The Synthesis and Characterization of 1,3-Bis

Home , Isoindoline, Phthalimide, Phthalonitrile

THE SYNTHESIS AND CHARACTERIZATION OF

1,3-BIS(ARYLIMINO)ISOINDOLINES USING

PHTHALONITRILE OR DIIMINOISOINDOLINE AS STARTING MATERIAL

A Thesis

Presented to

The Graduate Faculty of The University of Akron

In Partial Fulfillment

of the Requirements for the Degree

Master of Science

Joshua L. Chavez

December 2011

THE SYNTHESIS AND CHARACTERIZATION OF

1,3-BIS(ARYLIMINO)ISOINDOLINES USING

PHTHALONITRILE OR DIIMINOISOINDOLINE AS STARTING MATERIAL

Joshua L. Chavez

Thesis

Approved: Accepted:

______Advisor Dean of the College Chris J. Ziegler Chand K. Midha

______Faculty Reader Dean of the Graduate School Michael J. Taschner George R. Newkome

______Department Chair Date Kim C. Calvo

ABSTRACT

Both diiminoisoindoline and phthalonitrile can be used as synthetic precursors for the synthesis of bis-substituted isoindolines.1 Early investigation by Linstead et al. used diiminoisoindoline as a starting material.1,8,23 Siegle later modified the synthesis by using phthalonitrile as a synthetic precursor.24 This direct synthetic route did not include the isolation of diiminoisoindolione in the production of the bis-substituted isoindoline. A variety of adducts have been used to investigate the reactivity of phthalonitrile and diiminoisoindoline with primary aromatic amines. These adducts include aminophenol where the amine group can be ortho, meta or para to the alcohol substituent. A unique feature of the 2-aminophenol is that an intramolecular cyclization occurs which forms two benzoxazoles ortho to each other on a benzene which originated as the phthalonitrile.

The other adducts such as the 3 and 4-aminophenols simply underwent a nucleophilic addition followed by intramolecular cyclization to produce the diiminoisoindoline-like compound with two adducts attached. In addition to a direct synthetic route of bis- substituted isoindolines, the formation of a three membered ring, 2-amino-phenoxazin-3- one, was produced due to the oxidation and condensation of the 2-aminophenol upon reflux.

iii

DEDICATION

To my parents and sister

ACKNOWLEDGEMENTS

I would like to thank my advisor Dr. Chris Ziegler for all of his support, guidance and patience he has shown me throughout my time here in Akron. In particular, I would like to acknowledge all of his helpful feedback in regards to writing this thesis. None of this would have been possible if it wasn’t for you. I would also like to extend gratitude to

Dr. Mike Taschner and Dr. Kim Calvo for taking the time to review this thesis.

TABLE OF CONTENTS Page

LIST OF TABLES ...... vii

LIST OF FIGURES ...... viii

LIST OF SCHEMES ...... xi

CHAPTER

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

Phthalocyanine and porphyrin macrocycles ...... 1

Subphthalocyanine ...... 9

Hemiporphyrazine...... 10

Triazolehemiporphyrazine ...... 14

Cyclization of amino alcohols ...... 19

Bis-substituted isoindoline ...... 20

II. THE SYNTHESIS AND BIS-SUBSTITUTEDISOINDOLINE USING DIIMINOISOINDOLINE AS ASTARTING MATERIAL…………………...………...27

Chapter II Experimental ...... 28

Chapter II Results and Discussion ...... 33

III. A DIRECT SYNTHETIC ROUTE FOR THE SYNTHESIS OF BIS-SUBSTITUTED ISOINDOLINES USING PHTHALONITRILE AS A STARTING MATERIAL………………….………………47

Chapter III Experimental ...... 47

Chapter III Results and Discussion ...... 54

REFERENCES…………………………………………………………………….…….63

LIST OF TABLES

Table Page

2.1 Crystal data and structure refinement for compound 1……………………….35

2.2 Crystal data and structure refinement for compound 2……………….…...….39

2.3 Crystal data and structure refinement for compound 3……………….………42

2.4 Crystal data and structure refinement for compound 4…………..…………...45

3.1 Crystal data and structure refinement for compound 6……………………..…62

vii

LIST OF FIGURES

Figure Page

1.1 Structures of porphyrin and phthalocyanine...... 1

1.2 Synthesis of regular porphyrin via condensation of pyrroles and aldehydes ...... 2

1.3 Possible isomeric mixtures of porphyrin synthesis ...... 3

1.4 Structure of phthalocyanine ...... 4

1.5 Structures of a benzoporphyrin(A) and an azaporphyrin(B) ...... 5

1.6 Possible precursors of phthalocyanine synthesis ...... 6

1.7 Synthetic pathway for phthalocyanine or diiminoisoindoline synthesis ...... 8

1.8 Synthetic pathway for isoindoline derivatives from ethylcyanoacetate...... 9

1.9 Synthesis of supphthalocyanine ...... 10

1.10 Structure of hemiporphyrazine ...... 11

1.11 Synthesis of hemiporphyrazine...... 12

1.12 Reaction of 3-imino-1-ketoisoindoline with a primary amine ...... 13

1.13 Structure of triazohemiporphyrazine ...... 14

1.14 Triazohemiporphyrazine derivatives shown to increase solubility...... 15

1.15 Regioselective synthetic pathway using stepwise methodology of the synthesis of triazolehemiporphyrazine ...... 16

1.16 Open three unit compound ...... 17

1.17 Possible reaction products of three unit compound reacted with benzene-1,3-diamine ...... 17

1.18 Various diamines used for macrocyclic formation with diiminoisoindoline...... 18

viii

1.19 Synthesis of 2-substituted 2-oxazolines and 4H-5,6-dihydrooxazine ...... 19

1.20 Synthesis of 1,3-bis(2’-pyridylimino)isoindoline ...... 20

1.21 An example of a palladium complex ...... 21

1.22 Coordination of cadmium with pyridine and imine nitrogens ...... 24

1.23 Reactions of Zn(II) with isoindoline ligand ...... 24

2.1 13C NMR spectra of compound 1 ...... 34

2.2 ESI mass spectrum of compound 1 ...... 34

2.3 The structure of compound 1 with 35% thermal ellipsoids. Hydrogen atoms have been omitted for clarity...... 36

2.4 13C NMR spectra of compound 2 ...... 37

2.5 ESI mass spectrum of compound 2 ...... 38

2.6 The structure of compound 2 with 35% thermal ellipsoids. Hydrogen atoms have been omitted for clarity ...... 40

2.7 ESI mass spectrum of compound 3 ...... 41

2.8 Compound 3 with 35% thermal ellipsoids. Hydrogen atoms have been omitted for clarity with the exception of the OH group on the phenol adduct ...... 43

2.9 ESI mass spectrum of compound 4 ...... 44

2.10 Compound 4 with 35% thermal ellipsoids. Hydrogen atoms have been omitted for clarity ...... 46

3.1 1H NMR spectra of compound 5...... 55

3.2 ESI mass spectrum of compound 5 ...... 55

3.3 ESI mass spectrum of compound 7 ...... 56

3.4 ESI mass spectrum of compound 2 ...... 57

3.5 1H NMR spectra of compounds 2 and 6 ...... 58

3.6 1H NMR spectra of compound 6...... 59

3.7 1H NMR spectra of compound 6...... 60

3.8 The structure of compound 6 with 35% thermal ellipsoids. All hydrogen atoms are present in the structure ...... 62

LIST OF SCHEMES

Scheme Page

2.1 The synthesis of bis-substituted isoindoline using diiminoisoindoline ...... 27

2.2 The synthesis of1,3-bis(2-hydroxypropylimino)isoindoline (1) ...... 29

2.3 The synthesis of 1,2-bis(benzoxazol)benzene (2)...... 30

2.4 The synthesis of 3-phenoliminoisoindoline (3) ...... 31

2.5 The synthesis of 1,3-bis(4-phenolimino)isoindoline (4) ...... 32

3.1 The synthesis of bis-substituted isoindolinen using phthalonitrile as a starting material ...... 48

3.2 The synthesis of 1,3-bis(1-imino-2-hydroxy-propane)isoindoline (5) ...... 49

3.3 The synthesis of 2-amino-phenoxazin-3-one (6) ...... 50

3.4 The synthesis of 1,3-bis-(3-phenolimino)isoindoline (7) ...... 51

3.5 The synthesis of 1,2-bis(benzoxazol)benzene (2) using phthalonitrile as a starting material ...... 52

3.6 The synthesis of 2-amino-phenoxazin-3-one (6) ...... 53

CHAPTER I

PHTHALOCYANINE AND PORPHYRIN MACROCYCLES

The porphyrins and phthalocyanines have been heavily investigated in the chemical literature over the past century and new contributions to this branch of chemistry are continuously being made. The structures of porphyrin and phthalocyanine are shown in Figure 1.1. For much of the twentieth century, there was a concerted effort to develop new methods for synthesizing both of these macrocycle types.1

Figure 1.1 Structures of porphyrin and phthalocyanine1

The classic Adler synthesis of porphyrins, shown in Figure 1.2, is carried out by refluxing equal molar equivalents of pyrrole and aldehydes in an acidic medium. Substituents can be placed along periphery of the porphyrin if substituted aldehydes are used. Bipyrroles are not effective in the synthesis of porphyrins because of their direct pyrrole-pyrrole link

1 without a bridging carbon atom.2 These compounds have also undergone extensive metalation studies with many elements from the periodic table.3

Figure 1.2 Synthesis of regular porphyrin via condensation

of pyrroles and aldehydes

An alternate approach to the synthesis of porphyrins is by using dipyrrolic intermediates. Common intermediates are dipyrromethenes and dipyrromethanes.1 A problem which arises in this methodology is that mixtures can result due to equal reactivity at both end of the dipyrrolic starting materials as shown in Figure 1.3. In addition, dipyrromethenes and dipyrromethanes can isomerize in the presence of acidic catalysts.1

Figure 1.3 Possible isomeric mixtures of porphyrin synthesis

One macrocycle in particular, phthalocyanine (Figure 1.4) has become one of the most important heterocyclic macrocycles of the 20th and 21st centuries. This conjugated macrocycle has been recognized for its unique stability and easy preparation.5 Due to its stability and numerous applications, phthalocyanine is regarded as one of the most highly studied macrocylces in coordination chemistry.7 There are two primary differences between porphyrin and phthalocyanine: phthalocyanines are composed of isoindolines rather than simple pyrroles, and in phthalocyanine the meso positions are occupied by nitrogen atoms.8

Phthalocyanine was formally discovered in 1928 by chance as a byproduct of the synthesis of phthalimide in the Grangemouth Works of Scottish Dyes, Ltd.1 During the course of the synthesis, ammonia was passed through molten phthalic anhydride in iron vessels and a blue material appeared. The investigation of this new material was carried out in 1929 under J.F.Thorpe, and the Research Committee of the Dyestuffs Group of

Imperial Chemical Industries.6 The group discovered that it was highly insoluble in most organic solvents as well as water and both acidic and basic conditions. However, the iron containing phthalocyanine did decompose in hot nitric acid as well as cold acidic

3 permanganate solution which resulted in phthalimide and free iron ions that formed ferric salts. In hot sulfuric acid, the macrocycle decomposes into phthalic acid and phthalimide along with ferrous and ammonium sulfates. The preference for the formation of phthalocyanine can be attributed to the fact that byproducts of the reaction may be unstable.6

Figure 1.4 Structure of phthalocyanine

Phthalocyanines have been used as dyes due to their intense blue-green color and photostability. Like other tetrapyrrolic compounds, phthalocyanines can coordinate a variety of metals across the periodic table. Copper phthalocyanine is an important synthetic pigment currently used in industry. Phthalocyanine pigments and dyes are produced on the scale of tens of thousands of tons per year.10 A variety of substituents have been added to phthalocyanine in order to increase solubility for various applications.

These substituents are typically located on the benzene rings on the periphery of the macrocycle and can occupy any of the possible 16 positions available on the macrocycle.

Physical, chemical as well as electronic properties are also affected by these different functionalities. Substituents can be simple or complex ranging from alkyl chains, ethers, amines, and crown ethers, to dendrimers and high ordered aromatics.8

To investigate the effects of the structure of phthalocyanines and porphyrins on their chemical and physical properties, similar compounds with modified skeletons have been produced. Two intermediates between porphyrin and phthalocyanine are benzoporphyrin and azaporphyrin. Benzoporphyrin is a phthalocyanine analog with the isoindoline linked together not with nitrogen, but with CH groups instead.7 Azaporphyrin is a porphyrin analog with bridging nitrogen atoms at the meso positions.8 Other derivatives have been synthesized where the macrocycle is composed of one meso carbon atom and three meso nitrogens were used or one meso nitrogen atom and three meso carbon atoms as shown in Figure 1.59

Figure 1.5 Structures of a benzoporphyrin(A) and an azaporphyrin(B)7,8,9

The synthesis of phthalocyanine can be carried using a variety of precursors. The mechanisms of these reactions are believed to be condensation reactions which undergo a

5 stepwise polymerization of the precursors followed by ring closure and coordination to a metal center. Ring closure has several driving forces such as the stabilization through coordination to the metal, thermodynamic conditions, as well as the aromatic nature of the phthalocyanine system.10 A primary characteristic of the precursors of phthalocyanines is that there must be ortho-substitution on the benzene ring. These precursors can include phthalic acid, phthalonitrile, phthalic anhydride, phthalimide, diiminoisoindoline, and o-cyanobenzamide (Figure 1.6). 1

Figure 1.6 Possible precursors of phthalocyanine synthesis

Several examples illustrate the synthesis of phthalocyanines with or without coordination to a metal. Tomoda et al. produced the macrocycle by simply refluxing phthalonitrile with a base such as ammonia, 1,8-diazabicycloundec-7-ene (DBU), or 1,5- diazabicyclo(4.3.0)non-5-ene (DBN) in a solvent.11 Modification of this method to

6 metalate the macrocycle can be done by using similar reaction conditions with the solvent pentanol and metal salts. Cyclotetramerisation of the phthalonitrile will result in the metallophthalocyanine.12 Other starting materials have also proven useful in the synthesis of phthalocyanine. Phthalimide, phthalic anhydride as well as phthalic acid can all be used as precursors. These starting materials must also be accompanied with a nitrogen source such as ammonia.1

Phthalonitrile is a very common and reliable precursor for phthalocyanine synthesis. Reactions typically involve heating phthalonitrile in a high boiling solvent along with a metal ion as a template.1 This is a favorable reaction because a nitrogen source is already present in the cyano group, which is not the case for phthalic anhydride or phthalimide. In addition, metals along with their salts, oxides, sulfates, and halides react very easily with phthalonitriles to form metallophthalocyanine complexes.1

Phthalonitrile is also a precursor for diiminoisoindoline.1 Diiminoisoindoline can then be used as a precursor for phthalocyanine and their analogs which can be prepared in a single step upon reflux. To synthesize diiminoisoindoline, phthalonitrile is refluxed in ammonia gas in the presence of catalytic sodium methoxide and methanol as a solvent.

Diiminoisoindoline is then isolated to produce a green colored powder.1 Traditionally, four molar equivalents of diiminoisoindoline or phthalonitrile undergo a condensation reaction to produce the phthalocyanine macrocycle using n-butanol as a solvent as shown in Figure 1.7. However, diiminoisoindoline can undergo reaction with heterocyclic or aromatic compounds to produce phthalocyanine variants.1

Figure 1.7 Synthetic pathway for phthalocyanine or

diiminoisoindoline synthesis

Diiminoisoindoline also forms various condensation products. Cyanoacetates can react with diiminoisoindoline to form various analogs.9 Condensation of diiminoisoindoline with ethyl cyanoacetate produced a condensation product with the molecular formula C18H15O4N3 along with ammonia as a byproduct when reacted in ethanol (Figure 1.8). In addition, this product was also produced from phthalonitrile, guanidine, and ethyl cyanoacetate. Decarboxylation of this product with pyridine and copper produced 1,3-di(cyanomethylene)isoindoline. When ethyl cyanoacetate was reacted with the pyrrolidine derivative succinimide, only one condensation product was produced with the molecular formula of C9H11O2N3. Under hydrolysis this reaction can produce the pyrrolidone derivative as shown in Figure 1.8.9

Figure 1.8 Synthetic pathway for isoindoline

derivatives from ethylcyanoacetate.

Subphthalocyanine

A class of phthalocyanines which only incorporates three isoindoline units surrounding a boron atom to form contracted phthalocyanine was discovered in 1972 by

Meller and Ossko. The subphthalocyanine macrocycle was discovered by accident in an attempt to produce a boron phthalocyanine.13 These macrocycles are synthesized by reacting phthalonitriles with boron derivatives such as boron trihalides to produce purple compounds with a non-planar cone Figure 1.9.14 These subphthalocyanines are less stable than phthalocyanine. However coordination to the central boron atom is strong enough to hold the macrocycle together if further reactions are needed to add additional substituents or modifications.15 These macrocycles possess aromatic delocalized 14-

9 electron systems.16 Phthalocyanine can be produced from this subphthalocyanine upon cleavage of the constrained ring by the further reaction with diiminoisiondoline. High phthalocyanine yields are usually achieved by reacting subphthalocyanines with no substituents or electron-withdrawing groups and diiminoisoindoline having electron- donor groups.1

Figure 1.9 Synthesis of subphthalocyanine

A variety of trisubstituted boron reagents have been tested in the synthesis of the subphthalocyanines. Reactivity towards phthalonitrile is in the order of BBr3>BCl3>

BF3> BPh3> B(alkyl)3, where boron trichloride is the most commonly reported reagent in the literature.15

Hemiporphyrazine

In the 1950s J.A. Elvidge and R.P Linstead developed a family of phthalocyanine analogs know as the hemiporphyrazines (Figure 1.10).

Hemiporphyrazines are members of a class of porphyrin analogs known as

10 azaporphyrins.8 The primary characteristic of these phthalocyanine analogs is that one or more of the isoindoline units are replaced with a different aromatic group or heterocyclic species to close up the ring and form a macrocycle. In addition, these macrocycles are thermodynamically stable. However, they are labile in acidic conditions due to their Schiff base properties.17 The hemiporphyrazine, as shown in Figure 1.10, is nonaromatic, as it is composed of a 28 -electron system. The preparation of these hemiporphyrazine macrocycles are relatively easy. As reported by Elvidge and Linstead,

1,3-diiminoisoindoline was condensed with 2,6-diaminopyridine in equal molar ratios.

The locations of the two amine functional groups on the pyridine allows for a crossover[2+2] cyclotetramerization of both the diiminoisoindoline as well as the 2,6- diaminopyridine.18 Numerous techniques have been used to characterize these ligands such as 1H and 13C NMR spectroscopy, mass spectroscopy as well as X-ray crystallography.

Figure 1.10 Structure of hemiporphyrazine

Elvidge and Linstead discovered this macrocycle using diiminoisoindoline as a starting material. Two molar equivalents of diiminoisoindoline are able to undergo condensation with two molar equivalents of m-phenylenediamine yielding a heterocycle.

The production of this macrocycle yields four moles of ammonia as shown in the reaction scheme in Figure 1.11.8

Figure 1.11 Synthesis of hemiporphyrazine

It is possible that the intermediate in Figure 1.11 could polymerize and undergo a linear polycondensation or produce a macrocycle containing more than four units.

However, this is not observed.17 In addition, the stereochemistry of the phenylendiamine linked to the isoindoline plays a major role in the formation of the macrocyclic compound. This macrocycle is similar to the phthalocyanine in size as well as in its coordinating abilities to metal ions. Both pyridine nitrogen atoms and both isoindoline nitrogen atoms can coordinate to the metal ions giving the resultant complex a square planar geometry. Cu(II), Mn(II), Pb(II), Hg(II), and Ni(II) acetates have all show facile coordination to this macrocycle.8

Elvidge and Linstead also investigated the effects of the 3-imino-1- ketoisoindoline when reacted with a primary amine. The carbonyl group of this starting material does not react with any bases to eliminate water. When two molar equivalents

12 of 3-imino-1-ketoisoindoline are reacted in the presence m-phenylenediamine in boiling alcohol the condensation product A in Figure 1.12 is produced. When the same conditions were employed with 2,6-diaminopyridine, a 2-unit monocondensation product formed B as shown in Figure 1.12. Initially, it was believed that that this product could undergo a self condensation reaction which would lead to a four-unit macrocycle with the elimination of two equivalents of water. This 2-unit condensation can undergo further reaction when heated in n-butanol along with one molar equivalent of 3-imino-1- ketoisoindoline to produce a bis-condensation product C shown in Figure 1.12. This three-unit product C did not undergo further reaction with 2,6-diaminopyridine in boiling nitrobenzene. This is a strong indicator that the imino-group is much more reactive than the carbonyl group towards primary amines. Therefore, diiminoisoindoline has been used as the primary starting material for the synthesis of phthalocyanine and hemiporphyrazine macrocycles.19

Figure 1.12 Reaction of 3-imino-1-ketoisoindoline with a primary amine

Triazolehemiporphyrazine

The macrocycle formed with equal equivalents of diiminoisoindoline is not just limited to m-phenylenediamine or 2,6-diaminopyridine. Hemiporphyrazines are capable of forming a variety of macrocycle types. Triazolehemiporphyrazine, first produced by

Campbell et al, was synthesized by reacting o-dicyanobenzene with 3,5-diamino-1,2,4- triazole to produce the hemiporphyrazine analog as shown in Figure 1.13.17

Figure 1.13 Structure of triazolehemiporphyrazine

This species has been synthesized with various substituents as well as metallation with

Co, Mg, Zn, Pb, and Fe.17 Other methods of synthesis were carried out with diiminoisoindoline and 3,5-diamino-1,2,4-triazole and metal complexes were formed with Cu, Ni, Co, Zn and Cd.17 Attempts to oxidize this macrocycle to an aromatic species proved to be unsuccessful. A major reason for this is that the non-aromatic triazolehemiporphyrazine is much more stable. This macrocycle was also found in good yield, about 75-80%, and it was determined that the more insoluble the macrocycle, the higher the yield.17

Studies of these macrocycles have proven to be very difficult due to their lack of solubility. Various substituents have been introduced to the macrocycle in order to increase solubility. This also resulted in a variety of hemiporphyrazine analogs which can undergo metalation. Two such compounds are shown in Figure 1.1420, 21

Figure 1.14 Triazolehemiporphyrazine derivatives shown to

increase solubility

A mixture of regioisomers are obtained in this reaction which result when there is unsymmetrical substitution with one or both of the starting reagents. A regioselective synthetic approach can be shown in Figure 1.15 A condensation reaction of 5,6-dicyano-

1,3-diiminoisoindoline with 1-dodecyl-3,5-diamino-1,2,4-triazole produced the two isomeric compounds A and B. These were then separated using column chromatography.

Product A was then reacted with a variety of monosubstitued diiminoisoindolines to produce triazolehemiporphyrazine.17

Figure 1.15 Regioselective synthetic pathway using

stepwise methodology of the synthesis of triazolehemiporphyrazine

More recently, hemiporphyrazine has been synthesized using three different units to make up the macrocycle. Two equivalents of diiminoisoindoline are reacted with one equivalent of 3,5-diamino-1,2,4-triazole to produce an open three unit compound. This open three unit compound is not very stable and attempts have been made to increase the stability of this molecule in order to produce the macrocycle. By coordinating the open molecule with a metal ion Figure 1.16, the metal complex is now able to undergo a reaction with a diamino compound to close up the already metallated macrocycle.

Various reactions have occurred on the open three membered ring species from Figure

1.16 without a metal center. When one equivalent of benzene-1,3-diamine is reacted with the open three unit compound from Fig 1.17, a mixture of products may occur.

Figure 1.16 Open three unit compound

Figure 1.17 Possible reaction products of three unit compound

reacted with benzene-1,3-diamine

Diiminoisoindoline has also been shown to form macrocyclic compounds with

2,7-diaminaphthalene, and 2,8-diaminoacridine, as well as 3,5-diaminopyridine as starting materials as shown in Figure 1.18

Figure 1.18 Various diamines used for macrocyclic formation

with diiminoisoindoline

These macrocycles are thermodynamically stable and the benzene as well as the naphthalene derived macrocycles are resistant to hydrolysis when exposed to boiling hydrochloric acid. The macrocycles composed of the acridine, 3,5-pyridine as well as the

2,6-pyridine all undergo hydrolysis. The 2,6-pyridine macrocycle still remained soluble in dilute cool acidic conditions, while the other macrocycles precipitated. Metallations of these macrocycles were investigated, and it appeared that the macrocycle with the 2,6- pyridine unit was the only one able to complex with one equivalent of a metal ion. The macrocycle compose of 3,5-pyridine metallated with copper and zinc acetate in DMF showed that two metal atoms were combined with one macrocycle along with acetate and water.23

Cyclization of amino alcohols

Investigations also turned to the synthesis and metallation of non macrocyclic compounds derived from phthalonitrile precursors. In 1977, Siegl described the reaction of benzonitrile with one equivalent of 2-aminoethanol or 3-aminopropanol to produce a

2-phenol-2-oxazoline or a 2-phenol-4H-5,6-dihyrooxazine respectively. Figure 1.19 shows the reaction scheme for the synthesis of the oxazoline compound.

Figure 1.19 Synthesis of 2-substituted 2-oxazolines

and 4H-5,6-dihydrooxazine

The synthesis of these oxazoline rings requires 10% CaCl2 as a Lewis acid catalyst. It is believed that there is an interaction with the metal center and the nitrogen lone pair. This will result in activation of the carbon-nitrogen bond due to polarization, resulting in better suitability towards nucleophilic attack. Other alkaline earth salts were also investigated as potential catalysts.24

Bis-substituted isoindolines

Siegl also investigated the synthesis of bis-substituted isoindolines. This was done without the synthesis and isolation of diiminoisoindoline as was reported in the earlier literature by Linsted.19 Instead a direct synthetic route was accomplished upon reflux of phthalonitrile along with a primary aromatic amine.19 The new method reported by Siegl utilizes nitrile activation followed by nucleophilic addition to produce 1,3-bis(2- pyridylimino)isoindoline as shown in Figure 1.20. This reaction is accomplished in a high temperature solvent with a 1:2 ratio of phthalonitrile and 2-aminopyridine in 1- butanol as the solvent. Intramolecular cyclization will result in 1-arylimino-3- iminoisoindoline which is then followed by a second nucleophilic attack by a second aromatic primary amine with the loss of ammonia to form the desired product as a chelating ligand. An interesting feature of the bis(2-iminopyridyl)isoindoline is that it is capable of undergoing a tautomerization where the N-H proton is able to shift between identical imine nitrogen atoms. This type of synthesis is also useful in the formation of a macrocycle if the starting materials are in a 2:2 ratio of phthalonitrile and diaminopyridine.24

Figure 1.20 Synthesis of 1,3-bis(2’-pyridylimino)isoindoline

A specific example of a 1:1 ligand to metal ratio is shown in Figure 1.21 This type of coordination can be achieved when the ligand coordinates with palladium(II)chlordide. The two pyridine rings are arranged syn- syn with respect to the isoindoline.25

Figure 1.21 An example of a palladium complex25

An interesting feature of the 1,3-bis(2’-pyridylimino)isoindoline compound is that its metal complexes have also been shown to mimic catalase enzymes which can decompose hydrogen peroxide to oxygen and water in a protonated and deprotonated form to protect organisms from reactive oxygen species which can lead to early aging in cells.26,27,28 The effects of this ligand when coordinated to to manganese(II) were investigated in solutions of H2O2 in CH3CN as well as in aqueous solutions containing a variety of nitrogen bases such as 1-methylimidazole, imidazole as well as pyridine. High

21 oxidation states of manganese play a role as the redox center in several enzymes as well as in ribonucleotiede reductase, catalase and peroxidase as well as in superoxide dismutase from mitochondria.26,28

The metal complex synthesis involved preparing a solution with equal molar

. equivalents of MnCl2 4H2O and isoindoline in CH3CN and CH3OH as the solvents. The solution was refluxed for 24 hours followed by a removing the solvent, washing the crude product with cold methanol and diethylether followed by recrystallization. The authors determined that the neutral ligand coordinated to the Mn(II) ion while two chloride anions also bound and balanced the charge. This resulted in a distorted trigonal bipyramidal geometry in the metal complex. Once the complex was produced and isolated, the catalytic activities were then determined.28

The catalase activity of the complex was then investigated in CH3CN as well as in an aqueous solution. The catalytic activity of the complex was very poor in CH3CN.

However, an improvement in the decomposition of hydrogen peroxide resulted when the complex was exposed to a base such as 1-methylimidazole, imidazole, or pyridine.

Imidazole along with substituted imidazoles seemed to be the most effective bases in aiding the production of water and oxygen from hydrogen peroxide. Strong -donating abilities of these bases may prove to be a reason why this occurs. Pyridine proved to be somewhat effective, while 2,6-di-tert-butylpyridine had no effect.28

The kinetics effects of this catalytic reaction were also investigated. Acceleration of the decomposition of H2O2 was observed as the concentration of pyridine or imidazole was increased. The disproportionation rate of the H2O2 is first-order when there is a

22 constant amount of H2O2 in the presence of excess imidazole. Decomposition occurs linearly with catalyst concentration.26

Basic conditions were used and it was found that the catalytic activity of the complex was dependent on the pH of the solution. Initially, there is increasing decomposition of the H2O2 as the pH steadily increased. However at about pH 9.6, the generation of oxygen gas decreased. This could be likely due to mineral forms of manganese being formed at a higher pH.28 In the coordination of metal complexes from these isoindoline ligands, the size of the metal ion as well as steric effects of the various substituents play a role in how well these ligands are able to coordinate to their metal

29,30 centers. An octahedral complex forms with the stoichiometry M(4’-MeL)2 where the metal is one of the transition block elements. The isoindoline ligand coordinates in a tridentate fashion.29

Other investigations into the coordination geometry and binding capabilities of this ligand with various metal ions also examined the electron donating ability of substituents at various positions on the pyridine ring. A bidentate mode of the ligand

. - forms with Zn(II) from Zn(ClO4)2 6H2O in a 1:1 ratio with 4’-RL in methanol to form

30 the complex [Zn3(4’-MeL)4](ClO4)2. However, a trigonal bipyramidal complex is formed when the ligand is reacted with Cu(ClO4)26H2O. Several reports have investigated isoindoline ligands with methyl substituents attached to the 6 and 6’ position of the pyridine 6’-MeLH. At first glance, it is believed that this ligand would not be able to bind to any metal ion because of steric effects due to the two methyl groups. This is the case when the ligand reacts with cadmium ion in methanol, which was done by taking

. Cd(NO3)2 4H2O in methanol and stirring the solution. The ligand 6’-MeLH was added

23 while stirring continued. After workup of the reaction mixture, yellow crystals formed and were washed with cold methanol. In the resultant complex, the ligand coordinates with the metal ion to one pyridine nitrogen and one imine nitrogen as shown in Figure

1.22.29 A tridentate binding mode is not observed as would be the case in a classic bis(2iminopyridyl)isoindoline complex. The bulky methyl groups on the outside of the pyridine ring on the 6 position, prevent the coordination of the metal ion in a tridentate fashion.29

Figure 1.22 Coordination of cadmium with pyridine

and imine nitrogens

. A similar reaction took place with Zn(ClO4)2 6H2O. The reaction was unusual due to the fact that no isoindoline complex formed. Instead one of the pyridine arms of the 6’-MeLH ligand detached and leaves as 2-amino-6-methyl-pyridine. The nucleophile is obtained from the solvent methanol in a solvolysis reaction. Hydrolysis then follows and converts the dimethylacetal group into a ketone which can be found in Figure 1.23

Figure 1.23 Reactions of Zn(II) with isoindoline ligand

The same ligand, 6’-MeLH was also refluxed in methanol with Pd(COD)Cl2 and another coordination complex was discovered. X-Ray crystal structure indicates that the complex is distorted square planar complex with the metal ion coordinated by two nitrogen atoms as well as one carbon atom on the pyridine ring. This tridentate ligand is distorted due to the location of the 6’ methyl group adjacent to the coordinating nitrogen on the pyridine ring. 29

Palladium(II) was also coordinated with 1,3-bis(4,6-dimethylpyridyl-2- imino)isoindoline. One and two equivalents of palladium acetate were inserted into the ligand and coordination was observed. When one equivalent of palladium acetate was reacted with the 4,6-Me2BPI lignad, a distorted coordination complex at the Pd(II) center was observed likely due to steric crowding. A tridentate ligand coordinates to the metal ion and the Pd(II) is bound by the nitrogen atom found on the isoindoline as well as the two pyridine nitrogen atoms. When two equivalents of Pd(OAc)2 are reacted with the

4,6-Me2BPI ligand, coordination occurs at two different sites. It was observed that the ligand coordinates with the metal ion via one pyridine nitrogen and one imine nitrogen.

In addition, the ligand coordinates in a tridentate fashion via the isoindoline nitrogen atom, a pyridine nitrogen atom, and a pyridine carbon atom.29

The syntheses of macrocyclic compounds as well as bis-substituted isoindolines all employing diiminoisoindoline as a starting material have been investigated over the past century. From its accidental discovery in the early 20th century, phthalocyanine has undergone numerous studies to determine structure, optimum synthetic methodologies, as well as likely metal ions which can be used in coordination. Various analogs and phthalocyanine-inspired chelates have been produced by placing simple or complex substituents on various positions of the periphery of the isoindoline unit. Elvidge and

Linstead continued their investigation by substituting one or more of the isoindoline units with an aromatic or hetero-aromatic species which is known as the hemiporphyrazine macrocycle. Substituents were necessary to enhance solubility which also aided in the development of analogs of the hemiporphyrazine. These hemiporphyrazines share similar binding capabilities with the phthalocyanine macrocycle. Non-macrocyclic bis- substituted isoindolines were also produced by reacting diiminoisoindoline with two equivalents of a primary aromatic amine.

Chapter II

THE SYNTHESIS OF BIS-SUBSTITUTED

ISOINDOLINE USING DIIMINOISOINDOLINE AS A

STARTING MATERIAL

The synthesis of bis-substituted isoindolines can proceed via several routes. In this chapter, bis-substituted isoindolines are synthesized using diiminoisoindoline as a starting material. Diiminoisoindoline was synthesized and then was used in a second reaction with an amino alcohol. Nucleophilic attack by the amine on the imines of the diiminoisoindoline can result in the formation of an isoindoline imino alcohol adduct.

Diiminoisoindoline is produced by reacting phthalonitrile with ammonia gas in methanol in the presence of sodium methoxide as a catalyst.1 Initially, ammonia gas and sodium methoxide in methanol will lead to the formation of the carboximidiate. The formation of the diiminoisoindoline is then accomplished by refluxing the carboximidiate with ammonia and sodium methoxide. Once the diiminoisoindoline is isolated, it can then be used as starting material for the formation of the bis-substituted isoindoline.

Scheme 2.1 The synthesis of bis-substituted isoindoline using diiminoisoindoline

In this chapter, the reactions of diiminoisoindoline with a variety of amino alcohols are described. A variety of adducts then form which provide insight into the reactivity of diiminoisoindoline with these compounds. The alcohols include aminophenols where the amine group can be ortho, meta or para to the phenol substituent. A unique feature of the 2-aminophenol is that an intramolecular cyclization occurs which forms two benzo-oxazoles ortho to each other on a benzene ring derived from the diiminoisoindoline. The other adducts such as the 3 and 4-aminophenols simply underwent a nucleophilic addition to produce the diiminoisoindoline compound with one or two phenols attached.

Chapter II Experimental

General Methods: Unless otherwise noted, all reagents and solvents were purchased from Sigma Aldrich, Acros Organics or Alfa Aesar and used without further purification. Mass spectra were recorded using a LCT electrospray spectrometer at the

Mass Spectrometry Facility at the University of Akron. Solution NMR spectroscopy was performed on a Varian VXR 300 MHz instrument.

X-ray intensity data were measured at 100 K (Bruker KYRO-FLEX) on a Bruker

SMART APEX CCD-based X-ray diffractometer system equipped with a Mo-target X- ray tube ( = 0.71073 Å) operated at 2000 W power. The crystals were mounted on a cryoloop using Paratone N-Exxon oil and placed under a stream of nitrogen at 100 K.

The detector was placed at a distance of 5.009 cm from the crystals. The data were corrected for absorption with the SADABS program. The structures were refined using

28 the Bruker SHELXTL Software Package (Version 6.1), and were solved using direct methods until the final anisotropic full-matrix, least squares refinement of F2 converged.

Scheme 2.2 The synthesis of 1,3-bis(2-hydroxypropylimino)isoindoline (1)

Preparation of 1,3-bis(2-hydroxypropylimino)isoindoline (1, Scheme 2.2): This species was synthesized by refluxing 0.300 grams (2.06 x 10-3 moles) of diiminoisoindoline and refluxing in 150 mL of hot methanol with two equivalents of 1- amino-2-propanol (4.13 x 10-2 moles) for 16 hours. The green solution underwent very little color change throughout the course of the reaction. At the end of the reaction, a light green solution remained in the flask. The solvent was removed under reduced pressure and then the solid product re-dissolved and re-crystallized in a minimum amount of methanol. A precipitate formed when diethyl ether was added to the flask. The contents in the flask were then filtered by using a vacuum filter apparatus and a beige powder was collected and characterized. Solubility tests indicated that the product is most soluble in methanol and chloroform with applied heat. Crystals suitable for single crystal X-ray diffraction grew from chloroform diffused with diethyl ether. 1,3-bis(1-

1 imino-2-hydroxypropane)isoindoline: Yield: 83.1%. H NMR (CD3OD, 300MHz) δ=

7.86 (J, 2H), 7.56 (J, 2H), 4.12 (J, 4H), 3.73 (J, 2H), 1.25 (m, 6H) ppm; 13C

NMR(CD3OD, 300MHz) δ= 138.5, 131.9, 122.3, 69.3, 68.6, 55.4, 21.5 ppm. ESI MS

(positive ion) calculated for 1+: 261.15 m/z; found 262.2 m/z. Crystal data and structure refinement parameters are summarized in Table 2.1.

Scheme 2.3 The synthesis of 1,2-bis(benzoxazol)benzene (2)

Preparation of 1,2-bis(benzoxazol)benzene (2, Scheme 2.3): This species was synthesized by refluxing 1.0 grams (6.9 x 10-3 moles) of diiminoisoindoline in 150 mL of hot methanol with two equivalents of 2-aminophenol (1.37 x 10-2 moles) for 16 hours.

The green solution turned brown within several minutes upon reflux. Once the reaction was completed, a dark solution had formed along with a black precipitate. The solvent was removed under reduced pressure and then re-dissolved and re-crystallized in a minimum amount of methanol. A precipitate formed when diethyl ether was added to the flask. The contents in the flask were then filtered using a vacuum filter apparatus and the precipitate was collected and characterized that formed on the filter. Solubility tests indicated that the product is most soluble in methanol and chloroform with applied heat.

Crystals suitable for single crystal X-ray diffraction grew from chloroform diffused with

1 diethyl ether. Yield: 36.9%. H NMR (CDCl3, 300MHz) δ=8.17 (J, 2H), 7.71 (J, 2H),

13 7,74(m 4H), 7,39(m 4H) ppm; C NMR (300MHz, CD3Cl) δ=162.2, 151, 141.8, 131.1,

127.5, 125.3, 124.4, 120.4, 110.6 ppm. ESI MS (positive ion) calculated for 2+: 312.09 m/z; found 313.2 m/z. Crystal data and structure refinement parameters are summarized in Table 2.2.

Scheme 2.4 The synthesis of 3-phenoliminoisoindoline (3)

Preparation of 3-phenoliminoisoindoline (3, Scheme 2.4): The synthesis of compound 4 was carried out by refluxing 1.0 g (6.9 x 10-3moles) of diiminoisoindoline in

150 mL of hot methanol with two equivalents of 3-aminophenol (1.37 x 10-2 moles) for

16 hours. A dark solution with a black tar like precipitate formed after reflux. The solvent was removed under pressure and then re-dissolved and re-crystallized in a minimum amount of methanol. The black tar like substance remained and was filtered off using methanol followed by diethyl ether. After about 24 hours, a yellow precipitate began to form in the filtrate of the flask. The solvent was removed under pressure and then the product was re-dissolved and re-crystallized in a minimum amount of methanol.

A precipitate formed when diethyl ether was added to the flask. This precipitate was once again filtered using a vacuum filter apparatus. Crystals suitable for single crystal X- ray diffraction grew from methanol diffused with diethyl ether. Yield: 34.25%. 1H NMR

(300MHz): δ=7.90(J, 1H), 7.79(J, 1H), 7.60(J, 2H), 7.18(J, 1H) 6.55(s, 1H), 6.52(J, 1H) ppm; 13C NMR(300MHz): δ= 133.10, 123.34, 112.59 ppm. ESI MS (positive ion) calculated for 3+ :237.09 m/z; found: 238.1. Crystal data and structure refinement parameters are summarized in Table 2.3.

Scheme 2.5 The synthesis of 1,3-bis(4-phenolimino)isoindoline (4)

Preparation of 1,3-bis(4-phenolimino)isoindoline (4, Scheme 2.5): The synthesis of compound 4 was carried out by refluxing 1.0 g (6.9 x 10-3 moles) of diiminoisoindoline in 150 mL of hot methanol with two equivalents of 4-aminophenol (1.37 x 10-2 moles) for

16 hours. The reaction solution turned a yellow orange color with no visible precipitate.

The solvent was removed under pressure and then re-dissolved and re-crystallized in a minimum amount of methanol. A precipitate was produced when diethyl ether was added to the flask. The contents in the flask were then filtered using a vacuum filter apparatus and the precipitate was collected and characterized. Crystals suitable for single crystal X-ray diffraction grew from methanol diffused with diethyl ether. Yield:

1 50.24%. 1,3-bis(4-phenolimino)isoindoline: H NMR (CD3OD, 300MHz): δ= 8.02(J,

13 2H), 7.71(J, 2H), 7.61(J,4H), 6.84(J, 4H), 3.35(s, 1H) ppm; C NMR (CD3OD,

300MHz): δ= 127.8, 118.7, 118.4, 118.1, 117.8, 112.0, 73.6, 73.1, 72.7 ppm; High res.

ESI MS (positive ion) calculated for 4+: 329.12 m/z; found: 330.2 m/z. Crystal data and structure refinement parameters are summarized in Table 2.4.

Chapter II Results and Discussion

The compound 1,3-bis(1-imino-2-hydroxypropane)isoindoline (1) was synthesized as described in the previous section with two equivalents of 1-amino-2- propanol. The solution remained a light green color when the reflux was completed.

After purification, various characterization techniques were employed in determining the structure of the compound. Mass spectroscopy indicated that the major product is the formation of the bis-adduct species. The two equivalents of 2-propyl amine reacted with the diiminoisoindoline and produced a compound that crystallized in a triclinic crystal system. The two 1-amino-2-propanol adducts have free rotation around the sp3 hybridized carbons and result in a non-planar structure shown in Figure 2.3. Both the alcohol functional groups are oriented in opposite directions indicating this free rotation.

In addition, a chloride counter ion was present due to the protonation of one of the imine nitrogen atoms. This Schiff base is the most basic site on the compound allowing for easy protonation.

Figure 2.1 13C NMR spectra of compound 1

Figure 2.2 ESI mass spectrum of compound 1

Table 2.1. Crystal data and structure refinement for compound 1

Identification code 1 Empirical formula C14 H Cl2 N3 O2 Formula weight 314.08 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Triclinic Space group P-1 Unit cell dimensions a = 8.241(2) Å = 70.844(5)°. b = 11.919(3) Å = 89.900(5)°. c = 16.363(4) Å  = 78.388(5)°. Volume 1483.6(7) Å3 Z 4 Density (calculated) 1.406 Mg/m3 Absorption coefficient 0.443 mm-1 F(000) 624 Crystal size 0.496 x 0.159 x 0.131 mm3 Theta range for data collection 2.53 to 27.51°. Index ranges -10<=h<=10, -15<=k<=15, -21<=l<=21 Reflections collected 21596 Independent reflections 6772 [R(int) = 0.0657] Completeness to theta = 27.51° 99.2 % Absorption correction Multi-scan Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 6772 / 0 / 441 Goodness-of-fit on F2 1.802 Final R indices [I>2sigma(I)] R1 = 0.1014, wR2 = 0.2751 R indices (all data) R1 = 0.1298, wR2 = 0.2897 Largest diff. peak and hole 2.181 and -0.951 e.Å-3

Figure 2.3: The structure of compound 1 with 35% thermal ellipsoids. Hydrogen

atoms have been omitted for clarity.

Compound 2 was synthesized as described in the previous section with moderate yields. Crystallization of the material in various solvents resulted in the 1,2-bis-

(benzoxazol)benzene. 1H and 13C NMR spectra showed that a mixture of products were in the crude material. The major product according to mass spectrometry showed that there was a direct addition of the 2-aminophenol to the isoindoline (m/z: 330.2) Figure

2.5. Nucleophilic attack by the primary amine on the 2-aminophenol on the diiminoisoindoline forms a secondary ketimine. Although this bis-substituted isoindoline was the major product, X-ray crystallography showed that there was a formation of a benzoxazol species as the product underwent intermolecular cyclizaton as shown in

Figure 2.6 This compound crystallizes in a monoclinic crystal system. Both of the benzoxazol adducts are attached ortho to each other on the benzene ring and show free rotation. The compound is a neutral species and thus has no need for any counter ion.

Figure 2.4 13C NMR spectra of compound 2

Figure 2.5 ESI mass spectrum of compound 2

Table 2.2. Crystal data and structure refinement for compound 2

Identification code 2 Empirical formula C20 H13 N2 O2 Formula weight 313.32 Temperature 273(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1)/c Unit cell dimensions a = 17.151(3) Å = 90°. b = 5.7635(10) Å = 104.885(2)°. c = 14.795(3) Å  = 90°. Volume 1413.4(4) Å3 Z 4 Density (calculated) 1.472 Mg/m3 Absorption coefficient 0.097 mm-1 F(000) 652 Crystal size 0.22 x 0.06 x 0.04 mm3 Theta range for data collection 2.46 to 27.00°. Index ranges -21<=h<=21, -7<=k<=7, -18<=l<=18 Reflections collected 10738 Independent reflections 3031 [R(int) = 0.0444] Completeness to theta = 27.00° 98.1 % Absorption correction Multi-scan Max. and min. transmission 0.9961 and 0.9790 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 3031 / 0 / 217 Goodness-of-fit on F2 1.041 Final R indices [I>2sigma(I)] R1 = 0.0477, wR2 = 0.1160 R indices (all data) R1 = 0.0756, wR2 = 0.1330 Largest diff. peak and hole 0.319 and -0.285 e.Å-3

Figure 2.6: The structure of compound 2 with 35% thermal ellipsoids. Hydrogen

atoms have been omitted for clarity.

Compound 3 was synthesized as described in the previous section.

Diiminoisoindoline was reacted with two equivalents of 3-aminophenol to produce the mono-substituted isoindoline species. The black tar-like substance which collected in the flask was not soluble in most organic solvents and was therefore not characterized. The

3-aminophenol reaction mixture was likely to undergo polymerization to produce this dark tar like substance. A yellow precipitate formed in the filtrate which was characterized and resulted in compound 3. The single adduct attached to the isoindoline species is able to undergo free rotation resulting in a non-planar configuration shown in

Figure 2.8. No counter ions were present in the crystal structure indicating a neutral species. Compound 3 crystallizes in a monoclinic crystal system.

Figure 2.7 ESI mass spectrum of compound 3

Table 2.3. Crystal data and structure refinement for compound 3

Identification code 3 Empirical formula C14 H11 N3 O Formula weight 237.26 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Monoclinic Space group P2(1)/c Unit cell dimensions a = 4.6570(4) Å = 90°. b = 18.5276(17) Å = 96.982(5)°. c = 13.0971(11) Å  = 90°. Volume 1121.68(17) Å3 Z 4 Density (calculated) 1.405 Mg/m3 Absorption coefficient 0.745 mm-1 F(000) 496 Crystal size 0.16 x 0.11 x 0.08 mm3 Theta range for data collection 4.77 to 67.37°. Index ranges -5<=h<=5, -21<=k<=22, -10<=l<=15 Reflections collected 6051 Independent reflections 1925 [R(int) = 0.0237] Completeness to theta = 67.37° 95.2 % Absorption correction None Max. and min. transmission 0.9401 and 0.8920 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 1925 / 0 / 163 Goodness-of-fit on F2 0.525 Final R indices [I>2sigma(I)] R1 = 0.0345, wR2 = 0.1014 R indices (all data) R1 = 0.0382, wR2 = 0.1087 Largest diff. peak and hole 0.233 and -0.177 e.Å-3

Figure 2.8: The structure of compound 3 with 35% thermal ellipsoids. Hydrogen atoms

have been omitted for clarity with the exception of the OH group on the phenol adduct.

Compound 4 was synthesized as described above. Diiminoisoindoline and two equivalents of 4-aminophenol were reacted together to produce 4. The yellow precipitate which was collected via vacuum filtration was characterized using 1H and 13C NMR, mass spectroscopy and X-ray crystallography. These characterization methods identified that the two equivalents of 4-aminophenol both underwent reaction with the diiminoisoindoline to produce the bis-substituted isoindoline species. Mass Spectrometry shown in Figure 2.9 shows 330.2m/z as the major product indicating that there is attachment of the two phenols to the imine functional groups. Free rotation of the two adducts result in a non-planar compound shown in Figure 2.10. This compound crystallizes in a monoclinic crystal system and is a neutral species with no need for any counterion.

Figure 2.9 ESI mass spectrum of compound 4

Table 2.4. Crystal data and structure refinement for compound 4

Identification code 4 Empirical formula C20 H19 N3 O2 Formula weight 333.38 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Monoclinic Space group C2/c Unit cell dimensions a = 23.7267(18) Å = 90°. b = 15.6529(12) Å = 114.975(4)°. c = 10.4421(7) Å  = 90°. Volume 3515.5(4) Å3 Z 8 Density (calculated) 1.260 Mg/m3 Absorption coefficient 0.668 mm-1 F(000) 1408 Crystal size 0.09 x 0.05 x 0.04 mm3 Theta range for data collection 3.49 to 67.65°. Index ranges -28<=h<=28, -18<=k<=18, -12<=l<=8 Reflections collected 9566 Independent reflections 2995 [R(int) = 0.0273] Completeness to theta = 67.65° 93.9 % Absorption correction Multi-scan Max. and min. transmission 0.9738 and 0.9454 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2995 / 0 / 228 Goodness-of-fit on F2 1.878 Final R indices [I>2sigma(I)] R1 = 0.1596, wR2 = 0.4175 R indices (all data) R1 = 0.1707, wR2 = 0.4230 Largest diff. peak and hole 4.264 and -0.466 e.Å-3

Figure 2.10: Compound 4 with 35% thermal ellipsoids. Hydrogen atoms have been

omitted for clarity

Chapter III

A DIRECT SYNTHETIC ROUTE FOR THE SYNTHESIS OF

BIS-SUBSTITUTED ISOINDOLINES USING PHTHALONITRILE AS A

STARTING MATERIAL

The synthesis of bis-substituted isoindolines using diiminoisoindoline as an intermediate was first reported by Linstead et al.1,8,23 The 1,3-bis(2- pyridylimino)isoindoline compound was later synthesized using phthalonitrile as a starting material by Siegl.24 This direct synthetic route was accomplished upon reflux of phthalonitrile along with a primary aromatic amine in the presence of anhydrous calcium chloride as the catalyst, as shown in Scheme 3.1. This new method utilizes nitrile activation followed by nucleophilic addition to produce the bis-substituted isoindolines without the direct synthesis and isolation of diiminoisoindoline as a starting material. A variety of adducts have been used to investigate the reactivity of phthalonitrile with the amines. These adducts include aminophenol where the amine group can be ortho, meta or para to the alcohol substituent. A unique feature of the 2-aminophenol is that an intramolecular cyclization occurs which forms two benzoxazoles ortho to each other on a benzene which originated as the phthalonitrile. The other adducts such as the 3 and 4- aminophenols simply underwent a nucleophilic addition followed by intramolecular cyclization to produce the diiminoisoindoline like compound with two adducts attached.

Scheme 3.1 The synthesis of bis-substituted isoindoline using

phthalonitrile as a starting material

In addition, to a direct synthetic route of bis-substituted isoindolines, the formation of a three member ring, 2-amino-phenoxazin-3-one (6), was produced due to the oxidation and condensation of the 2-aminophenol upon reflux. This compound has been shown to display anti-imflammatory and immunomodulatory properties.31,32 There are several synthetic routes which lead to the 2-amino-phenoxazin-3-one all of which are involve the oxidative condensation of 2-aminophenol.31,32,33

Chapter III Experimental

Mass Spectrometry Facility at the University of Akron. Solution NMR spectroscopy was performed on a Varian VXR 300 MHz instrument.

X-ray intensity data were measured at 100 K (Bruker KYRO-FLEX) on a Bruker

SMART APEX CCD-based X-ray diffractometer system equipped with a Mo-target X- ray tube ( = 0.71073 Å) operated at 2000 W power. The crystals were mounted on a

48 cryoloop using Paratone N-Exxon oil and placed under a stream of nitrogen at 100 K.

The detector was placed at a distance of 5.009 cm from the crystals. The data were corrected for absorption with the SADABS program. The structures were refined using the Bruker SHELXTL Software Package (Version 6.1), and were solved using direct methods until the final anisotropic full-matrix, least squares refinement of F2 converged.

Scheme 3.2 The synthesis of 1,3-bis(1-imino-2-hydroxy-propane)isoindoline (5)

Preparation of 1,3-bis(1-imino-2-hydroxy-propane)isoindoline (5, Scheme 3.2):

This species was synthesized by reacting 0.50 grams (3.90 x 10-3 moles) of phthalonitrile with two equivalents of ethanol amine (7.80 x 10-3moles) in refluxing methanol (150 mL) for 16 hours. Once the reaction was finished, the light green solution turned a dark brown red color. The solvent was removed by rotary evaporation and then the product was recrystallized from a minimum amount of methanol. A precipitate formed when diethyl ether was added to the flask. The precipitate was then filtered and collected as a beige powder. Solubility tests indicated that the product was most soluble in methanol and chloroform with applied heat. Crystals suitable for X-ray diffraction were grown from chloroform diffused with diethyl ether. Yield: 31.8%. 1,3-bis(e1-imino-2-hydroxy-

1 propane)isoindoline: H NMR( CD3OD, 300MHz): δ= 7.79 (q, 4H), 7.56 (q, 4H), 4.87 (s,

13 4H), 3.86 (s, 4H) ppm; C NMR ( CD3OD, 300MHz):δ= 130.4, 120.7, 61.1 ppm. ESI

MS (positive ion) calculated for 5+: 233.12 m/z; found 233.8 m/z.

Scheme 3.3 The synthesis of 2-amino-phenoxazin-3-one (6)

Preparation of 2-amino-phenoxazin-3-one in the presence of phthalonitrile (2,

Scheme 3.3): The attempted synthesis of compound 2 was done by refluxing 1.0 g

(7.8x10-3moles) of phthalonitrile with two equivalents of 2-aminophenol

(1.56 x10-3moles) in hot methanol (150 mL) for 16 hours. The green solution turned brown within several minutes upon reflux. Once the reaction was finished, a dark solution formed along with no visible precipitate. The solvent was removed under reduced pressure and the product was recrystallized in a minimum amount of methanol.

A precipitate formed when hexane was added to the flask. The precipitate was then collected by filtration. The solid product was determined to be compound 2 as described

1 in the previous chapter. Yield: 30.7%. H NMR( CD3OD, 300MHz): δ= 7.91 (q, 2H),

13 7.84 (q, 2H), 6.73(m) ppm. C NMR (CD3OD, 300MHz):δ= 133.5, 119.6, 118.7, 116.1,

114.1 ppm. ESI MS (positive ion) calculated for 2+: 312.09 m/z; found 313.1 m/z

A second product also was present that was located in the filtrate, and was determined to be (6) which was also characterized. This reaction also resulted in a fused three ring system possibly due to the oxidation of the 2-aminophenol. Solubility tests indicate that this second product is most soluble in methanol and chloroform with applied heat. Crystals suitable for single crystal X-ray diffraction in methanol diffused with

1 13 hexane. Yield: 48.7%. H NMR (300MHz, CD3OD):δ= 6.74 (m), 4.83 (s, 2H) ppm; C

NMR (300MHz, CD3OD):δ= 145.1, 134.6, 119.6, 118.8, 116.1, 114.1 ppm.

Scheme 3.4 The synthesis of 1,3-bis-(3-phenolimino)isoindoline (7)

Preparation of 1,3-bis-(3-phenolimino)isoindoline (7, Scheme 3.4): The synthesis of compound 7 was carried out by taking 1.0 g (7.8 x 10-3moles) of diiminoisoindoline and reacting it with two equivalents of 2-aminophenol (1.56 x 10-3 mols) in 150 mL at reflux for 16 hours. The solution turned brown within several minutes of refluxing.

The solvent was removed by rotary evaporation and then recrystallized in a minimum

51 amount of methanol. Precipitation was increased via addition of hexane to the solution.

The precipitate was then collected by vacuum filtration. Solubility tests indicate that the product is most soluble in methanol and chloroform with applied heat. Crystals suitable for X-ray diffraction were grown from chloroform diffused with hexane. Yield: 44.4%.

1 H NMR (300MHz, CD3OD):δ= 7.97 (J, 2H), 7.85 (J, 2H), 6.91 (J, 2H), 6.23 (J, 2H),

13 6.16 (J, 2H) ppm. C NMR (300MHz, CD3OD):δ= 157.7, 133.5, 133.3, 129.2, 115.3,

107.1, 105.1, 102.3 ppm. ESI MS (positive ion) calculated for 7+: 329.12 m/z; Found:

329 m/z.

Scheme 3.5 The synthesis of 1,2-bis(benzoxazol)benzene (2)

using phthalonitrile as the starting material

Synthesis of 1,2-bis-(benzoxazol)benzene (2, Scheme 3.5): The synthesis of compound 2 was carried out by taking 1.0 g (7.8 x10-3moles) of phthalonitrile and refluxing it with two equivalents of 2-aminophenol (1.56 x10-3mols) in 150 mL of methanol for 16h. Anhydrous calcium chloride was used as a catalyst in the reaction.

The green solution turned brown within several minutes upon reflux. Once the reaction was completed, a dark solution formed along with no visible precipitate. The solvent was removed by rotary evaporation and the solid product recrystallized in a minimum amount

52 of methanol. Precipitate formed when hexane was added to the flask. The contents in the flask were then filtered out by vacuum filtration and the solid product collected. The product collected on the filter resulted in (2). Compound 6 was not present in the reaction. In this case, oxidation of the 2-aminophenol likely did not occur due to the presence of catalytic amounts of anhydrous calcium chloride. Solubility tests indicated that the product is most soluble in methanol and chloroform with applied heat. The product was separately dissolved in methanol and chloroform and then diffused with

1 diethyl ether and hexane. Yield: 18.3%. H NMR (300MHz, CD3OD):δ= 7.86(J, 2H),

13 7.73(J, 2H) ppm; C NMR (300MHz, CD3OD):δ= 145.1, 134.6, 133.5, 128, 9, 127.4,

125.1, 119.6, 118.8, 116.1, 115.7, 114.1, 103.3 ppm. ESI MS (positive ion) calculated for 2+: 312.09 m/z; found 313.1 m/z

Scheme 3.6 The synthesis of 2-amino-phenoxazin-3-one (6)

The direct synthesis of 2-amino-phenoxazin-3-one (6, Scheme 3.6): Compound 6 was synthesized by taking 2.0 g (7.8x10-3 mols) of 2-aminophenol and refluxing it in 150 mL of hot methanol for 16 hours. The green solution turned brown within several minutes upon reflux. Once the reflux was finished, a dark red solution formed with no visible precipitate. The solvent was removed under pressure and then re-dissolved and re-crystallized in a minimum amount of methanol. The contents in the flask were then filtered out using a vacuum filter apparatus and the precipitate was collected and

53 characterize. The material which gathered in the flask was characterized. This resulted in a three fused ring system possibly due to the oxidation of the 2-aminophenol.

Solubility tests indicate that the product is most soluble in methanol and chloroform with applied heat. Product was separately dissolved in methanol and chloroform and then diffused with diethyl ether and hexane. Crystal formation grew best in methanol diffused

1 13 with hexane. Yield: 51.6%. H NMR (300MHz, CD3OD): δ= 6.71(m) ppm. C NMR

(300MHz, CD3OD):δ= 146.6, 136.1, 126.6, 121.2, 120.3, 117.6, 115.7 ppm.

Chapter III Results and Discussion

The formation of compound 5 was synthesized as described in the previous section. Formation of the diiminoisoindoline was done in situ followed by a direct nucleophilic addition of the primary amines. The 1H NMR spectra in Figure 3.1 indicates that there is a AA’BB’ spin system on the aromatic region of the isoindoline unit. The

ESI mass spectrum shows m/z of 233.8 being the highest intensity in Figure 3.2. This indicates that both of the ethanolamine adducts underwent nucleophilic addition to the isoindoline unit.

Figure 3.1 1H NMR spectrum of compound 5

Figure 3.2 ESI mass spectrum of compound 5

The synthesis of (7) was performed according to the procedure in the previous section. Phthalonitrile and two equivalents of 3-aminophenol were reacted together to produce compound 7. The yellow precipitate which was collected via vacuum filtration

55 was characterized using 1H and 13C NMR spectroscopy as well as mass spectrometry.

These characterization methods identified that the two equivalents of 3-aminophenol both underwent reaction with the phthalonitrile to produce the bis-substituted isoindoline species. The mass spectrum in Figure 3.3 shows 329.0 m/z as the major product indicating that there is an attachment of the two aminophenol adducts to the isoindoline.

Figure 3.3 ESI mass spectrum of compound 7

1,2-bis-(benzoxazol)benzene (2) was also synthesized directly from phthalonitrile.

Phthalonitrile and two equivalents of 2-aminophenol along with anhydrous calcium chloride were used as a catalyst. The product collected on the filter was characterized using 1H and 13C NMR as well as mass spectrometry. Mass spectrometry taken on this sample shows that there is 313.1 m/z being the highest intensity in Figure 3.4. This

56 indicates that intermolecular cyclization occurred on both adducts to produce the two benzoxazol species resulting in (2).

Figure 3.4 ESI mass spectrum of compound 2

The reaction mixture of compounds 2 and 6 shown in scheme 3.3 were produced according to the procedure as described above. Compound 2 was isolated and characterized. The 1H NMR spectra of (2) indicates that there is a mixture between compounds 2 and 6. This can be observed in Figure 3.5. A splitting pattern from the

AA’BB’ spin system from the isoindoline unit of the molecule can be observed downfield, while a multiplet splitting pattern can be observed upfield from compound 6

The 1H NMR of compound 6 shown in Figure 3.6 does not have a splitting pattern from the AA’, BB’ spin system. Instead, a multiple splitting pattern is observed from the fused

57 three member ring system. This indicates that compound 6 is isolated and compound 2 is not observed in the reaction mixture.

Figure 3.5 1H NMR spectrum of compounds 2 and 6

Figure 3.6 1H NMR spectrum of compound 6

The dimerization of the 2-aminophenol to produce (6) was not expected under the above described reaction conditions. Initially, the reaction was only supposed to produce (2) which was observed when the reaction of diiminoisoindoline was reacted with two equivalents of 2-aminophenol described in chapter II. Oxidation of the 2- aminophenol occurred to produce the tricyclic molecule. The anhydrous calcium chloride which was used as a catalyst was partially hydrated which reduced the ability of the reaction to produce the 1,2-bis(benzoxazol)benzene (2) exclusively. 1H NMR in

Figure 3.7 shows a multiplet splitting pattern indicative of compound 2. The location of the chemical shift and splitting pattern is also strikingly similar to the 1H NMR shown in

Figure 3.6.

Figure 3.7 1H NMR spectra of compound 6

Table 3.1. Crystal data and structure refinement parameters for compound 6

Identification code 6 Empirical formula C12 H8 N2 O2 Formula weight 212.20 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1)/c Unit cell dimensions a = 12.8668(14) Å = 90°. b = 5.0431(6) Å = 98.984(7)°. c = 14.5132(15) Å  = 90°. Volume 930.19(18) Å3 Z 4 Density (calculated) 1.515 Mg/m3 Absorption coefficient 0.106 mm-1 F(000) 440 Crystal size 0.47 x 0.20 x 0.09 mm3 Theta range for data collection 1.60 to 27.51°. Index ranges -16<=h<=16, -6<=k<=6, -18<=l<=18 Reflections collected 11277 Independent reflections 2139 [R(int) = 0.0240] Completeness to theta = 27.51° 99.9 % Absorption correction Multi-scan Max. and min. transmission 0.9907 and 0.9518 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2139 / 0 / 145 Goodness-of-fit on F2 0.870 Final R indices [I>2sigma(I)] R1 = 0.0407, wR2 = 0.1252 R indices (all data) R1 = 0.0491, wR2 = 0.1340 Largest diff. peak and hole 0.333 and -0.249 e.Å-3

Figure 3.8: The structure of compound 6 with 35% thermal ellipsoids. All hydrogen

atoms are present in the structure.

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