The Synthesis and Characterization of the Bis-Substituted

Home , Phthalazine

THE SYNTHESIS AND CHARACTERIZATION OF THE BIS-SUBSTITUTED

PHTHALAZINES USING BIS- SUBSTITUTED ISOINDOLINES AS STARTING

MATERIAL AND THEIR METALS COMPLEXES

THE SYNTHESIS AND CHARECTRIZATION OF THE SCHIFF BASE LIGANDS

WITH A VARIETY OF METALS

A Thesis

Presented to

The Graduate Faculty of The University of Akron

In Partial Fulfillment

of the Requirements for the Degree

Master of Science

Nada Saleh Alzahrani

August, 2014

THE SYNTHESIS AND CHARACTERIZATION OF THE BIS-SUBSTITUTED

PHTHALAZINES USING BIS- SUBSTITUTED ISOINDOLINES AS STARTING

MATERIAL AND THEIR METALS COMPLEXES

THE SYNTHESIS AND CHARECTRIZATION OF THE SCHIFF BASE LIGANDS

WITH A VARIETY OF METALS

Nada Saleh Alzahrani

Thesis

Approved: Accepted:

______Advisor Dean of the College Dr. Christopher J. Ziegler Dr. Chand K. Midha

______Faculty Reader Dean of the Graduate School Dr. Wiley J. Youngs Dr. George R. Newkome

______Department Chair Date Dr. Michael J. Taschner

ABSTRACT

Two new bis-substituted phthalazine compounds have been prepared from bis- substituted isoindoline compounds by reaction with hydrazine monohydrate in the presence of an organic solvent. 1,4-Bis-(2-benzimidazolylimino)phthalazine (1) was produced from 1,3-bis-(2-benzimidazolylimino)isoindoline while 1,4-bis-(2- thiazolylimino)phthalazine (2) was produced from 1,3-bis-(2-thiazolylimino)isoindoline.

A series of metal complexes were also synthesized from these ligands including copper

(3), iron (4), zinc (5) and nickel (6) with 2:3, 2:2, 1:1, 1:2 metal:ligand stoichiometries respectively and then characterized using different methods. In most cases, the phthalazine reverted to the corresponding isoindoline when reacted with metals as shown in their X-ray structures.

We have also reported the synthesis of metals complexes formed from Schiff bases produced via one pot conditions. The Schiff bases were derived from the reaction of aniline with 2-pyridinecarboxaldehyde in the presence of the metal salt. The synthesized compounds including manganese (7), cobalt (8), nickel (9) and zinc (10) were characterized using mass spectrometry, IR spectroscopy, and X-ray crystallography.

The complexes 7, 8, 10 formed in isostructural trimetallic complexes while in the case of

9 a monometallic complex formed.

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DEDICATION

To my parent, husband, son, brothers and sisters.

ACKNOWLEDGEMENTS

I would like to thank my advisor Dr. Chris Ziegler for all of his support and help.

I came to Akron University with poor experience about how can I do research. Dr.

Ziegler, was teaching me everything step by step. So I really appreciated his encouragement and support to complete my master thesis. Also I am pleased to extend my sincere thanks to Dr. Wiley Youngs and Dr. Michael J. Taschner for the time to read my thesis. Finally, I am thankful and appreciate everyone in Dr. Ziegler’s group for their help.

TABLE OF CONTENTS

Page

LIST OF TABLES...... viii

LIST OF FIGURES...... ix

LIST OF SCHEMES...... xi

CHAPTER

I. INTRODUCTION...... 1

1.1 Phthalocyanine macrocycles...... 1

1.2 Bis-substitutied isoindolines...... 3

1.3 Phthalazines...... 7

1.4 Schiff bases...... 13

II. THE SYNTHESIS AND CHARACTERIZATION OF THE BIS-SUBSTITUTED PHTHALAZINES USING BIS- SUBSTITUTED ISOINDOLINES AS STARTING MATERIAL AND THEIR METALS COMPLEXES...... 22

2.1 Introduction...... 22

2.2 Experimental...... 24

2.3 Results and discussion...... 31

III. THE SYNTHESIS AND CHARECTRIZATION OF THE SCHIFF BASE LIGANDS WITH A VARIETY OF METALS...... 50

3.1 Introduction...... 50

3.2 Experimental...... 52

3.3 Results and discussion...... 56

IV. CONCLUSIONS AND FUTURE LOOK...... 72

REFERENCES...... 74

vii

LIST OF TABLES

Table Page

2.1 Crystal data and structure refinement parameters for compound 3...... 36

2.2 Crystal data and structure refinement parameters for compound 4...... 40

2.3 Crystal data and structure refinement parameters for compound 5...... 44

2.4 Crystal data and structure refinement parameters for compound 6...... 48

3.1 Crystal data and structure refinement parameters for compound 7...... 58

3.2 Crystal data and structure refinement parameters for compound 8...... 62

3.3 Crystal data and structure refinement parameters for compound 9...... 66

3.4 Crystal data and structure refinement parameters for compound 10...... 70

viii

LIST OF FIGURES

Figure Page

1.1 Structures of porphyrin and phthalocyanine...... 2

1.2 The structure of 1,3-bis(2-thiazolylimino)isoindoline. Hydrogen atoms have been omitted for clarity...... 5

1.3 The structure of 1,3-bis(2-benzimidazolylimino)isoindoline. Non-ionizable hydrogen atoms have been omitted for clarity...... 6

1.4 Structure of the four diaza analogues...... 7

1.5 Crystal structure of PAP...... 11

1.6 The structure of Cu2LCl3(OH)H2O...... 12

1.7 The two general structures of Schiff bases...... 13

1.8 The structure of N-benzylidene aniline...... 14

1.9 Structure of bindentate ligands with some transition metals...... 18

1.10 Neurotensin(8-13)peptide with lysine at amine terminus bound to the rhenium pyca unit; 3: R= FMOC, 4: R= fluorescein...... 21

2.1 ESI mass spectrum of compound 1...... 31

2.2 1H NMR spectrum of compound 1...... 32

2.3 MALDI mass spectrum of compound 2...... 33

2.4 1H NMR spectrum of compound 2...... 33

2.5 ESI mass spectrum of compound 3...... 35

2.6 IR spectrum of compound 3...... 35

2.7 The structure of compound 3 with 35% thermal ellipsoids. Hydrogen atoms have been omitted for clarity...... 37

2.8 ESI mass spectrum of compound 4...... 39

2.9 IR spectrum of compound 4...... 39

2.10 The structure of compound 4 with 35% thermal ellipsoids. Hydrogen atoms have been omitted for clarity...... 41

2.11 ESI mass spectrum of compound 5...... 43

2.12 IR spectrum of compound 5...... 43

2.13 The structure of compound 5 with 35% thermal ellipsoids. Hydrogen atoms have been omitted for clarity...... 45

2.14 ESI mass spectrum of compound 6...... 47

2.15 IR spectrum of compound 6...... 47

2.16 The structure of compound 6 with 35% thermal ellipsoids. Hydrogen atoms have been omitted for clarity...... 49

3.1 ESI mass spectrum of compound 7...... 57

3.2 IR spectrum of compound 7...... 57

3.3 The structure of compound 7 with 35% thermal ellipsoids. Hydrogen atoms have been omitted for clarity...... 59

3.4 ESI mass spectrum of compound 8...... 61

3.5 IR spectrum of compound 8...... 61

3.6 The structure of compound 8 with 35% thermal ellipsoids. Hydrogen atoms have been omitted for clarity...... 63

3.7 ESI mass spectrum of compound 9...... 65

3.8 IR spectrum of compound 9...... 65

3.9 The structure of compound 9 with 35% thermal ellipsoids. Hydrogen atoms have been omitted for clarity...... 67

3.10 ESI mass spectrum of compound 10...... 69

3.11 IR spectrum of compound 10...... 69

3.12 The structure of compound 10 with 35% thermal ellipsoids. Hydrogen atoms have been omitted for clarity...... 71

LIST OF SCHEMES

Scheme Page

1.1 Syntheses of phthalocyanine and diiaminoisoindoline...... 3

1.2 Synthesis of 1,3-bis(2-pyridylimino)isoindoline using phthalonitrile or diiminoisoindoline...... 4

1.3 Synthesis of metal complexes using 1,3-bis(2-benzimidazolylimino)isoindoline...... 6

1.4 High yield synthetic methods of phthalazine from α, α, α’, α’- tetrachloro-o-xylene (right) and o-phthaladehyde (left) ...... 8

1.5 Synthesis of 1,4-dihydrazinophthalazine using phthalonitrile...... 9

1.6 One pot synthesis of two phthalazine derivatives from same reactants but at different reaction conditions...... 10

1.7 Syntheses of 1,4-di(2-pyridyl)aminophthalazine...... 11

1.8 General synthesis of Schiff bases...... 14

1.9 Mechanism for acid catalyzed Schiff base synthesis...... 16

1.10 Reductive amination of aldehydes and ketons...... 18

1.11 The synthesis of Re(CO)3 pyridine-imine complexes with pendant phenol groups..20

2.1 The synthesis of 1,4-bis (2-substituted) phthalazine using 1,3-bis (2-substituted) isoindoline……………………………………………………………………...... 23

2.2 The synthesis of 1,4-bis (2-benzimidazolylimino) phthalazine using 1,3-bis (2- benzimidazolylimino) isoindoline (1) ...... 25

2.3 The synthesis of 1,4-bis (2-thiazolylimino) phthalazine using 1,3-bis (2- thiazolylimino) isoindoline (2)...... 26

2.4 The reaction to produce the copper complex (3)…...... 27

2.5 The reaction to produce the iron complex (4)...... 28

2.6 The reaction to produce the zinc complex (5)………..…...... 29

2.7 The reaction to produce the nickel complex (6)...... 30

3.1 The reaction of Schiff bases ligand with various metals...... 51

3.2 The reaction of Schiff base ligand with metal acetates...... 53

3.3 The reaction of Schiff base ligand with nickel (II) nitrate (9) ...... 54

xii

CHAPTER I

INTRODUCTION

1.1 Phthalocyanine macrocycles

Phthalocyanines (PCs) are interesting macrocyclic compounds with many applications as they have exceptional chemical and physical properties.1 Linstead was the first to describe their structures in the 1930s although they were discovered accidentally earlier in 1907.1 These compounds are stable, and their characteristics make them some of the most preferred in making colorants like direct dyes, solvent dyes and vat dyes.1

They are also used widely in making particular pigments. Phthalocyanines are known for their characteristic range of colors from red, purple, green-yellow and finally to blue colors due to the various substitutions taking place on the PC skeleton.1

Phthalocyanine applications continue to be used in modern industrial process. Solar cell technology benefits from the compounds as they are useful as photocatalysts.1,2

Furthermore, the medical industry utilizes phthalocyanines in photodynamic therapy to treat some illnesses.1 The field of engineering and physics also benefits from gas sensors developed from phthalocyanines.1 Phthalocyanines are nontoxic, simple to prepare in large quantities, and stable due to their 18 electron aromatic ring.

Phthalocyanines are macrocyclic compounds that have a conjugated system with 18 π electrons and are stable chemically and thermally.3 The phthalocyanine structure has some similarities with the porphyrin structure, which is shown in Figure 1.1.

Phthalocyanine is made up of four isoindoline rings linked together by bridging nitrogen atoms. The center has four nitrogen atoms facing the core of the ring which can bind metal ions.

Figure 1.1 Structures of porphyrin and phthalocyanine.

Various compounds can be used to synthesize phthalocyanines, and one common reagent is diiminoisoindoline. Diiminoisoindoline is synthesized by refluxing phthalonitrile with ammonia gas where methanol used as the solvent and sodium as the catalyst.4 The diiminoisoindoline isolated from this procedure is a green powder.4 This compound can then be used to synthesize the phthalocyanine macrocycle using a standard method, such as via metal templating. In addition, phthalocyanine variants can be produced when diiminoisoindoline is reacted with aromatic or heterocyclic compounds.4

Scheme 1.1 Syntheses of phthalocyanine and diiaminoisoindoline.4

1.2 Bis-substitutied isoindolines

Many of these compounds can be prepared upon reacting phthalonitrile with primary amine.5,6 In 1976, Siegl was able to produce 1,3-bis-(2-pyridylimino)isoindoline in a stable form by reacting one equivalent of phthalonitile with two equivalents of 2- aminopyridine in butanol. This reaction goes through two steps: first, 1-arylimino-3- iminoisoindoline forms as an intramolecular cyclization product. Then the reaction completes by the addition of a second molecule of aminopyridine which forms the desired compound 1,3-bis-(2-pyridylimino)isoindoline (BPI) with loss of ammonia.6

This method was developed following Linstead’s method to produce 1,3-bis-(2- pyridylimino)isindoline by using diiaminoisoindoline as a starting material with primary amine.6

Scheme 1.2 Synthesis of 1,3-bis(2-pyridylimino)isoindoline using phthalonitrile5 or diiminoisoindoline6

Elvidge and Linstead predicted the possible reactivity of BPI with nickel and they

7 isolated two types of complexes Ni(BPI)2 and Ni(BPI)OAc. In 1967 Hurley and co- workers reacted the chelate with metals including zinc, nickel, cobalt, iron and cadmium to obtain BPI metal complexes.7 Siegl continued work on the coordination chemistry of

BPI.7,8 He was able to use direct method to produce metals complexes via refluxing phthalonitrile with 2-aminopyridine and the transition metals at the same time in methanol as a solvent for 6-24 hours.8 The crystal structure of the Ni complex and its electronic absorption spectrum have been reported.9

Another important substituted isoindoline is 1,3-bis(2-thiazolylimino)isoindoline

(BTI) which also has been used as chelate for metallation reactions. This ligand has been studied previously with some metals including copper, palladium, and iron by Meder and

Gade, Broring and co-workers, and Pap and co-workers respectively.10 In 2011, Ziegler

4 reported the complexes of the ligand with manganese, cobalt, and zinc as well as iron which was previously reported. All of the metal complexes had either 2:1 or 1:1 ligand to metal stoichiometries. The X-ray structure of 1,3-bis-(2-thiazolylimino)isoindoline shown in Figure 1.2.10

Figure 1.2 The structure of 1,3-bis(2-thiazolylimino)isoindoline. Hydrogen atoms have been omitted for clarity.10

1,3-bis(2-benzimidazolylimino)isoindoline has also been shown to have reactivity with metals. This compound was investigated and reacted with various transition metals by Speier and co-workers.11-15 Recently, Ziegler was successful in elucidating the structure of the ligand and its metal complexes via X-ray crystallography as shown in

Figure 1.3.16 He reacted diiminoisoindoline with two equivalents of 2- aminobenzimidazole and the isolated compound 1,3-bis(2- benzimidazolylimino)isoindoline where then reacted with several transition metals in

DMF including nickel, iron, copper, cobalt and zinc.16 The metal complexes have a 1:1 metal to ligand ratio as shown in Scheme 1.3.

Figure 1.3 The structure of 1,3-bis(2-benzimidazolylimino)isoindoline. Non-ionizable hydrogen atoms have been omitted for clarity.16

Scheme 1.3 Synthesis of metal complexes using 1,3-bis(2-benzimidazolylimino) isoindoline.16

1.3 Phthalazines

Phthalazine belongs to the azine class of molecules, and the simplest examples are a group of twelve monocyclic heteroaromatic nitrogen compounds formed by replacement of CH by N in a benzene ring.17 These also include diazines or two fused six-membered rings, which are naphthalene analogues, with number of combinations of nitrogen heterocycles. Out of these there are four diaza analogues, with the two nitrogen atoms on the same ring: cinnoline, phthalazine, quinazoline and quinaxoline.18 The structures of these four analogues are shown in Figure 1.4 below:

Figure 1.4 Structure of the four diaza analogues.17

The delocalized π-electrons in the ring give rise to electron density distributions and the electronic structure of these compounds has been calculated by different research groups.19 These densities can be used to explain the chemical behavior of phthalazine, for example, its reactivity with halogens, thiolates and other reagents. They can be substituted at positions C1 to C4 and it can be easily made to undergo nucleophilic substitution. Electrophilic substitution of phthalazine is also possible, producing 5- nitrophthalazine resulting upon nitration.19Gabriel and Pinkus synthesized first unsubstitutied phthalazine in 1893. It was produced from α, α, α’, α’- tetrachloro-o-

7 xylene by reacting it with aqueous hydrazine for two hours under pressure and at elevated temperature of 150 °C.19 The method was further developed and new synthetic routes were also discovered. The original method, for example, required hydrazine sulfate dissolved in sulfuric acid that is concentrated more than 90% and heating the precursor or xylene to obtain yields around 86% .19-20 A higher yield 96% of phthalazine was obtained by reacting solution of o-phthaladehyde and ethanol and drop wise adding to hydrazine hydrate in an ice bath.21 The two reaction syntheses outlined above are shown in Scheme

1.4:

Scheme 1.4 High yield synthesis methods of phthalazine from α, α, α’, α’- tetrachloro-o- xylene (right)19 and o-phthaladehyde (left).19,20

Phthalazine and its derivatives are often synthesized from benzene by cyclization

22 or by condensing with acyclic synthons. One commonly used method involves C1-C8 bond formation through isomerization or dehydration of appropriate substrates.

Phthalazine can also be synthesized by cyclization of a substrate companied with the loss of alcohol, water, acetic acid, ammonia or other groups.22 Phthalazine derivatives, especially those having attached aryl groups, can be synthesized using a synthon unit

(usually hydrazine or its derivative) that supplies the N2 + N3 atoms. The substrate is the type 1-aldehydo-2-ketobenzene and the reaction yields a product of the type 1-alkyl (or aryl) phthalazine.22

If a 1,2-dicyanobenzene (phthalonitrile) is used as starting material in the presence of hydrazine, it leads to the formation of 1,4-dihydrazinophthalazine (DHPH) with phthalazinediamine as the intermediate reaction product.22 The reaction is shown in

Scheme 1.5 below:

Scheme 1.5 Synthesis of 1,4-dihydrazinophthalazine using phthalonitrile.22

Recently DHPH and acetylacetone (MeCOCH2COMe) have been used in the one pot synthesis of an aryl phthalazine with the formula 1,4-bis-(3,5-dimethyl-pyrazol-1-yl)- phthalazine. One equivalent of DHPH and two equivalents of acetylacetone (acac) react in the presence of acetic acid at 90 °C for two hours to give a 95% yield of the final product. The hydrazine derivatives transform to pyrazoles at 90 °C, while the reaction at a higher temperature yields 6-(3,5-dimethyl-pyrazol-1-yl)-3-methyl-

[1,2,4]triazolo[3,4-a]phthalazine. For this second reaction to occur, the acetylacetone has to mix with two equivalents of Et3N, while the reaction mixture has to be heated for 3 hours at 130 °C.23 These reactions are shown in Scheme 1.6 below:

Scheme 1.6 One pot synthesis of two phthalazine derivatives from same reactants but at different reaction conditions.23

Phthalazine derivatives have been used as ligands or chelates with a number of transition metals. For example 1,4-bis(pyridine-2-ylamino)phthalazine with Cu(II) was investigated in 1969 by Elvidge and co-workers.24 The ligand was synthesized by the traditional method using monohydrate hydrazine with 1,3-bis(2-pyridylimino)isoindoline to insert the nitrogen atom in the five membered ring on the isoindoline ring (tridentate ligand) to expand it to be phthalazine ring with six membered ring including two nitrogen atoms instead of one. Another method they used was by reacting the 1,4-diaryl phthalazine with two amine groups. The ligands were then used to react with copper salts to form binuclear copper complexes.24 The synthetic route for 1,4-bis(pyridine-2- ylamino)phthalazine (PAP) is shown in Scheme 1.7. The ligand in this case prefers to bind to two metals via the four nitrogen atoms and the metal ions bind additional ligands as shown in Figure 1.6.

Scheme 1.7 Syntheses of 1,4-di(2-pyridyl)aminophthalazine.24

Figure 1.5 Crystal structure of PAP.7

24 Figure 1.6 The structure of Cu2LCl3(OH)H2O.

Numerous transition metals complexes were also synthesized, characterized and studied with this ligand such as nickel and zinc.24,25 Most studies were carried out by

Thompson and co-workers and were focused on the synthesis, characterization and reactivity of tetradentate ligands with copper.24, 26-28

In chapter II, the chemistry of 1,4-bis-(2-substitutied)phthalazines derivatives from isoindoline compounds will be discussed. 1,4-bis-(2-thiazolylimino)phthalazine and

1,4-bis(2-benzimidazolylimino)phthalazine were synthesized using 1,3-bis(2- thiazolylimino)isoindoline and 1,3-bis(2-benzimidazolylimino)isoindoline respectively upon reaction with hydrazine. Also, the reactivity of these ligands with series of transition metals was investigated.

1.4 Schiff bases

Schiff bases or imines can be defined as compounds that contain an azomethine group (-C=N-) which is a nitrogen atom with an aryl or alkyl groups that is also bound to a carbon atom through a double bond.29-34 This functional group was discovered in 1864 by a German scientist named Hugo Schiff.35,36 They are synthesized by the condensation of carbonyl compounds with primary amines.29,31,33,37,38 This synthesis is usually carried out by using organic solvents and can take place under catalysis and high temperature.36

Over the past decades, Schiff base compounds have been studied and gained significant interest due to their stability, multiple uses, and ease of preparation.29,35,39 These compounds have a variety of applications in many fields. In the medicinal and biological chemistry fields they are used as antitumor, antimalarial, antibacterial, antitubercular, antiinflammatory, antiviral, antioxidant, and fungicidal agents.30,40-49 Schiff bases with transition metals are also used as catalysts in some dehydrogenation and oxidation processes.50 The Schiff bases have the general structures as shown below in Figure 1.7.

Figure 1.7: The two general structures of Schiff bases.51

Scheme 1.8 General synthesis of Schiff bases.51

One of the simplest Schiff base ligands is N-benzylidene aniline which also called

(N,1-di(phenyl) methanimine) and has the structure as shown in Figure 1.8.52 The synthesis of this Schiff base compound can be achieved by refluxing a mixture of aniline, benzaldehyde, and trimethyl amine in benzene for 24 hours.52 The method was later modified by refluxing a mixture of aniline and benzaldehyde in methyl alcohol as solvent for 24 hours52 or by refluxing the mixture in ethanol at 40-50 C for two hours to obtain

87% yield53 or by using toluene as solvent to yield 60%.54

Figure 1.8 The structure of N-benzylidene aniline.52

Green chemistry plays an essential role in the preservation of the environment.

Using green chemical methods can be challenging where low environmental impact and safely is desired. This field has gained much attention recently, and the synthesis and properties of Schiff base ligands have also been examined in low reaction temperatures and moderate conditions.52 Synthesis of Schiff base compounds without catalysis or solvent is convenient.55,56 Some studies were focused on using this method which leads to excellent product yield with catalysts or solvents free conditions at room temperature.55,56

For example N-benzylidene-aniline obtained in 99% yield by reacting equal molar equivalents of benzaldehydes with anilines in water and stirred 30 min at room temperature.55

More recently, synthesis of N-benzylidene aniline was achieved by using a natural acid (lemon juice). This method takes 30 min to obtain 89% yield of product. The advantages of using this method are that it is very safe, economic, easy, and clean. The mechanism of this reaction can be via two possible methods. In method I, the synthesis of

Schiff bases was depending on the nucleophilic attack while in method II was on the water removal rate.56

Scheme 1.9 Mechanism for acid catalyzed Schiff base synthesis.56

Schiff bases ligands that have aryl groups, especially those derived from aniline, have become some of the most important Schiff bases in many fields.41-47 A variety of substituents has been added to the aniline group to increase its activity for these applications. Many have studied these compounds with different substituents on the aniline ranging from simple atoms such as H, and some halogen atoms (Br, Cl, I) to

32,52,57 groups like NO2, OMe and different substituents of aldehydes.

For example, 4-chloro-N-(pyridine-2-ylmethylene) benzenamine is a new Schiff base ligand produced by mixing of para chloro aniline with pyridine-2-carboxaldehyde in methanol with present of acetic acid. This compound showed anti-fungal and antibacterial activities when tested in vitro.57 Also 1-(2-(3-hydroxy-4- methoxybenzylideneamino)-5-chlorophenyl)-2,2,2-trifluoroethanone showed similar activites.30

In general, the synthesis of Schiff bases compounds requires high temperatures achieved via refluxing, or catalysis in organic solvents. More recently, many publications have been presented that find new methods to produce Schiff bases compounds.51,55,56 For example, Khetanin and co-workers used microwave irradiation as a good way to synthesize Schiff base compounds from salicylaldehyde. This study was focused in comparing the yield achieved by conventional methods with the new method.

It was found that the traditional method obtained 78% yield of product while in new method produced 94.4% yield in a very short time. Preparation of Schiff bases using microwave irradiation method has some advantages including speed and low cost.51

Synthesis of reduced Schiff’s bases has been formed by reduction sodium borohydride (NaBH4) in 2,2,2-trifluoroethanol (TFE) (Scheme 1.10) after reacting of chloroaniline and chlorobenzayldehyde.54,58-59 These compound with single bond between carbon and nitrogen C-N were then reacted with first row of transition metals including copper (II), zinc (II), and nickel (II) in a 1:2 metal: ligand mixture. Metal complexes were produced in crystalline form and have the structures shown in Figure

1.9.58

Scheme 1.10: Reductive amination of aldehydes and ketones.59

Figure 1.9: Structure of bidentate reduced Schiff base ligands with some transition metals.58

Over the last couple of years, many studies have focused in the chemistry of the

60,61 Re(CO)3 core. Re(CO)3 can be used as a model to study the reactivity of Tc(CO)3 core.62 Reacting Re with Schiff base ligands can be used to generate highly stable

63 compounds. Another interest in the Re(CO)3 unit is bound to diimines that it metal to ligand charge transfer bands and can be used in electron transfer dyes.64,65 Rhenium complexes are useful in NLO materials, in solar energy conversion and in chemical and biological sensors.65-67 Heinze and coworkers worked with rhenium, platinum and palladium complexes that connected to diiamine ligands with phenol group. They demonstrated sensitivity to pH at room temperature and intense absorption in UV-visible when these compounds loss phenol proton.68 Later on, Ziegler and coworkers synthesized some of these compounds Re(CO)3 cores with diimine phenolic ligands but with pyridine-2-carboxyaldehyde ligand using one-pot conditions or sequential reaction as shown in Scheme 1.11. They were able to structurally characterize the compounds using single-crystal X-ray methods and studied the effect of the phenol group position. The studying showed differences in pH-dependent and UV-visible absorption between the six compounds that were synthesized.68

Scheme 1.11 The synthesis of Re(CO)3 pyridine-imine complexes with pendant phenol groups.68

Ziegler and coworkers have investigated the synthesis of Re(CO)3 compounds via one-pot reactions. In 2014, they synthesized eleven compounds by reacting [Re(CO)5X] where X= Cl, Br with o-, m-, or p-phenylenediamine and pyridine-2-carboxyaldehyde.

Most of these compounds were characterized using X-ray spectroscopy and all were able to study by UV-Vis spectroscopy and cyclic voltammetry.69 Another study by Ziegler and coworkers was focused on the synthesis of Re(CO)3 modified lysine which can be incorporated into solid phase peptide using one pot method.70 The structure of these compounds are shown in Figure 1.10.

Figure 1.10 Neurotensin(8-13) peptide with lysine at amine terminus bound to the rhenium pyca unit; 3: R= FMOC, 4: R= fluorescein.70

In chapter (III), the one pot synthesis of Schiff base metal complexes by reacting aniline with 2-pyridinecarboxaldehyde and series of transition metals including nickel, manganese, cobalt and zinc will be discussed. These compounds have been fully characterized, including by X-ray crystallography, mass spectrometry and IR spectroscopy.

CHAPTER II

THE SYNTHESIS AND CHARACTERIZATION OF THE BIS-SUBSTITUTED

PHTHALAZINES USING BIS- SUBSTITUTED ISOINDOLINES AS STARTING

MATERIAL AND THEIR METALS COMPLEXES

2.1 Introduction

Phthalocyanines are macrocyclic compounds and were first investigated by

Linstead in the1930s.1 Recently, the synthesis of the related molecules 1,3-bis-(2- benzimidazolylimino)isoindoline and 1,3-bis-(2-thiazolylimino)isoindoline have been investigated as the building blocks for and as related molecules to the phthalocyanines.

These compounds can also be used as starting materials to produce two additional derivatives: 1,4-bis-(2-benzimidazolylimino) phthalazine (1) and 1,4-bis-(2- thiazolylimino)phthalazine (2).

This synthesis of these compounds goes through a number of stages. First, phthalonitrile was refluxed in methanol with ammonia gas and sodium as a catalyst to produce diiminoisoindoline. The isolated diiminoisoindoline was then mixed with two equivalents of 2-aminobenzimidazole or aminothiazole respectively in butyl alcohol as

22 the solvent and refluxed 24 hours. These reactions produced 1,3-bis-(2- benzimidazolylimino) isoindoline and 1,3-bis-(2-thiazolylimino)isoindoline respectively.

The resulting compounds can be used in the new reaction with hydrazine monohydrate to produce the target compounds, which are 1,4-bis (2-benzimidazolylimino) phthalazine 1 and 1,4-bis (2-thiazolylimino)phthalazine 2.

Scheme 2.1 The synthesis of 1,4-bis-(2-substituted) phthalazine using 1,3-bis-(2- substituted)isoindoline.

In this chapter, the synthesis of 1,4-bis(2-benzimidazolylimino)phthalazine (1) and 1,4-bis(2-thiazolylimino)phthalazine (2) using 1,3-bis(2-benzimidazolylimino) isoindoline and 1,3-bis(2-thiazolylimino)isoindoline respectively are discussed. A variety of metals are then reacted with these phthalazines. In some cases, the corresponding isoindoline complexes, rather than the phthalazine complexes, were observed.

2.2 Experimental

General Methods: Unless otherwise stated, all reagents and solvents were purchased from Sigma, Aldrich, Acros Organics, or Alfa Aesar and used without further purification. Solution NMR spectroscopy was performed with Varian VXR 300 MHz and

Varian 500 MHz NMR instruments. Mass spectrometric analyses were carried out at the

Mass Spectrometry and Proteomics Facility at The Ohio State University in Columbus,

OH or at the University of Akron in Akron, OH.

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 (λ = 0.71073 Å) operated at 2000 W power or with a CCD based diffractometer with dual Cu/Mo ImuS microfocus optics (Cu-Kα radiation, λ = 1.54178 Å). 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 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 1,4-bis (2-benzimidazolylimino) phthalazine using 1,3-bis (2-benzimidazolylimino) isoindoline (1).

Synthesis of 1,4-bis-(2-benzimidazolylimino)phthalazine (1, Scheme 2.2): The starting material 1,3-bis-(2-benzimidazolylimino)isoindoline 0.188 g (0.499 mmol) was solubilized by refluxing in 10 mL of pyridine for 30 min. By the end of the refluxing, the initial yellow solution became green. Hydrazine monohydrate (25.5 μL) was then added to the green hot solution and the mixture was allowed to stand at room temperature overnight. The green solution was reverted to a yellow color and thin yellow crystals formed. The crystals were collected, and dried with diethyl ether. The target compound is soluble in dimethylformamide (DMF), tetrahydrofuran (THF), dimethyl sulfoxide

(DMSO) in the absence of heat, and in methanol with heating. 1,4-bis (2- benzimidazolylimino)phthalazine has formula (C22N8H16). Yield: 0.121 gm (62%). ESI

MS (positive ion) measured for compound 1: ([M+H]+) 392.42 m/z ; found 393 m/z. 1H

NMR ( DMSO, 300MHz): = 7.9 (q, 4H), 7.0 (q, 4H), 6.41 (q, 4H) ppm.

Scheme 2.3 The synthesis of 1,4-bis (2-thiazolylimino) phthalazine using 1,3-bis (2- thiazolylimino) isoindoline (2).

The method to synthesize 1,4-bis (2-thiazolylimino)phthalazine (2, Scheme 2.3 ) was identical to that of 1,4-bis (2-benzimidazolylimino)phthalazine 1 instead using 0.311 g (1.00 mmol) of the 1,3-bis (2-thiazolylimino)isoindoline. Thin yellow crystals were obtained from this reaction as well. The target compound 2 has poor solubility in common solvents except DMSO. 1,4-bis (2-thiazolylimino)phthalazine has formula

(C14N6S2H10). Yield: 19 mg (58%). MALDI MS (positive ion) measured for compound

2: ([M+H]+) 327.4 m/z; found 327.34 m/z. 1H NMR (DMSO, 300MHz): = 8.1 (s, 4H),

7.8 (s, 4H), 7.4 (q, 2H), 6.5 (s, 2H) ppm.

Scheme 2.4 The reaction to produce the copper complex (3).

Synthesis of compound 3 (3, Scheme 2.4): This compound was initially synthesized by dissolving 0.030 g (0.076 mmol) of the 1,4-bis (2- benzimidazolylimino)phthalazine in small amount of DMF and the solution was yellow.

In another a small vial, 0.014 g (0.077 mmol) of copper acetate was dissolved in the same solvent and the solution was blue. The two solutions were combined and the color of the mixture became very dark brown. Brown crystals were produced upon diffusion of the dimethylformamide solution with distilled water. The crystals were dried with diethyl ether and then collected and characterized at room temperature. Solubility tests showed that this compound is soluble in DMF, acetic acid, and acetonitrile. Compound 3 has formula (C66N24Cu2H44). Yield: 0.021 g (63%). ESI MS (positive ion) measured for compound 3: ([M+H]+) 1301.28 m/z; found 1301.28 m/z. IR bands (cm-1): 1658 w, 1625

27 w, 1519 m, 1460 m, 1399m, 1314 m, 1267 m, 1267 m, 1156 m, 1091 m, 1023 m.

Crystals from the diffusion solution were suitable for X-ray diffraction. Crystal data and structure refinement parameters are summarized in Table 2.1.

Scheme 2.5 The reaction to produce the iron complex (4).

The method to synthesize compound 4 (4, Scheme 2.5) was identical to that of compound 3 instead using 0.10 g (0.25 mmol) of 1,3-bis-(2-benzimidazolylimino) phthalazine and 0.064 g (0.265 mmol) of iron (III) nitrate. The two solutions were combined and the color of the mixture became brown. Brown crystals were produced upon diffusion of DMF solution with diethyl ether. Solubility tests showed that this compound is soluble in DMF, THF, DMSO, methanol, acetic acid, and acetonitrile but not in toluene, dichloromethane, and hexane. Yield: 0.087 g (69%). ESI MS calcd for

+ -1 (C44N16Fe2O7H28): 1004.49 m/z; found 1001.18 (M-NO3+K) m/z. IR bands (cm ): 1645 m, 1620 m, 1549 m, 1498 m, 1450 m, 1425 m, 1385 m, 1320 m, 1276 m, 1184 m, 1090 m, 1057 m. Crystals from the diffusion solution were suitable for X-ray diffraction.

Crystal data and structure refinement parameters are summarized in Table 2.2.

Scheme 2.6 The reaction to produce the zinc complex (5).

The method to synthesize compound 5 (5, Scheme 2.6) was identical to that of compound 4 instead using 0.1 g (0.25 mmol) of 1,3-bis (2-benzimidazolylimino) phthalazine and 0.058 g (0.26 mmol) of zinc acetate. Solubility tests showed that this compound (yellow crystals) is soluble in DMF, THF, DMSO, methanol, acetic acid, and acetonitrile. Yield: 0.09 (69%). IR bands (cm-1): 1652 w, 1622 w, 1513 m, 1467 m, 1424 m, 1385 m, 1318 m, 1284 m, 1212 m, 1190 m, 1111 m, 1039 m. ESI MS (positive ion)

+ calcd for (C24N7O3ZnH19): 517.83 m/z; found 517.11 m/z (M-CH3COO-H2O) . Crystals from the diffusion solution were suitable for X-ray diffraction. Crystal data and structure refinement parameters are summarized in Table 2.3.

Scheme 2.7: The reaction to produce the nickel complex (6).

The method to synthesize compound 6 (6, Scheme 2.7) was identical to 3 instead using 0.155 g (0.47 mmol) of 1,3-bis (2-thiazolyimino)phthalazine in DMSO and refluxing to 30 min and 0.145 g (0.498 mmol) of nickel (II) nitrate in methanol.

Solubility tests showed that this compound (orange crystals) is soluble in DMF, THF,

DMSO, acetic acid and acetonitrile. Yeild: 0.096 g (60%). IR bands (cm-1): 1594 w, 1506 m, 1489 m, 1370 m, 1301 m, 1287 m, 1187 m, 1092 m, 1058 m. ESI MS (positive ion)

+ calcd for (C28N10S4NiH16): 679.45 m/z; found 678.98 m/z (M+H) . Crystals from the diffusion solution were suitable for X-ray diffraction. Crystal data and structure refinement parameters are summarized in Table 2.4.

2.3 Results and discussion

The 1,4-bis (2-benzimidazolylimino) phthalazine compound (1) was synthesized as discussed in the experimental section. 1,3-bis (2-benimidazolylimino) isoindoline was reacted with hydrazine monohydrate to expand the ligand ring and produce 1 as indicated in Scheme (2.2). The yellow crystals were soluble in most organic solvents. They were collected and then characterized using 1H NMR spectroscopy and ESI mass spectrometry.

This characterization methods identified that the ring of 1,3-bis (2- benzimidazolylimino)isoindoline was expanded to give 1,4-bis (2-benzimidazolylimino) phthalazine. According to mass spectrometry in Figure (2.1), the desired compound showed major peak at 393.1 m/z which proved the addition of nitrogen to the five membered ring to increase ring size to a six membered ring.

Figure 2.1 ESI mass spectrum of compound 1.

Figure 2.2 1H NMR spectrum of compound 1

The 1,4-bis (2-thiazolylimino)phthalazine compound 2 was synthesized as discussed in the experimental section. This compound is identical to compound 1 instead with 2-aminothiazole substituted on the phthalazine ligand. This compound was not soluble in most organic solvent expect DMSO due to the presence of the aminothiazole ring and the lack of solubility made the synthesis of the metal complexes more difficult to achieve. The yellow crystals were collected and then characterized using 1H NMR spectroscopy and MALDI mass spectrometry. This characterization method identified that the ring of 1,3-bis (2-thiazolylimino) isoindoline was expanded to give 1,4-bis (2- thiazolylimino) phthalazine as compound 1. Mass spectrometry shown in Figure (2.3) shows a major peak at 327.34 m/z which confirm the expantion of the isoindoline ring to phthalazine ring.

Figure 2.3 MALDI mass spectrum of compound 2

Figure 2.4 1H NMR spectrum of compound 2

The reaction of 1,4-bis (2-benzimidazolylimino)phthalazine (1) with copper acetate in DMF solution led to 3 as crystals after vapor diffusion with distilled water. The brown crystals were characterized using mass spectroscopy, X-ray crystallography and

IR spectroscopy. Mass spectrometry result showed the desired peak at 1301.28 which is confirmed the formation of (C66N24Cu2H44). The IR peaks for the N=C groups appeared at 1658 and 1625 cm-1.

The X-ray of the compound 3 (Figure 2.1) showed a 2:3 copper: ligand complex with distorted square planar geometries at the metal centers. This compound crystallizes in a monoclinic crystal system with general formula (C66N24Cu2H44). One of the ligands is bound to the two metal atoms via all its heterocycle nitrogen atoms while the remaining ligands are each bound to one metal through one nitrogen atom from a phthalazine ring and one from a benzimidazole ring. The M-NIm for the ligand that connected to both Cu atoms were shorter at 1.978(3) and 1.974(4) Å than the M-

NPhthalazine at the same ligand, which were at 1.980(4) and 1.986(3) Å. For the other ligands that connected to Cu1 and Cu2, the M-NIm were at 1.971 and 1.964(4) Å and for the M-NPhthalazine were observed at 1.962(4) and 1.955(4) Å respectively. This means that the ligand is bounds to the Cu2 via two nitrogens was the binds more tightly compared to

2 the bridging ligand. Compared to literature the M-NIm bond lengths in Cu(C2H3O2)2 with the isoindoline ligand were at 1.964(3) and 1.970(3) Å which are similar to that of two ligands the bound partially to metals but for the M-NIsoindoline bond length was shorter at

1.949(4) Å than all M-NPhthalazine bonds.

Figure 2.5 ESI mass spectrum for compound 3

Figure 2.6 IR spectrum for compound 3

Table 2.1 Crystal data and structure refinement parameters for compound 3

Identification code 3 Empirical formula C75 H65 Cu2 N27 O7 Formula weight 1583.62 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1)/c Unit cell dimensions a = 16.640(2) Å α= 90°. b = 20.722(3) Å β= 102.210(4)°. c = 21.713(3) Å = 90°. 3 Volume 7317.3(19) Å Z 4 3 Density (calculated) 1.438 Mg/m -1 Absorption coefficient 0.657 mm F(000) 3272 3 Crystal size 0.430 x 0.412 x 0.397 mm Theta range for data collection 1.59 to 25.57°. Index ranges -20<=h<=15, -23<=k<=24, -25<=l<=25 Reflections collected 55248 Independent reflections 13012 [R(int) = 0.0814] Completeness to theta = 25.57° 94.7 % Absorption correction SADABS 2 Refinement method Full-matrix least-squares on F Data / restraints / parameters 13012 / 0 / 1006 2 Goodness-of-fit on F 1.033 Final R indices [I>2sigma(I)] R1 = 0.0598, wR2 = 0.1388 R indices (all data) R1 = 0.1060, wR2 = 0.1621 -3 Largest diff. peak and hole 1.238 and -0.545 e.Å

Figure 2.7 The structure of compound 3 with 35% thermal ellipsoids. Non-ionizable hydrogen atoms have been omitted for clarity.

Compound 4, which has the general formula of C44N16Fe2O7H28, crystallized in a monoclinic crystal system. It is produced upon the reaction of Fe(NO3)2 with 1,3-bis-(2- benzimidazolylimino)phthalazine in a 2:2 metal to ligand stoichiometry. Mass spectrometry showed a peak at 939.14 and isotope peak at 1041 which is compound 4

- with loss of NO3 and addition of potassium respectively. The N=C stretch is observed in the IR spectrum at 1645 and 1620 cm-1. The structure of the complex showed that the compound reverted to the isoindoline starting material. The X-ray structure elucidation showed a dimeric structure with each Fe atom bound to one ligand through the three nitrogen atoms, to a nitrate ion and to the second Fe via a bridging oxygen atom to form a trigonal bipyramidal geometry. The M-NIm bond lengths for Fe1 bond lengths were at

2.0711(18), 2.0824(18) Å while the M-Nisindoline bond length were shorter at 2.0650(18) Å and for M-O was shorter at 1.7828(15) Å than M-O (NO3) at 2.0676(15) Å. For the second part of this compound with Fe2 the M-NIm bond lengths were at 2.0782(18) and

2.0676(18) Å and for M-Nisoindoline bond length was the shortest one at 2.0458(18) Å compared to all Fe-N bond length in this compound. The distance of M-O was at

- 1.7832(15) Å which were similar to the first part with Fe1 and for M-OAc present at

1.7832(15) Å. Examination of the bond lengths of literature10 with this compound showed some similarity of M-N bonds at 2.045(3) and 2.073(3) Å. This compound showing angles of 120.2°, 120.9° and 120.8°, 120° between the central isoindoline ring and the two benzimidazole rings and 168.79° and 170.83° angles respectively between the benzimidazole rings.

Figure 2.8 ESI mass spectrum for compound 4

Figure 2.9 IR spectrum for compound 4

Table 2.2 Crystal data and structure refinement parameters for compound 4

Identification code 4 Empirical formula C56 H56 Fe2 N20 O11 Formula weight 1296.91 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Triclinic Space group P-1 Unit cell dimensions a = 13.0944(6) Å α= 80.293(2)°. b = 15.2382(7) Å β= 75.489(2)°. c = 15.2585(7) Å = 82.920(2)°. 3 Volume 2894.8(2) Å Z 2 3 Density (calculated) 1.488 Mg/m -1 Absorption coefficient 0.581 mm F(000) 1344 3 Crystal size 0.49 x 0.43 x 0.30 mm Theta range for data collection 1.61 to 25.08°. Index ranges -15<=h<=15, -17<=k<=18, -18<=l<=15 Reflections collected 37333 Independent reflections 10259 [R(int) = 0.0313] Completeness to theta = 25.08° 99.8 % Absorption correction SADABS Max. and min. transmission 0.8468 and 0.7659 2 Refinement method Full-matrix least-squares on F Data / restraints / parameters 10259 / 0 / 810 2 Goodness-of-fit on F 0.966 Final R indices [I>2sigma(I)] R1 = 0.0355, wR2 = 0.0836 R indices (all data) R1 = 0.0445, wR2 = 0.0887 -3 Largest diff. peak and hole 0.637 and -0.326 e.Å

Figure 2.10 The structure of compound 4 with 35% thermal ellipsoids. Hydrogen atoms have been omitted for clarity.

Reaction of zinc acetate with 1,3-bis-(2-benzimidazolylimino)phthalazine yielded single crystals of compound 5. It was isolated in a monoclinic crystals system with formation of a 1:1 ligand: metal complex. Mass spectrometry showed peak at 440.06

- which is the molecular weight of the desired compound with loss of CH3COO and one molecule of water. The IR spectrum showed the N=C stretch of in peaks at 1652 and

1622 cm-1. The structure of the complex showed that the compound reverted to the isoindoline starting material. The X-ray structure in Figure (2.13) shows 5 with a general formula of (C24N7O3ZnH19). The Zn(II) center is in a trigonal pyramidal structure. The bond lengths of M-NIm are observed at 2.066(4) and 2.065(4) Å and were shorter than those of similar zinc complex in the literature, which are between 2.081(4) and 2.085(4)

10 Å. For the M-Nisoindoline bond length was the shortest bonds at 2.053(4) Å compared to

10 other M-N bond lengths in this compound and to M-Nisoindoline bonds in literature. The

- bond length of M-OH2 was longer at 2.161(3) Å than the bond length of M-OAc at

2.066(3) Å.

Figure 2.11 ESI mass spectrum of compound 5

Figure 2.12 IR spectrum of compound 5

Table 2.3 Crystal data and structure refinement parameters for compound 5

Identification code 5 Empirical formula C27 H24 N8 O4 Zn Formula weight 589.91 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group C2/c Unit cell dimensions a = 26.856(9) Å α= 90°. b = 13.795(4) Å β= 125.264(9)°. c = 23.182(8) Å = 90°. Volume 7012(4) Å3 Z 8 Density (calculated) 1.118 Mg/m3 Absorption coefficient 0.738 mm-1 F(000) 2432 Crystal size 0.25 x 0.24 x 0.13 mm3 Theta range for data collection 1.74 to 25.58°. Index ranges -32<=h<=32, -16<=k<=16, -28<=l<=27 Reflections collected 26044 Independent reflections 6563 [R(int) = 0.0972] Completeness to theta = 25.58° 99.5 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7452 and 0.6836 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 6563 / 0 / 364 Goodness-of-fit on F2 0.996 Final R indices [I>2sigma(I)] R1 = 0.0695, wR2 = 0.1807 R indices (all data) R1 = 0.1098, wR2 = 0.2022 Largest diff. peak and hole 1.043 and -0.506 e.Å-3

Figure 2.13 The structure of compound 5 with 35% thermal ellipsoids. Hydrogen atoms have been omitted for clarity.

The reaction of nickel nitrate with 1,3-bis (2-thiazolylimino)phthalazine led to compound 6 which has a general formula of C28N10S4NiH16. Mass spectrometry showed the desired peak at 678.98 which is confirmed the molecular formula. In the IR spectrum, the N=C Schiff base stretch absorbance appears at 1594 cm-1. X-ray crystallography was used to elucidate the structure in a triclinic crystal system. The Ni ion binds to two ligands in a 1:2 fashion. And the Ni(II) center is in an octahedral structure. The M-NIm bond lengths with the first ligand were at 2.099(4), 2.106(4) Å and longer than with the second ligand at 2.093(4) and 2.093(4) Å and that in Ni(C2H3O2)2.4H2O with one ligand

10 reported previously. For M-Nisoindoline was the shortest at 2.038(4) Å compared to another ligand at 2.051 Å and that in lietrature10 at 2.011(3) Å.

Figure 2.14 ESI mass spectrum for compound 6

Figure 2.15 IR spectrum for compound 6

Table 2.4 Crystal data and structure refinement parameters for compound 6

Identification code 6 Empirical formula C28 H16 N10 Ni S4 Formula weight 679.46 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Triclinic Space group P-1 Unit cell dimensions a = 8.7123(5) Å α= 73.090(4)°. b = 11.4396(8) Å β= 77.609(5)°. c = 16.6990(10) Å = 77.415(5)°. 3 Volume 1533.58(17) Å Z 2 3 Density (calculated) 1.471 Mg/m -1 Absorption coefficient 3.769 mm F(000) 692 3 Crystal size 0.090 x 0.074 x 0.072 mm Theta range for data collection 5.88 to 62.00°. Index ranges -9<=h<=9, -12<=k<=10, -19<=l<=18 Reflections collected 10677 Independent reflections 4636 [R(int) = 0.0603] Completeness to theta = 62.00° 96.2 % 2 Refinement method Full-matrix least-squares on F Data / restraints / parameters 4636 / 0 / 388 2 Goodness-of-fit on F 0.953 Final R indices [I>2sigma(I)] R1 = 0.0571, wR2 = 0.1429 R indices (all data) R1 = 0.0840, wR2 = 0.1561 -3 Largest diff. peak and hole 0.897 and -0.460 e.Å

Figure 2.16 The structure of compound 6 with 35% thermal ellipsoids. Hydrogen atoms have been omitted for clarity.

CHAPTER III

THE SYNTHESIS AND CHARECTRIZATION OF THE SCHIFF BASES LIGANDS

WITH A VARIETY OF METALS

3.1 Introduction

In 1864 Hugo Schiff was discovered a new class of compounds that were named after him.35,36 Schiff bases are common ligands that contain a nitrogen atom connected to a carbon atom via double bond and to an alkyl or aryl groups.29-34 Schiff bases are also known as imines. The synthesis of Schiff bases compounds can be achieved by reacting carbonyl groups with primary amines under high temperature either using an organic medium or catalysit.36 In this work we investigated the metal mediated formation of

Schiff base complexes using one pot conditions. We reacted aniline with 2- pyridinecarboxaldehyde to make a Schiff base through the nitrogen from aniline and the carbon from 2-pyridinecarboxaldehyde (pyca) forming a double bond between these atoms. This reaction was carried out in the presence of several metal salts. This synthesis is going through several steps. Two equivalents of aniline were added to two equivalents of 2-pyridinecarboxaldehyde then dissolved in methanol. Varities of metals were also dissolving completely in methanol and the two solutions were then combined. The final

50 step for this synthesis was diffusing in an insoluble solvent to isolate the desired compounds as crystalline solids.

Scheme 3.1 The reaction of Schiff bases ligand with various metals.

In this chapter, the synthesis and characterizations of several Schiff base metal complexes are presented. For three metals, isostructural trimetallic complexes for generated, and for the Ni(II) reaction, a monometallic complex was produced. The products were characterized by using mass spectrometry, X-ray crystallography, IR spectroscopy.

3.2 Experimental

Varian 500 MHz NMR instruments. Mass spectrometric analyses were carried out at the

Mass Spectrometry and Proteomics Facility at The Ohio State University in Columbus,

OH or at the University of Akron in Akron, OH.

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 or with a CCDbased diffractometer with dual Cu/Mo ImuS microfocus optics (Cu-Kα radiation, λ = 1.54178 Å). 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.

Scheme 3.2 The reaction of Schiff base ligand with metal acetates.

Synthesis of compound 7 (7, Scheme 3.2): This compound was initially synthesized by dissolving 0.245 g (1.00 mmol) of manganese acetate tetrahydrate in 3 mL of methanol in a small vial and the solution was yellow. In another a small vial, 180

μL of aniline and 180 μL of pyridine-2-carboxyladehyde were mixed together and then dissolved in small amount of the same solvent. The two solutions were combined and the color of the mixture became between orange and red. The mixture was refluxed for four hours and then diffused with a second solvent. Brown crystals were produced upon diffusion of the methanol solution with ethyl ether, acetone, and tetrahydrofuran. The crystals were dried with diethyl ether and then collected and characterized at room temperature. Solubility tests showed that this compound is soluble in DMF, DMSO, acetic acid, and methanol but did not dissolve in acetonitrile or dichloromethane. Yield:

0.239 g (81%). IR bands (cm-1): 1557 m, 1411 s, 1337 m, 1148 w, 1049 m, 1010 m. ESI

MS (positive ion) calcd for C36N4O12Mn3H38: 883.52 m/z; found 883.48 m/z ([M-

+ CH3CO2] ). Crystals from the diffusion diethyl ether solution were suitable for X-ray

53 diffraction. Crystal data and structure refinement parameters are summarized in Table

3.1.

Synthesis of compound 8 (8, Scheme 3.2) was identical to 7 instead using 0.249 g

(1.00 mmol) of cobalt acetate tetrahydrate. Brown crystals were obtained from this reaction upon diffusion as well. Solubility tests showed that this compound is soluble in acetic acid, and partially in acetonitrile with applied of heat but did not dissolve in DMF,

THF, DMSO, methanol, and dichloromethane. Yield: 0.242 g (81%). IR bands (cm-1):

1590 m, 1537 m, 1492 m, 1455 m, 1410 s, 1369 m, 1335m, 1303 w, 1149 m, 1047 m,

1018 m. ESI MS (positive ion) calcd for C36N4O12Co3H38: 895.50 m/z; found 895.468

+ ([M-CH3CO2] ) m/z. Crystals from the diffusion solution were suitable for X-ray diffraction. Crystal data and structure refinement parameters are summarized in Table

3.2.

Scheme 3.3 The reaction of Schiff bases ligand with nickel (II) nitrate (9).

The method to synthesize compound 9 (9, Scheme 3.3) was identical to that of 7 instead using 0.290 g (1 mmol) of nickel nitrate hexahydrate. Black crystals were obtained from this reaction as well. Solubility tests showed that this compound is soluble in acetic acid, and partially in acetonitrile with the application of heat but did not dissolve in DMF, DMSO, acetic acid, and acetonitrile. Yield: 0.15 g (32%). IR bands (cm-1): 1630 m, 1592 m, 1485 m, 1446 m, 1391 m, 1299 s, 1268 m, 1194 m, 1151 m, 1100 m, 1032 m. ESI MS (positive ion) calcd for C25N5O4NiH24: 517.18 m/z; found 517.14 m/z ([M-

+ CH3OH] ). Crystals from the diffusion solution were suitable for X-ray diffraction.

Crystal data and structure refinement parameters are summarized in Table 3.3.

The method to synthesize compound 10 (10, Scheme 3.2) was identical to that of

7 instead using 0.219 g (1 mmol) of zinc acetate dihydrate. Yellow crystals were obtained from this reaction. Solubility tests showed that this compound is soluble in acetic acid, and partially in acetonitrile with applied of heat but did not dissolve in DMF, DMSO, acetic acid, and acetonitrile. Yield: 0.217 g (71%). IR bands (cm-1): 1592 s, 1490 m, 1418 s, 1363 m, 1322 m, 1020 m. ESI MS (positive ion): calcd for C36N4O12Zn3H38: 916.85

+ m/z; found 916.67 m/z ([M- C12N2H10Zn] ). Crystals from the diffusion solution were suitable for X-ray diffraction. Crystal data and structure refinement parameters are summarized in Table 3.4.

3.3 Results and discussion

Compound 7 with a general formula of C36N4O12Mn3H38 was synthesized according to the route shown in Scheme 3.2. Two equivalents of pyridine-2- carboxyaldehyde mixed with two equivalents of aniline in MeOH then mixed with a solution of manganese acetate followed by vapor diffusion with ethyl ether, acetone or

THF. The desired compound was collected and characterized using mass spectrometry,

X-ray crystallography and IR spectroscopy. The mass spectrometry result showed peak at

824 m/z which is the molecular weight of the desired compound with loss of an acetate anion. The IR spectroscopy showed peak area of the N=C Schiff base stretch absorbance at 1557 cm-1. X-ray structure and data confirmed that two ligands were reacted with three manganese atoms. Two of these atoms were bound to the ligand by two bonds through nitrogen atoms and four bonds with acetate ions while the third Mn in the center bound to four acetate ions and to the two manganese atoms via oxygen bridges from acetate. This structure divides to two equal parts. The bond length of M-Naniline was longer at

2.3458(16) than that of M-Npyca at 2.2304(16) Å. The Mn-O bond lengths for Mn1 were shorter at 2.0882(13), 2.0979(14) Å compared to Mn2 at 2.1653(13) and 2.1520(13) Å.

The M-O distances of Mn that connected to one acetate ion through both oxygen atoms were at 2.1940(13), and 2.3605(13) Å.

Display Report

Analysis Info Acquisition Date 1/28/2014 1:09:16 PM Analysis Name D:\Data\2014\X012814M.d Method pos_tune_low.m Operator BDAL@DE Sample Name 18140 Pyca3 Mn Instrument maXis 4G 20196 Comment

Acquisition Parameter Source Type ESI Ion Polarity Positive Set Nebulizer 0.3 Bar Focus Not active Set Capillary 4500 V Set Dry Heater 180 °C Scan Begin 50 m/z Set End Plate Offset -500 V Set Dry Gas 4.0 l/min Scan End 1500 m/z Set Collision Cell RF 800.0 Vpp Set Divert Valve Waste

Intens. +MS, 0.1-0.5min #(6-27) x105 824.0445 5

2 814.9242

805.8036 856.0687 786.9282

0 780 800 820 840 860 880 900 m/z

Please acknowledge funding P30 CA016058 and NSF Award 1040302 on publications resulting from this data. Figure 3.1 ESI mass spectrum for compound 7

Bruker Compass DataAnalysis 4.0 printed: 1/28/2014 1:14:30 PM Page 1 of 1

Figure 3.2 IR spectrum for compound 7

Table 3.1 Crystal data and structure refinement parameters for compound 7

Identification code 7 Empirical formula C18 H19 Mn1.50 N2 O6 Formula weight 441.76 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Triclinic Space group P-1 Unit cell dimensions a = 7.9057(3) Å α= 70.184(2)°. b = 9.5041(3) Å β= 83.431(2)°. c = 13.2974(5) Å = 87.986(2)°. Volume 933.78(6) Å3 Z 2 3 Density (calculated) 1.571 Mg/m -1 Absorption coefficient 1.067 mm F(000) 453 3 Crystal size 0.45 x 0.38 x 0.24 mm Theta range for data collection 1.64 to 27.00°. Index ranges -10<=h<=10, -12<=k<=11, -16<=l<=16 Reflections collected 14473 Independent reflections 4047 [R(int) = 0.0332] Completeness to theta = 27.00° 99.7 % Absorption correction SADABS Max. and min. transmission 0.7837 and 0.6469 2 Refinement method Full-matrix least-squares on F Data / restraints / parameters 4047 / 0 / 253 2 Goodness-of-fit on F 0.882 Final R indices [I>2sigma(I)] R1 = 0.0331, wR2 = 0.0914 R indices (all data) R1 = 0.0374, wR2 = 0.0963 -3 Largest diff. peak and hole 1.176 and -0.553 e.Å

Figure 3.3 The structure of compound 7 with 35% thermal ellipsoids. Hydrogen atoms have been omitted for clarity.

Compound 8 with general formula C36N4O12Co3H38 was elucidated in the triclinic crystal system from crystals produced upon the reaction of cobalt acetate with MeOH solutions of pyridine-2-carboxyaldehyde and aniline as described in the experimental section. Structure elucidation of the brown crystals demonstrated that a 2:3 ligand to metal complex was yielded with an identical structure to that seen for the Mn complex 7.

Mass spectrometry of this compound showed the desired peak of the compound 895.50 m/z with loss of acetate ion at 836 m/z. In the IR spectrum, the peak for the N=C Schiff base stretch absorbance appears at 1590 cm-1. All M-N and M-O bond lengths were slightly shorter than 7, which is consistent with the smaller radius of the Co(II) ion. The bond lengths of M-N were range between 2.1(2) and 2.223(2) Å. For M1-O bond lengths were shorter at 2.023(2) and 2.034(2) Å than that between M1 and the two oxygen atoms in the same acetate ion at 2.1309(19) and 2.223(2) Å. For the second metal M-O bond lengths were longer at 2.0657(19), 2.0701(19) and 2.1098(19) Å.

Display Report

Analysis Info Acquisition Date 1/28/2014 1:32:15 PM Analysis Name D:\Data\2014\X012814O.d Method pos_tune_low.m Operator BDAL@DE Sample Name 18140 Pyca CO Instrument maXis 4G 20196 Comment Acquisition Parameter Source Type ESI Ion Polarity Positive Set Nebulizer 0.3 Bar Focus Not active Set Capillary 4500 V Set Dry Heater 180 °C Scan Begin 50 m/z Set End Plate Offset -500 V Set Dry Gas 4.0 l/min Scan End 1500 m/z Set Collision Cell RF 800.0 Vpp Set Divert Valve Waste

Intens. 836.0280 +MS, 0.2-0.5min #(10-29) x105 2.5

2.0

1.5

1.0

802.9070 0.5

808.0311

794.0152

0.0 790 800 810 820 830 840 850 860 870 m/z Please acknowledge funding P30 CA016058 and NSF Award 1040302 on publications resulting from this data. Figure 3.4 ESI mass spectrum for compound 8

Bruker Compass DataAnalysis 4.0 printed: 1/28/2014 1:39:45 PM Page 1 of 1

Figure 3.5 IR spectrum for compound 8

Table 3.2 Crystal data and structure refinement parameters for compound 8

Identification code 8 Empirical formula C21 H27 Co1.50 N2 O8 Formula weight 523.84 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Triclinic Space group P-1 Unit cell dimensions a = 7.9062(5) Å α= 84.605(3)°. b = 11.6491(7) Å β= 82.502(3)°. c = 12.9282(8) Å = 70.987(2)°. 3 Volume 1114.42(12) Å Z 2 3 Density (calculated) 1.561 Mg/m -1 Absorption coefficient 1.180 mm F(000) 543 3 Crystal size 0.30 x 0.15 x 0.14 mm Theta range for data collection 1.59 to 24.85°. Index ranges -9<=h<=9, -13<=k<=13, -15<=l<=15 Reflections collected 16430 Independent reflections 3848 [R(int) = 0.0288] Completeness to theta = 24.85° 99.7 % Absorption correction SADABS Max. and min. transmission 0.8570 and 0.7156 2 Refinement method Full-matrix least-squares on F Data / restraints / parameters 3848 / 0 / 298 Goodness-of-fit on F2 1.104 Final R indices [I>2sigma(I)] R1 = 0.0391, wR2 = 0.1299 R indices (all data) R1 = 0.0445, wR2 = 0.1371 -3 Largest diff. peak and hole 0.911 and -1.003 e.Å

Figure 3.6 The structure of compound 8 with 35% thermal ellipsoids. Hydrogen atoms have been omitted for clarity.

The reaction of nickel nitrate with two equivalents of both pyridine-2- carboxyaldehyde and aniline yielded compound 9 with general formula C25N5O4NiH24.

The compound crystallized in the triclinic crystal system. Mass spectrometry for this compound showed a peak at 484 instead of 517 m/z due to the loss of methanol

(CH3OH). The IR spectroscopy peak area of the N=C Schiff base stretch absorbance was shifted to show at 1592 cm-1. Crystals of 9 growth using diethyl ether as a secondary solvent via vapor diffusion. The X-ray structure for this compound showed a difference in structure from compounds 7, 8, and 10. This compound has a 1:2 metal to ligand ratio.

The nickel arranges in the center of the monomeric complex with an octahedral geometry. The M-N bonds to the first ligand were longer at 2.0754(17) and 2.1056(16) Å than that with the second ligand at 2.0668(17) and 2.0888(17) Å. The distance of M-OH was longer at 2.0821(14) than M-NO3 at 2.0440(14) Å.

Figure 3.7 ESI mass spectrum for compound 9

Figure 3.8 IR spectrum for compound 9

Table 3.3 Crystal data and structure refinement parameters for compound 9

Identification code 9 Empirical formula C25 H24 N6 Ni O7 Formula weight 579.21 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Triclinic Space group P-1 Unit cell dimensions a = 8.7498(4) Å α= 72.947(2)°. b = 10.1163(5) Å β= 76.749(2)°. c = 15.4105(8) Å = 85.712(2)°. 3 Volume 1269.33(11) Å Z 2 3 Density (calculated) 1.515 Mg/m -1 Absorption coefficient 0.822 mm F(000) 600 3 Crystal size 0.271 x 0.204 x 0.172 mm Theta range for data collection 1.42 to 24.85°. Index ranges -10<=h<=10, -11<=k<=11, -17<=l<=18 Reflections collected 18309 Independent reflections 4390 [R(int) = 0.0277] Completeness to theta = 24.85° 99.6 % Absorption correction SADABS 2 Refinement method Full-matrix least-squares on F Data / restraints / parameters 4390 / 0 / 353 2 Goodness-of-fit on F 0.887 Final R indices [I>2sigma(I)] R1 = 0.0302, wR2 = 0.1025 R indices (all data) R1 = 0.0348, wR2 = 0.1098 -3 Largest diff. peak and hole 0.406 and -0.357 e.Å

Figure 3.9 The structure of compound 9 with 35% thermal ellipsoids. Hydrogen atoms have been omitted for clarity.

The reaction of zinc acetate with the pyridine-2-carboxyaldehyde and aniline in methanol solution leads to the formation of compound 10 which showed similarities with other structures 7 and 8. As in 7 and 8, the ratio of metal to ligand is 3:2. Compound 10 has general formula C34N4O14Zn3H32. The mass spectrometry appeared peak at 669 due to the separation of one Schiff base ligand from the complex. The IR spectrum shows a

N=C Schiff base stretch absorbance at 1592 cm-1. Crystals of 10 were grown from vapor diffusion of diethyl ether into a methanol solution of the complex, and 10 crystallized in the triclinic crystal system. The structure is shown in Figure 3.4. The M-N bond lengths here were the shortest at 2.0647(17) Å for the pyridine nitrogen and the longest at

2.2957(16) Å for the Schiff base nitrogen compared to the other compounds in this chapter. The bond lengths for M1-O were shorter at 2.0491(14), 1.9897(14) and

1.9949(12) Å than that for M2-O at 2.0559(13), 2.0946(13), and 2.1420(14) Å respectively.

Figure 3.10 ESI mass spectrum for compound 10

Figure 3.11 IR spectrum for compound 10

Table 3.4 Crystal data and structure refinement parameters for compound 10

Identification code 10 Empirical formula C36 H38 N4 O12 Zn3 Formula weight 914.81 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Triclinic Space group P-1 Unit cell dimensions a = 18.4867(9) Å α= 90°. b = 9.6551(5) Å β= 102.631(2)°. c = 23.8072(13) Å = 90°. 3 Volume 4146.5(4) Å Z 4 3 Density (calculated) 1.465 Mg/m -1 Absorption coefficient 1.783 mm F(000) 1872 3 Crystal size 0.457 x 0.306 x 0.238 mm Theta range for data collection 2.26 to 27.20°. Index ranges -23<=h<=23, -12<=k<=12, -30<=l<=23 Reflections collected 17739 Independent reflections 4614 [R(int) = 0.0344] Completeness to theta = 27.20° 99.6 % 2 Refinement method Full-matrix least-squares on F Data / restraints / parameters 4614 / 0 / 254 2 Goodness-of-fit on F 1.095 Final R indices [I>2sigma(I)] R1 = 0.0301, wR2 = 0.0778 R indices (all data) R1 = 0.0351, wR2 = 0.0800 -3 Largest diff. peak and hole 0.955 and -0.559 e.Å

Figure 3.12 The structure of compound 10 with 35% thermal ellipsoids. Hydrogen atoms have been omitted for clarity.

CHAPTER IV

CONCLUSIONS AND FUTURE WORK

We have synthesized two bis-substituted phthalazine ligands. Bis-substituted phthalazines resulted from the reaction of bis-substituted isoindolines with hydrazine monohydrate. The free phthalazine ligand (2) showed poor solubility with common organic solvents due to the presence of sulfur in the two thiazole substituted rings while the second pthalazine ligand (1) that has two aminothiazole rings was very soluble in most solvents. The N,N,N,N-tetradentate ligands, 1,4-bis-(2-benzimidazolylimino) phthalazine (1) and 1,4-bis-(2-thiazolylimino)phthalazine (2) readily reacted with some transition metals to produce the copper complex (3), the iron complex (4), the zinc complex (5) and the nickel complex (6) which were structurally characterized. In some cases, the structure of the complexes showed that the compounds reverted to the isoindoline starting material. The stoichiometries of the complexes were found to be 2:3,

2:2, 1:1, 1:2 metal:ligand with distorted square planar, trigonal bipyramidal, trigonal pyramidal, octahedral geometries at the metal center.

We have also reported the synthesis of Schiff base ligands using one pot conditions by reacting two equivalents of aniline with two equivalents of 2- pyridinecarboxaldehyde and then reacting with metal salts to obtain four complexes. The complexes were the manganese complex (7), the cobalt complex (8), the nickel complex

(9) and the zinc complex (10). All these compounds share the same trimetallic structures except the nickel complex which has monometallic structure.

Our group will continue our investigations into isoindoline and phthalazine compounds and their derivatives as chelates and their reactivity with metals to yield new metal complexes. We will also continue our work into the chemistry of Schiff bases as ligands and their metal complexes.

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