydroxamic acid group following the copoly-


merization step.




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