I SYNTHESIS of LIGANDS and MACROCYCLES BASED on 1,3

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SYNTHESIS OF LIGANDS AND MACROCYCLES BASED ON 1,3-

DIIMINOISOINDOLINES AND STUDY OF NEW HIGHLY FLUORESCENT AND

SYMMETRIC PYRROLE-BF2 CHROMOPHORES

A Dissertation

Presented to

The Graduate Faculty of The University of Akron

In Partial Fulfillment

of the Requirements for the Degree

Doctor of Philosophy

Ingrid-Suzy Tamgho

December, 2014

SYNTHESIS OF LIGANDS AND MACROCYCLES BASED ON 1,3-

DIIMINOISOINDOLINES AND STUDY OF NEW HIGHLY FLUORESCENT AND

SYMMETRIC PYRROLE-BF2 CHROMOPHORES

Ingrid-Suzy Tamgho

Dissertation

Approved: Accepted:

______Advisor Department Chair Dr. Christopher J. Ziegler Dr. Kim Calvo

______Committee Member Dean of the College Dr. Claire A. Tessier Dr. Chand Midha

______Committee Member Dean of the Graduate School Dr. Michael J. Taschner Dr. George Newkome

______Committee Member Date Dr. Yi Pang

______Committee Member Dr. Kevin A. Cavicchi

ABSTRACT

Discovered in 1907 by Braun and Tcherniac, a phthalocyanine is a macrocycle composed of four isoindolines. The metal chemistry of this macrocycle is rich, as of today, the phthalocyanines are well-known dyes and photosensitizers. Among the variety of phthalocyanine precursors, 1,3-diiminoisoindoline and phthalonitrile are the most widely used. Indeed, new macrocyles and ligands are synthesized from these compounds, either by condensation of 1,3-diiminoisoindoline or the CaCl2-catalyzed reaction of phthalonitrile with an amine. Following these methods, we are able to prepare a series of compounds, the phthalocrown, and also revisit the chemistry of bis(alkylimino)isoindolines.

The first part of the dissertation describes the synthesis and characterization of phthalocrowns. They can be considered as chimera molecules composed of a crown ether and phthalocyanine. These compounds are synthesized via Schiff base-type condensation reactions between polyetherdiamines and 1,3-diiminoisoindoline, which can be generated from phthalonitrile.

Secondly, we revisit the chemistry of bis(alkylimino)isoindolines. These compounds can be generated via phthalonitrile and 1,3-diiminoisoindoline depending on the nature of the amine. Also, the metal chemistry of these compounds with Ag(I) is described.

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One important class of fluorescent dyes is known as BODIPY. This fluorophore consists of a dipyrromethene bound to a central BF2 unit. The compound is found to possess excellent photophysical properties such as high extinction coefficient and high quantum yield of emission. Moreover, BODIPY is insensitive to pH and solvent polarity and is photostable. Its versatility, introduced via the attachment of biomolecules or other moieties, allows these dyes to have important applications from biological imaging and sensing to light harvesting. In the final chapter, we discuss the synthesis of a novel family of fluorophores, the BOPHY. These dyes are synthesized via the Schiff-base reaction of a pyrrole carbaldehyde with hydrazine, followed with a BF2 complexation to yield highly fluorescent chromophores. The BOPHY optical properties are discussed in the final chapter as well.

DEDICATION

To my parents, my sister and brother

La vraie magie c’est le travail

ACKNOWLEDGEMENTS

First, I would like to thank God (Gue fuote Tchiepo Si). “I could have never made it without you. When I look back over what you brought me through, I realize that I made it because I had You to hold on to”.

I would also like to gratefully and sincerely thank my advisor Dr. Christopher J.

Ziegler for he is a great teacher, mentor and advisor. His guidance, his encouragement and patience made me become the confident scientist that I am today.

To Kullapa, Abed, Laura, Allen, Anthony, Roshinee, Jim, Sarah and Nada, I will always be thankful for your friendship, help and support. You made working in the lab an enjoyable experience. I will miss working with you guys.

I would like to acknowledge the department of Chemistry for giving me the opportunity to study in this university and financial support during these years. I will extend my thanks to Dr. Pang, Dr. Taschner, Dr. Tessier and Dr. Cavicchi from the

Polymer Engineering department for taking time to serve in my committee. Your helpful suggestions and advice were preciously appreciated and I am grateful that you considered me as being qualified to earn my Ph.D in chemistry.

Being an ocean away from home is not easy, I was lucky enough to meet friends in and outside the university that made me feel Akron as my second home. I would not be able to name all of you here, but you definitely know who you are.

A mon petit frère, Teddy et ma grande sœur, Stéphanie, cette dissertation est pour vous. Sans vous, je n’aurais pu jamais finir cette dissertation. Maman nous a toujours dit de prendre exemple sur nos ainés. Stéphanie, j’ai la chance de t’avoir comme grande sœur et meilleure amie. Tu as toujours été présente, tu m’as toujours supportée et voulu le meilleur pour nous tes petits (Teddy et moi). Teddy, petit, tu es aussi ma source d’inspiration et de motivation. Tu m’as montré que pour réussir et être le meilleur, il faut savoir se sacrifier et travailler très dur. Merci à vous, pour le soutien moral et financier

(hiiiii), j’espère que vous êtes fiers de votre petite (grande) sœur.

A mes parents, Alice et Jean-Bosco, sans qui je ne serais pas la. Je vous remercie du fond du cœur. Motokoua.

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TABLE OF CONTENTS

Page LIST OF TABLES ...... x

LIST OF FIGURES ...... xii

LIST OF SCHEMES...... xv

LIST OF ABBREVIATIONS ...... xvii

CHAPTER

I. INTRODUCTION AND BACKGROUND ...... 1

1.1 Introduction to DII and DII-based ligands ...... 1

1,3-diiminoisoindoline ...... 4

Chemistry of 1,3-diiminoisoindoline ...... 9

Oxime-DII ...... 10

Phthalazines ...... 11

1,1,3-trichloroisoindoline ...... 14

3-imino-1-oxoisoindoline ...... 15

Coordinating Bis(arylimino)isoindolines - 1,3-Bis(2-pyridylimino)isoindoline ...... 22

Alternative coordinating bis(arylimino)isoindolines ...... 33

Non-coordinating Bis(arylimino)isoindolines ...... 34

Bis(alkylimino)isoindolines ...... 36

1.2 BF2-based fluorophores ...... 37

Fluorescence ...... 38 viii

Classes of fluorophores ...... 40

BODIPY ...... 45

Aza-BODIPY ...... 54

BODIPY analogues ...... 58

II. THE PHTHALOCROWNS: ISOINDOLINE-CROWN ETHER MACROCYCLES ...... 63

Experimental ...... 65

Results and Discussion ...... 71

III. THE SYNTHESES AND STRUCTURES OF BIS(ALKYLIMINO)ISOINDOLINES ...... 78

Experimental ...... 82

Results and Discussion ...... 105

IV. A NEW HIGHLY FLUORESCENT AND SYMMETRIC PYRROLE-BF2 CHROMOPHORE: BOPHY ...... 118

Experimental ...... 119

Results and Discussion ...... 127

V. SUMMARY ...... 142

REFERENCES ...... 146

APPENDIX ...... 161

LIST OF TABLES

Table Page 2.1 Crystal data and structure refinement for 4-mono ...... 68

2.2 Crystal data and structure refinement for 4-ortho ...... 69

2.3 Crystal data and structure refinement for 6...... 70

3.1 Crystal data and structure refinement for 7 ...... 87

3.2 Crystal data and structure refinement for 8 ...... 88

3.3 Crystal data and structure refinement for Ag(8)oxo ...... 89

3.4 Crystal data and structure refinement for 9 ...... 90

3.5 Crystal data and structure refinement for 10 ...... 91

3.6 Crystal data and structure refinement for 14 ...... 92

3.7 Crystal data and structure refinement for 15 ...... 93

3.8 Crystal data and structure refinement for 16 ...... 94

3.9 Crystal data and structure refinement for 18 ...... 95

3.10 Crystal data and structure refinement for 19 ...... 96

3.11 Crystal data and structure refinement for 19.HCl ...... 97

3.12 Crystal data and structure refinement for Ag(19) ...... 98

3.13 Crystal data and structure refinement for 20 ...... 99

3.14 Crystal data and structure refinement for 20.HCl ...... 100

3.15 Crystal data and structure refinement for 21 ...... 101

3.16 Crystal data and structure refinement for 22 ...... 102

3.17 Crystal data and structure refinement for 23 ...... 103 x

3.18 The syntheses and yields of substituted isoindolines 7-23 ...... 106

4.1 Crystal data and structure refinement for 25...... 125

4.2 Crystal data and structure refinement for 26...... 126

4.3 Crystal data and structure refinement for 27 ...... 127

LIST OF FIGURES

Figure Page

1.1.1 Top view and side view of the sructure of H2Pc...... 4

1.1.2 Crystal structures of DII ...... 7

1.1.3 Structure of oxime-DII (left) and the hydrogen bonding network formed (right). Non-ionizable hydrogen atoms have been omitted for clarity ...... 11

1.1.4 Structure of phthalazine (left) and the hydrogen bonding network formed (right). Non-ionizable hydrogen atoms have been omitted for clarity...... 12

1.1.5 Structures of PAP (top) and Cu(Cl)PAP (bottom). Non-ionizable hydrogen atoms have been omitted for clarity ...... 13

1.1.6 Synthesis (top) and structure (bottom) of TCI ...... 15

1.1.7 Crystal structure of 1-imino-3-oxoisoindoline. Non-ionizable hydrogen atoms have been omitted for clarity...... 17

1.1.8 Hydrogen bonding network observed in the crystal structure of oxo-DII ...... 17

1.1.9 Tautomerism and crystal structure of 3-phenylimino-1-oxoisoindoline ...... 19

1.1.10 Synthesis of 1,3,5-triazapentadienato metal complexes (top) and structure of a copper complex (bottom). Non-ionizable hydrogen atoms have been omitted for clarity ...... 21

1.1.11 Crystal structure of Zn(oxoDII). Non-ionizable hydrogen atoms have been omitted for clarity ...... 22

1.1.12 Structure of Mo2(OAc)3BPI. Non-ionizable hydrogen atoms have been omitted for clarity...... 27

1.1.13 Crystal structures of 6-methylBPI metal complexes. (top – CdBPI, bottom left – Zn-oxoDII, bottom right – PdBPI). Non-ionizable hydrogen atoms have been omitted for clarity...... 28

xii

1.1.14 Structures of BF2BPI (left) and GaCl2BPI (right). Non-ionizable hydrogen atoms have been omitted for clarity...... 29

1.1.15 Structures of alternate bis(arylimino)isoindolines. Non-ionizable hydrogen atoms have been omitted for clarity...... 34

1.1.16 Structures of bis(phenylimino)isoindolines. Non-ionizable hydrogen atoms have been omitted for clarity...... 36

1.1.17 Structure of bis(isopropylimino)isoindoline and its yttrium complex. Non-ionizable hydrogen atoms have been omitted for clarity...... 37

1.2.1 Simplified Jablonski diagram ...... 38

1.2.2 Major classes of fluorophores employed in chemical biology...... 41

1.2.3 Structure of the parent BODIPY. Non-ionizable hydrogen have been omitted ...... 46

1.2.4 Absorption/Emission spectra of BODIPY...... 47

1.2.5 Structure of tetraphenyl-aza-BODIPY ...... 55

2.1 Variable temperature 1H NMR of 3 in DMSO showing dynamic proton exchange behavior...... 74

2.2 Structure of 4 with 35% thermal ellipsoids (left) and the structure of 3 showing the internal hydrogen bond (right). Hydrogen atoms on the thermal ellispoid plot have been omitted for clarity .... 75

2.3 The structure of compound 6 with 35% thermal ellipsoids. Hydrogen atoms have been omitted for clarity...... 76

3.1 Structures of bis-substituted diiminoisoindolines with 35% thermal ellipsoids. Non-ionizable hydrogen atoms and the chloride anion for compound 10 have been omitted for clarity...... 107

3.2 Structures of bis-substituted diiminoisoindolines with 35% thermal ellipsoids. Non-ionizable hydrogen atoms have been omitted for clarity...... 108

3.3 Variable temperature 1H NMR of 13 (aromatic protons) in DMSO showing dynamic proton exchange behavior...... 110

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3.4 Variable temperature 1H NMR of 13 (aromatic protons) in 3:1 chloroform/acetone showing dynamic proton exchange behavior. The scale has been shifted for clarity purposes ...... 111

3.5 Variable temperature 1H NMR of 13 in 3:1 chloroform/acetone showing dynamic proton exchange behavior...... 111

3.6 Variable temperature 1H NMR of 13 in 3:1 chloroform/acetone showing dynamic proton exchange behavior...... 112

3.7 Structures of mono-substituted diiminoisoindolines 9 and 22 with 35% thermal ellipsoids. Non-ionizable hydrogen atoms have been omitted for clarity...... 113

3.8 Hydrogen bonding interactions observed in the structure of 9 (left) and 22 (right). Non-ionizable hydrogen atoms have been omitted for clarity...... 114

3.9 Crystal structure of Ag(8)oxo with 35% thermal ellipsoids. Non-ionizable hydrogen atoms have been omitted for clarity...... 115

3.10 Crystal structure of Ag(19). Non-ionizable hydrogen atoms have been omitted for clarity...... 117

3.11 Configuration of the silver hexamer ...... 117

4.1 The structures of 25, 26 and 27 with 35% thermal ellipsoids. Hydrogen atoms have been omitted for clarity...... 130

4.2 Absorption and emission spectra for 25 and 27 in CH2Cl2 ...... 132

4.3 Normalized absorbance spectra of compound 25 in different solvents...... 132

4.4 UV-Vis spectra of 25 in dichloromethane at different concentrations...... 133

4.5 Normalized absorbance spectra of compound 27 in different solvents ...... 133

4.6 UV-Vis spectra of 27 in dichloromethane at different concentrations...... 134

4.7 Change of optical density of 25 and 27 in toluene at the absorption maximum wavelength with the irradiation at 365 nm (4 W). Solutions were not degassed...... 134

4.8 Cyclic voltammograms of 24-27 in THF...... 135

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4.9 DFT predicted orbital energies for 25 and 27 with pictorial representation of the frontier MOs...... 137

4.10 PCM-DFT calculated (TPSSh/6-311G(d)) MO compositions of compound 25 in C2 (top) and Cs (bottom) symmetry...... 140

4.11 PCM-DFT calculated (TPSSh/6-311G(d)) MO compositions of compound 27 in C2 (top) and Cs (bottom) symmetry...... 138

4.12 Experimental (top) and TDDFT predicted (middle and bottom) absorption spectra of 25 and 27 in DCM ...... 139

4.13 PCM-DFT calculated (TPSSh/6-311G(d)) frontier MOs of compound 25...... 140

4.14 PCM-DFT calculated (TPSSh/6-311G(d)) frontier MOs of compound 27...... 141

LIST OF SCHEMES

Scheme Page 1.1.1 Synthetic route to metalated phthalocyanines ...... 2

1.1.2 Structures of porphyrin and phthalocyanine ...... 3

1.1.3 Improved synthesis of DII ...... 5

1.1.4 Proposed mechanism for the synthesis of DII ...... 6

1.1.5 Stereisomerism and tautomerism of DII ...... 7

1.1.6 Structures of various hemiporphyrazines ...... 8

1.1.7 Reactivity of DII ...... 10

1.1.8 Derivatized phthalazines ...... 12

1.1.9 Synthesis of 3-imino-1-oxoisoindoline ...... 16

1.1.10 Tautomeric forms of oxo-DII ...... 16

1.1.11 Reactivity of 3-imino-1-oxoisoindoline ...... 18

1.1.12 Methylation of toluidyl-oxo-DII ...... 20

1.1.13 Synthesis of BPI (Linstead's method) ...... 23

1.1.14 Synthesis of BPI (Siegl's method)...... 24

1.1.15 Synthesis of bisBPI ...... 25

1.1.16 Stereochemistry of chiral catalysts ...... 30

1.1.17 Synthesis of chiral BPIs ...... 31

1.1.18 Synthesis of bis(arylimino)isoindolines from TCI ...... 35

1.2.1 General structures of common fluorophores ...... 42

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1.2.2 Prototropic forms of fluorescein ...... 43

1.2.3 Structure of BODIPY and related compounds ...... 45

1.2.4 Synthetic routes to symmetric and asymmetric BODIPYs ...... 48

1.2.5 Modification centers of BODIPY ...... 49

1.2.6 General procedure for BODIPY functionalization ...... 50

1.2.7 Nitration and sulfonation of BODIPYs ...... 51

1.2.8 Functionalization of BODIPY dyes via Pd-catalyzed coupling reactions...... 51

1.2.9 π-extended BODIPY dyes ...... 52

1.2.10 Modification at the boron center ...... 54

1.2.11 Synthesis of azadipyrromethene from chalcones ...... 56

1.2.12 Synthesis of azadipyrromethene from nitroso derivatives ...... 56

1.2.13 Synthesis of azadipyrromethene from phthalonitriles ...... 56

1.2.14 Modified aza-BODIPY dyes ...... 58

1.2.15 First BODIPY analogues ...... 59

1.2.16 Examples of BODIPY analogues ...... 60

1.2.17 Examples of solid-state emitting fluorophores ...... 61

2.1 General synthesis of the phthalocrowns ...... 72

3.1 General synthesis of bis(alkylimino)isoindolines ...... 105

3.2 Proton exchange observed in bis(alkylimino)isoindolines...... 110

4.1 General synthesis of BOPHYs ...... 128

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LIST OF ABBREVIATIONS

H2Pc – free-base phthalocyanine

DII – 1,3-diiminoisoindoline

BPI – 1,3-bis(2-pyridylimino)isoindoline

PAP – 1,4-di(2’-pyridylamino)phthalazine

TCI – 1,1,3-Trichloroisoindoline

DMSO – Dimethyl sulfoxide

CD3OD – Deuterated methanol

CDCl3 – Deuterated chloroform

ET3N – Triethylamine

BODIPY – Boron dipyrromethene

THF – Tetrahydrofuran

DIPEA – N,N-Diisopropylethylamine

HOMO – Highest occupied molecular orbital

LUMO – Lowest unoccupied molecular orbital

VT-NMR – Variable temperature NMR

EtOAc – Ethyl Acetate

CH2Cl2/DCM – Dichloromethane

DFT – Density functional theory

TDDFT – Time-dependent density functional theory

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CHAPTER I

1 INTRODUCTION AND BACKGROUND

1.1. Introduction to DII and DII-based ligands

Phthalocyanine, one of the most widely used dyes in industry, was serendipitously discovered in 1907 as a highly colored by-product from the reaction of phthalimide and acetic anhydride to form o-cyanobenzamide.1 In 1927, the same by-product was also encountered during the reaction of ortho-dibromobenzene with copper cyanide.2 This colored compound was insoluble in a variety of solvents making its characterization difficult; however its stability in the solid state over a variety of conditions made it suitable for use as a synthetic dye and it was further developed by Scottish Dyes Ltd.3

Indeed, it was during the manufacturing of phthalimide from phthalic anhydride and ammonia in the presence of Fe, Ni or Cu metal salts of that a blue-purple deposit on the large vessels was observed. The first example of such a deposit was later characterized as an iron phthalocyanine, and a patent was filed in 1928 detailing the synthesis of these newly discovered dyes.3

Six years later, Linstead and coworkers, working in collaboration with the

Scottish Dyes Ltd, were finally able to characterize and name this intriguing by-product,

1 as phthalocyanine.4 Six papers were consecutively published, describing the synthesis and properties of metalated5 (Fe, Mg, Sb, Ni, Co, Cr, Bi, Mn, Ce, Sn, Al, Cu, Mb, W and

Ca) and metal-free phthalocyanines, as well as the structure determination of the macrocycle.6 It was noted that copper phthalocyanines (CuPc) were the most stable variant,7 that free base Pcs are difficult to synthesize directly from starting material and that they have to be produced from demetalation of alkali and alkaline earth metal complexes. Also phthalocyanines can only be generated from ortho-disubstituted benzenes (such as o-cyanobenzamide,5 phthalimide,5 phthalamide,5 and phthalonitrile8)

(Scheme 1.1.1).

Scheme 1.1.1 - Synthetic route to metalated phthalocyanines9

Although its structure was not fully elucidated until a year later, Linstead could, at that time, conclude that phthalocyanine was a symmetric macrocycle composed of four iminoisoindoline units and had a central cavity that can accommodate various metal ions. 2

Additionally, he was able to find a close connection with porphyrins, a similar tetrapyrrolic macrocycle that had both biological and industrial importance.6 In porphyrin, pyrrole units are linked via meso carbons whereas in phthalocyanines the benzopyrrole units are linked via nitrogen atoms (Scheme 1.1.2).

Scheme 1.1.2 - Structures of porphyrin and phthalocyanine6

In 1935, Robertson elucidated the structures of several phthalocyanines (H2Pc,

CuPc, NiPc and PtPc).10 Linstead’s proposed structure was validated as phthalocyanine is indeed a symmetric macrocycle composed of four benzopyrroles (Figure 1.1.1). In addition, bond lengths measurements confirmed the delocalization of electrons throughout the macrocycle; the free base phthalocyanine is aromatic.10–12 The radius of the inner cavity of Pc is 1.91 Å; most transition metals can fit inside the cavity and coordinate in a square planar configuration.13 When the metal cation is significantly larger, Pc will deform itself to bind the metal which will sit out of plane. In particular for lanthanides, Pcs form sandwich complexes (2:1 Pc:metal) to accommodate their increased radius.14 These features were initially confirmed by J. M. Robertson’s thorough work on the structures of metalated Pcs. In the case of M(II)Pc (where M= Be, Mn, Fe,

Co, Ni and Cu), the metal cation rested inside the cavity.13,15 The crystal structure of PtPc

3 differed from the previously mentioned metalated Pc as the macrocycle is bent (44° from the plane), confirming that the Pt(II) sits out of the plane.16

Figure 1.1.1 – Top view and side view of the sructure of H2Pc. Non-ionizable hydrogen atoms have been omitted for clarity.6

1,3-Diiminoisoindoline

Although many o-disubstituted benzenes can be used to produce phthalocyanines

(Scheme 1.1.1), phthalonitrile was the preferred precursor as it yielded high purity products. However, the reaction conditions were rather harsh as high-boiling solvents such as naphthalene, quinolone or chlorobenzene were needed despite the template reaction with a metal cation.17 There was interest in the development of alternate reagents for the synthesis of phthalocyanines that could be used under more mild conditions or without the use of templating ions. Considering these obstacles, in early 1950s, Linstead

4 synthesized 1,3-diiminoisoindoline (DII) while working on novel synthetic procedures for generating phthalocyanine.18 DII was first synthesized from the addition of liquid ammonia in a methanolic solution of phthalonitrile; the reaction mixture was heated in an autoclave for four hours to yield a beige/light green product.18 The overall yield of the reaction was excellent (almost quantitative), yet a small trace of phthalocyanine is produced. At the same time, another research group at the Bayer plant in Germany patented the discovery of salts of DII (nitrate and phosphate); these salts were obtained via the reaction of phthalonitrile and a nitrogen source such as ammonium nitrate or phosphate and urea.19 In 1956, DII was synthesized by using a catalytic amount of Na in methanol (Scheme 1.1.3) the sodium methylate formed would activate the nitrile group as described in the following proposed mechanism (Scheme 1.1.4).20 Isolation and characterization of both 1 and 2 support this proposed mechanism.21-22 Several methods23,24 have subsequently been developed but the sodium methoxide procedure has since been widely adopted for the preparation of DII.

Scheme 1.1.3 - Improved synthesis of DII25

Scheme 1.1.4 - Proposed mechanism for the synthesis of DII26

Although DII has been fully characterized by spectroscopic methods such as 1H and 13C NMR, mass spectrometry, UV-Vis and IR spectroscopies, its structure was only elucidated by X-ray methods in 2004.27 The structure of DII exhibits several features that are very remarkable. First, it was reported that, despite all other characterizations that showed evidence to the contrary, DII exists as the amino tautomeric form in the solid state. Second, two molecules coexist in the asymmetric unit, but they vary in stereochemistry at the imino nitrogen atom (Scheme 1.1.5 and Figure 1.1.2). Crystals grown from a hot benzene solution contained only the syn isomer. Bond distances confirmed the imino and amino nature of each C-N bond. The amino C-N distance ranges from 1.311(2) to 1.320(2) Å and the imino C-N distance are between 1.278(2) and

1.281(2) Å. These value ranges agree with similar parameters in previously elucidated bis(arylimino)isoindolines.28 These two amino forms of DII engage in intermolecular

6 hydrogen bonding through the amino and the isoindoline hydrogen of two facing molecules. The N-N distance of the N-H…N bond is 2.95 Å.

Scheme 1.1.5 - Stereisomerism and tautomerism of DII

Figure 1.1.2 – Crystal structures of DII tautomers.27,29

Recently, during the course of exploring the chemistry of phthalocyanine analogues, the Ziegler group was the first to solve the diimino structure of DII.29 The crystal space group is monoclinic like the previous structures. The bond lengths support the diimino and symmetric structure as both exocyclic C-N bonds are 1.214(3) and

1.218(3) Å, exhibiting true imine character and the isoindole C-N bonds measure

1.387(3) and 1.391(3) Å, proving their single bond character. Another feature is the position of the imine hydrogen; it is oriented toward the phenyl ring of the DII, in the syn configuration. Hydrogen bond dimers are formed in the crystal structure of the diimino

DII; the N-N bonds (NH…N) measure 2.88 Å for both interactions. These dimers stack in an alternate herringbone fashion.29

DII was found to be a reactive species, and would readily react with amines at both imine positions to yield macrocycles, ligands and chelates.18,30 The macrocycles produced by the condensation of DII with diamines are called hemiporphyrazines.31 They are analogous to phthalocyanines as one, two or three isoindolines units are replaced by aromatic30,31 (substituted benzenes, pyridine or azoles) or aliphatic32 rings (Scheme

1.1.6). Hemiporphyrazines are excellent chelating macrocycles and the applications of their metal complexes are extensive.31 However these macrocycles will not be reviewed at this point.

Scheme 1.1.6 - Structures of various hemiporphyrazines31

Chemistry of 1,3-diiminoisoindoline

When DII reacts with an amine (aryl or alkyl), a di-substituted ligand is produced.

In the case of an aryl amine, such as an aminopyridine, a chelating ligand is formed. 1,3-

Bis(2-pyridylimino)isoindoline also named BPI was the first chelating ligand synthesized by Linstead and coworkers.18 After its synthesis, BPI was reacted with nickel salts and methyl iodide in formamide. Three different products were isolated, the N-methylated derivative of BPI and two nickel BPI complexes. The discovery of DII-derived chelates led the way to a vast area of research. Indeed BPI metal complexes were found to have many applications in catalysis, additives for hydrocarbons and also as dyes.31 This will be discussed in depth later in this chapter.

Moreover, DII reacts with other “unique” amines. The reaction of DII and hydroxylamine hydrochloride in methanol results in a bis-oxime derivative, named 1,3- dihydroxyisoindoline.33,34 However, when DII reacts with hydrazine hydrate, a nitrogen is inserted into the isoindoline heterocycle to afford a diamine phthalazine.20,35 Both synthetic procedures are detailed in Scheme 1.1.7.

Scheme 1.1.7 – Reactivity of DII

Oxime-DII

The chemistry of the dioxime-DII has not been explored, and only two derivatives were synthesized. Acetic anhydride and dibenzoyl chloride reacted with dioxime-DII to afford the diacetate and dibenzoyl derivatives.34 In 2012, its structure along with unsubstituted phthalazine were elucidated by Ziegler and coworkers.29 The molecule’s unit cell is orthorhombic and its asymmetric unit is comprised ½ of the molecule.

Dioxime-DII is planar with both oxime units occupying the same plane as the isoindoline, they also are in the anti conformation relative to the phenyl ring. The molecule is completely symmetric, which is supported by examination of the bond distances. These bond lengths confirm the C=N-OH character of the oxime group; the N-O bond measures

1.4132(16) consistent with a single bond character whereas the C=N bond measures

1.2870(18) Å. Hydrogen bonding is featured in this compound between the oxime OH

10 units and the oxime nitrogen on neighboring compounds, forming herringbone-like layers. The OH…N distances measure approximately 2.74 Å (Figure 1.1.3).

Figure 1.1.3 - Structure of oxime-DII (left) and the hydrogen bonding network formed (right). Non-ionizable hydrogen atoms have been omitted for clarity. Dark grey, light grey, blue and red colors represent C, H, N, and O atoms respectively.29

Phthalazines

The structure of the hydrated phthalazine has also been elucidated (Figure

1.1.4).29 The asymmetric unit contains only ½ of the planar molecule. The alternation of single and double bond characters confirms that phthalazine is aromatic. The exocyclic

C-N bonds measure 1.3906(19) Å and the internal C-N bonds measures 1.306(2) Å consistent with a double and single character respectively. Similarly, phthalazine engages in extensive hydrogen bonding with itself via NH…N interactions, and the solvated water via NH…O interactions. The distances betweem the two heteroatoms are 3.01 Å (NH…N) and 2.83 and 2.96 Å (NH…O). This creates linear arrays of phthalazine and bridging water molecules; the arrays form π stacks distanced from each other by 3.52 Å.

Figure 1.1.4 - Structure of phthalazine (left) and the hydrogen bonding network formed (right). Non-ionizable hydrogen atoms have been omitted for clarity. Dark grey, light grey, blue and red colors represent C, H, N, and O atoms respectively.29

Like DII, phthalazines can form ligands or chelates; in 1957, a patent filed by

Bayer described the synthesis of 1,4-dihydrazinophthalazine from the reaction of DII and hydrazine hydrate in acetic acid.36 In 1969, the ligand was reacted with Co and Ni metal salts to yield tetradentate binuclear complexes.37 The magnetic properties of these complexes were studied as well as the electron interaction between the metal centers. The metal chemistry of this ligand has not been expanded upon with the exception of two molybdenum complexes that were reported in the 1980s.38,39

Scheme 1.1.8 - Derivatized phthalazines

During the same time, an analog of BPI and phthalazine had been synthesized:

1,4-di(2’-pyridylamino)phthalazine (PAP), product of the addition of hydrazine hydrate to BPI (Scheme 1.1.8 and Figure 1.1.5).40,41 PAP binds to metals in multiple ways; the most common is in a tetradentate fashion where PAP is bound two metal centers. The metal centers are bridged by the azine portion of the phthalazine and another anion such

- - - - - as OH , N3 , Cl , Br and IO3 ; the first example of a copper PAP complex is shown in

Figure 1.1.5.

Figure 1.1.5 - Structures of PAP (a) and Cu(Cl)PAP (b). Non-ionizable hydrogen atoms have been omitted for clarity. Dark grey, light grey, blue, orange and green colors represent C, H, N, Cu and Cl atoms respectively.40,41

In addition of being a tetradentate ligand, PAP can also be bidentate which results in mononuclear complexes. Various transition metal complexes (Mn, Fe, Co, Ni and Zn) have been synthesized and studied since the early 1970s.40,42–63 The most studied metal complexes of PAP are copper adducts. These complexes exhibit strong antiferromagnetic exchange between the Cu centers. Similar antiferromagnetic exchanges are encountered between Cu(II) centers in copper proteins and enzymes, making CuPAP complexes potential catalysts for oxygenation reactions.47,62

1,1,3-Trichloroisoindoline

At the same time DII was invented, German researchers at Bayer continued their work on the synthesis of starting materials for phthalocyanines.

The reaction of phthalimide with PCl5 in o-dichlorobenzene yields to 1,3,3- trichloroisoindoline (TCI) (Figure 1.1.6).19 Although it is not directly produced from DII,

TCI is still considered as a modified DII and also as a phthalocyanine precursors.17,64 The structure of trichloroisoindoline has been solved recently.29 The compound crystallizes in the orthorhombic space group and the heterocycle lies on a reflection plane. The main features of this molecule are the different lengths of C-Cl bonds. The sp3 C-Cl bond measures 1.7848(11) Å whereas the sp2 C-Cl bond is 1.706(2) Å. In addition to that, TCI is the only modified DII that does not engage in hydrogen bonding as it lacks ionizable hydrogen atoms. Due to its three chlorine atoms, TCI is highly reactive.

Bis(aryl/alkylimino)isoindolines can be prepared via nucleophilic substitution of these

14 chlorides by treating TCI with amines and a tertiary alkylamine as a base to scavenge the

HCl formed.65

Figure 1.1.6 – Synthesis (top) and structure (bottom) of TCI. Dark grey, light grey, blue and green colors represent C, H, N and Cl atoms respectively.29

3-imino-1-oxoisoindoline

3-Imino-1-oxoisoindoline (oxo-DII) is a partially hydrolyzed form of DII, where a carbonyl takes the place of one imine moiety. The synthesis of oxo-DII starts from phthalimide in a 3-step process as described in Scheme 1.1.9.5,66 The conditions may vary; o-cyanobenzamide can react with ammonia, sodium hydroxide, sodium methoxide or hydrochloric acid in ethanol to yield the oxo-DII.1,18,67,68 Additionally, water can also be added to DII, however, the hydrolysis reaction cannot be fully be controlled and many by-products are produced.20,67

Scheme 1.1.9 - Synthesis of 3-imino-1-oxoisoindoline

The crystal structure of the oxo-DII was observed in 2002 as a co-crystallized species with bis(dithiobiureto)nickel.69 The free molecule structure was first reported in

2009 (Figure 1.1.7).70 The oxo-DII exists in the zwitteronic amido form instead of the imino conformation which is confirmed by the electron density map around the nitrogen atoms and the C-N bond lengths (Scheme 1.1.10). The internal C-N bonds are 1.342 and

1.379 Å which are typical of single bond character whereas the exocyclic C-N measures

1.306 Å, indicative of a double bond character. Oxo-DII engages in hydrogen bonding with three other molecules; one via the carbonyl moiety and two via the protonated imino nitrogen (Figure 1.1.8). The distance between the two heteroatoms are NH...N = 2.916 Å and NH...O = 2.876 Å.

Scheme 1.1.10 – Tautomeric forms of oxo-DII

Figure 1.1.7 - Crystal structure of 1-imino-3-oxoisoindoline. Non-ionizable hydrogen atoms have been omitted for clarity. Dark grey, light grey, blue and red colors represent C, H, N and O atoms respectively.70

Figure 1.1.8 – Hydrogen bonding network observed in the crystal structure of oxo-DII. Dark grey, light grey, blue and red colors represent C, H, N, and O atoms respectively.70

In 2012, the Ziegler’s group reported a different structure of oxo-DII. Inspection of the bond lengths confirm the double bond character of both the C=O (1.212(2) Å) and the exocyclic imine C=N (1.218(2) Å). The internal C-N bonds are 1.401(2) Å and

1.383(2) Å, which are indicative of single bonds. The hydrogen at the imine position can have in two orientations, either syn or anti, as seen in the diimino form of DII (Scheme

1.1.5). In the oxo-DII structure, both syn and anti conformations, which co-crystallize 17 together, are observed to cause a positional disorder for the hydrogen. Oxo-DII engages in hydrogen bonding as well, via the isoindoline N-H group and the carbonyl of a facing molecule.

Linstead studied the chemistry of oxo-DII along with DII, and concluded that both nitrogen atoms of oxo-DII were reactive. Oxo-DII would condense with several hydrazines, hydroxylamine and arylamines with evolution of ammonia to yield 3- substituted-1-oxoisoindoles as shown in Scheme 1.1.11.18,71,72 The reaction of oxo-DII and methyl bisulfate yields to N-methyl-3-imino-1-oxoisoindoline upon deprotonation of the isoindole nitrogen.71 However, the carbonyl group stays inert in both acidic and basic conditions.18,73

Scheme 1.1.11 - Reactivity of 3-imino-1-oxoisoindoline.67,71,73

In the early 1980s, Spiessens et al. studied the synthesis, tautomerism and geometrical isomerism of 3-aryl/alkylimino-1-oxoisoindolines.67,73 The 1H and 13C NMR 18

6 spectra of these compounds were analyzed in both polar (DMSO-d ; CD3OD) and non- polar (CDCl3) solvents. For aryl derivatives, only the arylimino tautomeric form is present in solution in all solvents. Regarding the geometrical isomers, it was shown for aryl substituted (aryl = 3-pyridyl, phenyl and toluidyl) that the anti conformation was the predominant structure. The anti:syn ratio for these compounds was found to be 9:1 in

6 CDCl3 and 4:1 in DMSO-d . In the case of 2-pyridyl and 2-amino-6-pyridyl, NMR spectra confirmed that the anti conformation is the sole species in solution (DMSO and

CDCl3). The predominance of the anti conformation is attributed to steric hindrance in the syn conformation.73 In 2004, the crystal structure of 3-phenylimino-1-oxoisoindoline was elucidated, confirming the previous NMR studies of syn vs anti conformation of aryl oxo-DIIs (Figure 1.1.9).74 Both the unsubstituted and aryl oxo-DII species have the same bond lengths and it was noticed that the indole N had two single bonds and the exocyclic

N was a double bond. Hydrogen bonding was observed as well.

Figure 1.1.9 – Tautomerism and crystal structure of 3-phenylimino-1-oxoisoindoline. Dark grey, light grey, blue and red colors represent C, H, N and O atoms respectively.67

To prove the equilibrium between the imino and amino form of substituted oxo-

DII, the toluidyl adduct was refluxed with methyl iodide in toluene. Knowing that the reaction of benzopyrrole with methyl iodide yields to N-methyl benzopyrrole, the N- methylated oxo-DII should therefore be formed.75,76 However, the resulting product was 19 found to be 3-N-methyl-N-(p-tolyl)amino-1-oxoisoindoline. This confirms the equilibrium between amino/imino structure in solution (Scheme 1.1.12).

Scheme 1.1.12 – Methylation of toluidyl-oxo-DII

The structures of alkyl derivatives of oxo-DII partially differ from the aryl adducts. Only the imino tautomer is present in solution with the syn conformation being the predominant conformation in both polar and non-polar solvents. This was confirmed by both NMR and IR spectral studies. In the case of the 3-alkylimino-1-oxoisoindoline

(alkyl = methyl and butyl), the anti conformation prevails (95:5 anti:syn ratio) due to steric strain.67

In 2008, Kukushkin et al. studied the coupling between iminoisoindolinones and nitriles mediated by transition metal salts (Ni77, Cu78 and Pt79). The outcome was the formation of 1,3,5-triazapentadienato metal complexes (Figure 1.1.10). These papers report the first metal mediated coupling between an imine and an isonitrile yielding a chelate-stabilized iminocarbene species, and a novel synthetic route to phthalocyanines.77,79

Figure 1.1.10 - Synthesis of 1,3,5-triazapentadienato metal complexes (top) and structure of a copper complex (bottom). Non-ionizable hydrogen atoms have been omitted for clarity. Dark grey, light grey, blue, red and orange colors represent C, H, N, O and Cu atoms respectively. 77–79

The first complex of oxo-DII was reported by the same group a year later.70 The reaction of Zn(OAc)2 in an alkylated nitrile solvent did not yield the triazapentadienato complex as expected but rather the tetracoordinated Zn(oxoDII) complex. Indeed, the zinc cation is bound to two oxoDIIs via their isoindoline nitrogen and to two acetate anions in a slightly distorted tetrahedral geometry, as seen in Figure 1.1.11. The Zn-N bond measures 2.0012(15) Å which is in agreement with Nisoindoline-Zn bond length encountered in similar complexes.80 An extensive hydrogen bonding network is observed in the crystal structure. The intermolecular interaction involves the NH2 and an oxygen atom from the acetate anion coordinated to the same metal cation. 21

Figure 1.1.11 – Crystal structure of Zn(oxoDII). Non-ionizable hydrogen atoms have been omitted for clarity. Dark grey, light grey, blue, red and turquoise colors represent C, H, N, O and Zn atoms respectively.70

Coordinating Bis(arylimino)isoindolines -

1,3-Bis(2-pyridylimino)isoindoline

As mentioned previously, the reaction of DII with 2-aminopyridine formed the novel chelating agent 1,3-bis(2-pyridylimino)isoindoline, BPI (Scheme 1.1.13).18 Upon its reaction with nickel acetate, two Ni-BPI complexes were formed. A 2:1 ligand to metal ratio complex is observed where each BPI binds in a bidentate fashion and a 1:1 complex is also seen where BPI is a tridentate anionic chelate. After the first reports by

Lindstead in 1953 followed by Hurley in 1967, the metal chemistry of BPI was left largely unexplored.81

Scheme 1.1.13 - Synthesis of BPI (Linstead's method). 18

In the mid-1970s, Siegl’s work on 1,3-bis(arylimino)isoindolines led to the discovery of an alternate route for the synthesis of disubstituted DIIs. His work was inspired by the metal templated synthesis of MPc from phthalonitriles. Following the same procedure, phthalonitrile and 2-aminopyridine were refluxed in methanol in the presence of a M(OAc)2 (M= Co, Ni, Cu and Zn). The metal complexes of BPI were successfully isolated in poor to good yields depending on the metal (Zn: 21%, Co: 55%,

Cu: 60%, and Ni: 70%). The difference in yields can be explained by the preferred coordination chemistry of the metal cation. Siegl believed that the tetrahedral-favored coordination of Zn limits its complexation with BPI. In contrast, Co/Ni and Cu exhibit octahedral or square planar coordination geometries which are preferential to bind with

BPI.

The attempts to form bis(arylimino)isoindolines with aniline, 3 and 4- aminopyridine were unsuccessful. Siegl suggested that the metal cation activates the nitrile but not enough for it to react with aromatic amines that lack the appropriate stereochemical relationship between the coordination site and the reactive amino group.82

Following this work, Siegl continued his research for an efficient method for the synthesis of bis(arylimino)isoindolines. He investigated the utilization of alkaline earth metal ion as Lewis acid catalysts. A previous report showed that the metal coordinates to 23 the nitrogen lone pair of the cyano group, activating the nitrile moiety due to bond polarization. The activation would then allow a nucleophilic attack of an amine on the nitrile carbon. Several alkaline earth salts such as CaCl2, Mg(ClO4), or MgI2 were used. It is surmised that the cyclization and condensation of both arylamines are done in several steps, with the mono-aryliminoisoindoline being an intermediate. The proposed mechanism of this reaction is similar to the alkoxide catalyzed synthesis of DII (Scheme

1.1.4).

It was noticed that mild conditions prevented the formation of phthalocyanine, by- product usually encountered in reactions with DII. Moreover, this method allows the use of bulky and hindered amines such as 2-amino-6-methylpyridine for which direct condensation with DII and phthalonitrile failed. Siegl concluded that the optimum conditions for the synthesis of bis(arylimino)isoindolines were using anhydrous CaCl2 in refluxing butanol for 48h, as described in Scheme 1.1.14.83 To date, Siegl’s method is the most used for the synthesis of BPI and its analogs.74,84–96

Scheme 1.1.14 – Synthesis of BPI (Siegl's method).83

With this novel synthetic route, the metal chemistry of BPI flourished since the late 1970s. BPIs was found to form both homoleptic (M(BPI)2) and heteroleptic

(M(BPI)(X)) compounds depending on the salts employed. Reactions with perchlorate salts tend to form complexes where BPI binds as a neutral species. The ligand is believed to be protonated at one of the exocyclic nitrogen; indeed the reaction of the latter with a

97 nd rd base produced neutral M(BPI)2 compounds. The complexes with 2 and 3 row transition metals were studied as well. In 1976, the reaction of carbonyl salts of iridium and rhodium with BPI, the Ir(I) formed a 5-coordinate complex whereas Rh(I) complexes were four coordinate.98 The report showed that substitution on the pyridine ring could modify some properties of BPIs. Electron withdrawing groups would shift the metal carbonyl stretch to higher wavenumbers hence reducing the electron density at the metal center. Meanwhile, electron donating group such as alkyl groups increased the solubility of these complexes in organic solvents, making their purification and characterization simpler. Later, Siegl developed the first water-soluble BPI by adding a tetralkylammonium moiety on the phthalonitrile.95

Gagné and coworkers pursued their work on complexes of BPI by modifying their periphery or by integrating bridging ligands. In 1977, a binucleating BPI (bisBPI) was formed from the reaction of 1,2,4,5-tetracyanobenzene with 2-aminopyridine. This ligand is capable to bind two metal cations and to form dimers and organometallic polymers

(Scheme 1.1.15).99

Scheme 1.1.15 – Synthesis of bisBPI.99

The binucleating BPIs reacted with metal acetates (Mn(II), Fe(II), Co(II), Co(III),

Ni(II), Cu(II) and Zn(II)) to form heteroleptic complexes. The reaction of the latter with an excess of the ligand formed homoleptic polymeric complexes; these compounds were 25 useful to study metal-metal interactions. All complexes are high spin and paramagnetic, they exhibit quasi-reversible oxidation behavior however little interaction between metals was noticed.99,100 Ruthenium complexes of bisBPIs were prepared as well; the Ru(II)

+ complex can oxidize to Ru(III) with O2 or Ag . Additionally, Gagné and Siegl were able to prepare the first heteronuclear bimetallic complex of bisBPI, by reacting the Ru(II) first then adding the second metal (Cu and Pd). This stepwise method was employed because ruthenium is not likely to undergo ligand exchange.101 The following year, these

Ru(III) complexes were found to catalyze the auto-oxidation and electrochemical oxidation of alcohols to aldehydes and ketones, however the catalytic activity was poor at

STP.102

BPIs can feature unusual binding modes as well. When Mo2(OAc)4 is reacted with BPI, it forms complexes in which one BPI binds to a dimolybdenum unit which is bridged by three acetates. The structure of Mo2(OAc)3(BPI) was determined by NMR,

IR, electronic absorption and X-ray crystallography.103–105 Unlike other complex structures, BPI binds one molybdenum via an imino nitrogen, while the other metal is bound to the isoindoline and pyridine nitrogen atoms (Figure 1.1.12).

Figure 1.1.12 – Structure of Mo2(OAc)3BPI. Non-ionizable hydrogen atoms have been omitted for clarity. Dark grey, light grey, blue, red and turquoise colors represent C, H, N, O and Mo atoms respectively. 103

Moreover, steric hindrance can lead to uncommon BPI binding modes. The presence of methyl group on the 6th position on both pyridyl causes the binding mode of

BPI to various metal cations. Three cations were studied Zn2+, Cd2+ and Pd2+ as they all prefer different coordination geometries (tetrahedral, octahedral and square planar respectively). In the case of CdBPI, the elucidated structure shows that the metal is coordinated to two BPIs via one pyridine and one imine nitrogen of each isoindoline ligand. In the case of the reaction with Zn(ClO4)2, the isolated product is not a BPI but 1- imino-3-oxoisoindoline bidentate chelate. Two of these chelates bind to Zn in a tetrahedral geometry. The PdBPI produced is a severely distorted square planar complex.

Because of sterics, one pyridine is caused to flip to accommodate the metal cation. The

C-H bond of the pyridine is activated, forming a carbometalated NNC pincer ligand

106 (Figure 1.1.13). When reacted with 2 equivalents of Pd(OAc)2, 6-methylBPI binds to

27 two Pd, one with the CNN pincer ligand, and one via the “flipped” pyridine nitrogen and the adjacent imine.94,107

Figure 1.1.13 – Crystal structures of 6-methylBPI metal complexes. (top – CdBPI, bottom left – Zn-oxoDII, bottom right – PdBPI). Non-ionizable hydrogen atoms have been omitted for clarity. Dark grey, light grey, light blue, red, green, purple, yellow and dark blue colors represent C, H, N, O, Cl, Zn, Cd and Pd atoms respectively.106

The coordination chemistry of BPI was mainly focused on 3d metal cations.31 In

2013, Bender et al. reported the synthesis of group 13 complexes of BPIs. BPI was synthesized via Siegl’s method, and the metalation of BPI was run in refluxing toluene for 24 hours. Two structures were elucidated; the BF2 and GaCl2 complexes are shown in

Figure 1.1.14. The boron center is bound to both isoindoline and pyridyl nitrogen atoms.

This binding motif is similar to boron coordination in BODIPY compounds. For Al, Ga and In, the 1H and 13C NMR suggest that their complexes were symmetric, the crystal structure of the gallium complex confirmed the structures.108 28

Figure 1.1.14 - Structures of BF2BPI (left) and GaCl2BPI (right). Non-ionizable hydrogen atoms have been omitted for clarity. Dark grey, light grey, blue, light pink, dark pink, yellow and green colors represent C, H, N, B, Ga, F and Cl atoms respectively.108

Metal complexes of BPI have been found to have many applications. They are employed as catalysts for various organic transformation processes, models for biologically active compounds and enzymes, as well as additives for hydrocarbons where they are found to extend the lifespan of oils by preventing oxidation processes.31

Cobalt complexes of BPI were mostly studied for their catalytic activity. Indeed, in 1985, Mimoun et al. studied the role of Co(III)BPI peroxides in the aerobic oxidation of hydrocarbons.109 In 2008, Gade and coworkers developed several chiral BPIs to be used for enantioselective catalysis. Substitution on the indole will control the backside access of the metal center whereas substitution on the pyridyl moiety will make the BPI a stereodirecting ligand (Scheme 1.1.16).110

Scheme 1.1.16 – Stereochemistry of chiral catalysts

The BPI ligands were prepared via Siegl’s method with phthalonitriles and modified terpene 2-aminopyridines (Scheme 1.1.17). Iron and cobalt complexes of these ligands were studied for their potential use as catalysts for asymmetric hydrosilylation of ketones and asymmetric cyclopropanation respectively. The Fe-BPIs successfully optimized the hydrosilylation of acetophenone with high yields (>86%). Although, only the Fe-carbpi was the most enantioselective catalyst with a ee around 80% regardless of the isoindole substitution (H, Me or tetraphenyl) whereas the Fe-myrbpi compound gave the reaction product in ee of 27% only. Used for the asymmetric cyclopropanation of styrene, Co-BPIs catalysis activity follow the same trend as the Fe-BPIs with having excellent yields and selectivity; their enantio- and diastereo-selectivity were maximized when using the Co-carbpi (ee ~85%). The effects of the backbone and pyridine ring substitutions are more observed in the Co-BPIs. The tetraphenyl-substituted backbone improves the ee and the selectivity while having the chiral group away from the metal gave the product in both low selectivity and ee.92

Scheme 1.1.17 – Synthesis of chiral BPIs

A few years later, Gade developed a new family of chiral Co-BPIs for the enantioselective hydrosilylation of ketones with diethoxysilane. The corresponding alcohol was obtained in high yield (>90%) and high enantioselectivity (91% ee). Using the S,S cobalt chiral complex produced the R enantiomer of the alcohol while the R,R yields to the S enantiomer, proving their predicated selectivity. Additionally, it was found that bulky and long alkyl groups on the ether moiety of the ligand prevent the stereoselectivity but the backbone substitution does not affect the catalytic activity of these ligands.86 Another example of Co-BPIs catalyst also developed by Gade and coworkers is the radical polymerization of acrylates.93 A series of acetate and acetylacetonate (acac) cobalt bpi complexes were studied. Both backbone and pyridine ring were substituted with alkyl groups in order to study the effect of the complexes solubility and their catalytic activity. It was observed that the least soluble complexes, the acetates, were also the least efficient catalysts, whereas the acac complexes had more control over the polymerization. These complexes allow the polymerization of methyl and n-butyl acrylate with very low polydispersities (<1.20). Employing the pentacoordinate versus the hexacoordinate Co(acac)BPI improved the average molecular 31 weight with conversion of the polymer, these values were close to the theoretical values for living systems. The mechanism of the reaction can be determined by MS (LIFDI) and

NMR end-group analysis. The authors determined that the reactive intermediate is formed upon the reaction of CoII-BPI with an alkyl radical.

Metal complexes of BPIs (MBPIs) were also studied as model for enzymatic active sites. The purpose of these studies is to understand the mechanism of intracellular

O2 activation. MBPIs were employed to mimic some enzymes such as cytochrome c oxidase,111 superoxide dismutase,112,113 or galactose oxidase.114 MBPIs studied for this purpose include Cu,111,114,115 Mn,116 Co,117 and Fe112,118,119 as these metal cations important roles in living organisms are well-known. Most of the work done on Fe-BPIs was carried out by Speier and coworkers starting 2003. Indeed, they have prepared oxo- bridged dinuclear FeIII complexes of BPIs as they are present in non-heme proteins such as hemerythrin, ribonucleotide reductase and methane monooxygenase. It is also thought

118 that O2 activation is initiated by the binding of O2 to the diiron center. The FeBPI complex was prepared by reacting FeCl3•6H2O with BPI to form two FeBPI bridged by an oxygen atom. The complex was then reacted with Ag(OAc) to replace the chlorides by acetates. Both compounds were characterized by UV/Vis, IR, Mӧssbauer spectroscopy and only the chloro adduct structure was elucidated. The catalase activities of these compounds were studied by measuring the evolution of O2 in acetonitrile in the presence of H2O2. The Fe(BPI)Cl compound has a higher activity for the decomposition of the peroxide at room temperature with a yield of 87%. The reaction was also followed by

UV-Vis and shows the decomposition of the complex upon addition of H2O2. The complex also catalyzed the oxygenation of various alkanes; however the yields and

32 turnovers were poor. In a recent report, another FeBPI compound was studied

([Fe(BPI)(MeCN)3)](ClO4)2). It can catalyze the oxidation of thioanisoles and benzyl alcohols with H2O2 as the oxidant. A reaction intermediate has been isolated and characterized as being a peroxide-bridged diferric complex. This intermediate shows oxidation reactivity following the addition of H2O2 in acetonitrile. This result is

119 significant as it helps understand the mechanism of O2 activation in human cells.

Alternative coordinating bis(arylimino)isoindolines

The chemistry observed with BPIs can be extended to other coordinating heterocycles where pyridine is replaced by azoles such as benzimidazole (bimimd) and thiazole (BTI) (Figure 1.1.15).80,83,105,112,113,116,120–126 Their metal chemistry has not been extensively studied like the BPIs. Both Linstead’s and Siegl’s methods were used to prepare BTI and bimimd in high yields; their structures were solved by X-ray crystallography (Figure 1.1.15).80,122 It was observed that the non-protonated nitrogen from the azole ring face the indole nitrogen due to intramolecular hydrogen bonding. The distance between the indole and azole nitrogen atoms are between 2.69-2.72 Å. BTI and bimimd are both monoanionic ligands and bind efficiently to metal cations in a tridentate fashion similar to BPIs. In theory, BTI can bind through NNN, SNN or SNS binding modes, yet only the NNN was observed for all metal cations, with the exception being palladium. The sterically hindered BTI forces one of the thiazole rings to rotate, activating the C-H bond to accommodate the palladium cation.106 BTI tends to form homoleptic and heteroleptic complexes unlike bimimd which only forms heteroleptic

33 adducts. It is believed that the steric bulk of the benzimidazole prevents a 2:1 ligand:metal coordination.80 Metal complexes of BTI and bimimd have a broad variety of applications, some of which include use as dyes and a stabilizer for oil. More recently, along with BPIs, they have been used as models for enzymes and catalysts.31

Figure 1.1.15 - Structures of alternate bis(arylimino)isoindolines. Non-ionizable hydrogen atoms have been omitted for clarity. Dark grey, light grey, blue, red and gold colors represent C, H, N, and S atoms respectively. 80,122

Non-coordinating bis(arylimino)isoindolines

In 1952, Linstead introduced the synthesis of bis(arylimino)isoindolines via the reaction of DII with aniline or naphthylamine.18,71 Later, Soviet, French and Belgian groups prepared analogous compounds, mostly with p-substituted anilines.65,127–129 While the two latter groups used the Linstead’s method, the Soviets introduced an alternative

34 approach to synthesize these bis(arylimino)isoindolines. Primary amines were reacted with TCI in the presence of a base to scavenge the chlorine atoms (Scheme 1.1.18).65 As chlorides are excellent leaving groups, the reaction is accelerated compared to that of DII condensation.130

Scheme 1.1.18 – Synthesis of bis(arylimino)isoindolines from TCI

The amino/imino tautomerization of these derivatives were investigated by 1H,

13C NMR and UV/visible spectroscopies.127,128 Early NMR studies suggested that these compounds exist in the diimino form.128 In the 1980s, it was determined that a fast proton exchange between the isoindole and the exocyclic nitrogen atoms was responsible of the apparent symmetry of these compounds.65,127,129 No structures of these bis(arylimino)isoindolines were elucidated until 2004.74 Sandman and coworkers were able to isolate two conformers of bis(phenylimino)isoindolines as seen in Figure 1.1.16.

It should be noted that the di-substituted DII exists as the diimino form, agreeing with earlier studies.

Figure 1.1.16 – Structures of bis(phenylimino)isoindolines. Non-ionizable hydrogen atoms have been omitted for clarity. Dark grey, light grey, blue colors represent C, H, and N atoms respectively.74

Bis(alkylimino)isoindolines

Along with non-coordinating bis(arylimino)isoindolines, the chemistry of bis(alkylimino)isoindolines has been briefly explored. These latter were prepared primarily as an alternative method to synthesize DII from phthalonitriles. Few compounds were reported after their first synthesis by Linstead.18,65,120,129–131 For example, in 1984 a Japanese group used elemental sulfur as a catalyst.23,132 More recently, Maleev and coworkers developed a lanthanide-catalyzed amination of phthalonitriles.133,134 They were able to isolate and solve the structure of bis(isopropylimino)isoindoline. Later, the same group would report the metallation of

1,3-bis(isopropylimino)isoindolines with rare earth metals, both structures are shown in

Figure 1.1.17. The metal complexes exhibit photoluminescence in acetonitrile between

400-450 nm; however they are poorly emissive (Φ < 1%).133,134

Figure 1.1.17 – Structure of bis(isopropylimino)isoindoline and its yttrium complex. Non-ionizable hydrogen atoms have been omitted for clarity. Dark grey, light grey, blue and purple colors represent C, H, N, and Y atoms respectively.134

In 2013, the Ziegler group revisited the synthesis and structures of various bis(alkylimino)isoindolines.135 An extensive discussion of these compounds will be presented in chapter III.

1.2. BF2-based fluorophores

Organic fluorescent compounds have become an integral part at the frontier of chemistry, biology and physics. Indeed, since their discovery and first use in the late

1800s, fluorescent compounds have been used to analyze, detect and sense biological systems as well as developing fluorescence and laser microscopy and imaging.136 To extend their utility, fluorophores can be appended to a chelator, binding site or ligand which will direct the dye to a specific target. After binding, the fluorophore will emit light upon irradiation. These characteristics allowed fluorophores to be employed as

OLEDs, dye-sensitized cells for solar panels and laser dyes. Before discussing the different classes of fluorescent dyes, it is important to understand the concept of fluorescence and the photophysical processes involved.

Fluorescence

Luminescence describes the emission of light by a molecule in an excited electronic state and thus relaxing to the ground electronic state.136 It can occur by one of into two processes: phosphorescence and fluorescence. Both processes are a form of radiative decay that can occur after a photon is absorbed by a molecule. These processes can be illustrated by use of a Jablonski diagram (Figure 1.2.1).

Figure 1.2.1 – Simplified Jablonski diagram

Once a molecule absorbs light, it promotes an electron from the ground electronic state (in the case of a diamagnetic organic molecule, S0) to an excited electronic state

(S1,2,…). Following light absorption, the excited electron undergoes relaxation which can

38 be either radiative or non-radiative decays, or can undergo conversion to an alternate spin state.

Non-radiative relaxation processes include vibrational relaxation, internal conversion and intersystem crossing. The excited electron relaxes rapidly from a higher vibrational level to the lowest one of the same excited electronic state, this is called vibrational relaxation. This process is fast, 10-14 to 10-12 s and is more likely to occur immediately after light absorption. Alternatively, internal conversion involves the rapid

(~10-12 s) relaxation of the excited electron from a higher-energy to a lower-energy electronic state (S2 to S1 for example). An excited molecule can also undergo a spin conversion from the singlet excited state to the triplet excited state (S1 to T1). This spin conversion is called intersystem crossing. Due to the forbidden nature of the spin change and its long lifetime (~ 10-8 s), this process is unlikely to occur, however this process can be accelerated in molecules bearing heavy atoms such as iodine and bromine or 4d- and

5d- transition metals.137

Radiative decays include phosphorescence and fluorescence which are both types of luminescence.137,138 Phosphorescence is the emission of light from a triplet-excited state to the ground singlet state following intersystem crossing. Transitions to the ground state are spin-forbidden with slow emission rates lasting from milliseconds to several seconds.136 Due to the competition with various non-radiative, fluorescence and quenching which all are fast processes, phosphorescence is not usually encountered in organic molecules in the solution or liquid state at room temperature.138

Contrary to phosphorescence, fluorescence is a spin-allowed transition. A molecule (fluorophore) will emit light after absorbing light and undergoing several non-

39 radiative decays (internal conversion). The emission occurs at a different wavelength than absorption, usually at a higher wavelength due to energy losses. Fluorescence is mainly described by its lifetime, quantum yield and Stokes shift. The quantum yield (ΦF) is defined as the ratio of the number of emitted photons relative to the number of absorbed photons. The higher the quantum yield, the brighter the fluorophore and the lower the non-radiative decay. The fluorescence lifetime (τ) is a measure of how long the molecule spends in the excited state (the time it takes for the concentration to reduce to 1/e of the original value) emitting light and returning to the ground state; the lifetime for many fluorescent molecules are typically around 10 ns. The Stokes shift represents the difference of energy (wavelength) between the absorption and emission bands. Since fluorescence occurs after some loss of energy, the emission wavelength is higher than the absorption. A small Stokes shift means there is a minimal reorganization of a molecule upon excitation.139

Classes of fluorophores

Fluorophores have been used in biology for more than a century. With the development of fluorescence microscopy, it became possible to study living cells, tissues and bacteria. Currently, fluorescent dyes are employed in material science, medicine, biotechnology and environmental chemistry.136,140–142 To be a good candidate, a fluorophore must have decent photophysical and chemical properties. It should be stable in a variety of conditions (pH, solvent polarity, inertness in various media, lipophilicity) and also it should absorb and emit with the visible spectra region with a moderate to good quantum yield and adequate Stokes shift. Numerous classes of fluorophores (natural and

40 synthetic) possess such qualities and have been used for decades as chemical sensors

(Figure 1.2.2).141,142

Fluorescein and rhodamine dyes from the xanthene family, BODIPY (BOron-

DIPYrromethene) and coumarin dyes are the most popular fluorophores currently, thanks to their optimal properties. They possess high absorption coefficient, quantum yield of emission, photostabilities and long emission wavelength.136,143,144

Scheme 1.2.1 – General structures of common fluorophores

Fluorescein and rhodamine dyes are part of the xanthene family. They share the same core; while fluorescein possess a quinone-type moiety, rhodamine has both amine and imine termini (Scheme 1.2.1). In addition to these structural features, they both have an appended carboxylate which makes them pH sensitive.

Fluorescein was first synthesized in 1871 by Bayer via the reaction of phthalic anhydride with resorcinol.145 Until today it is the most utilized fluorophore in biology, chemistry and medicine due to its nearly ideal photophysical properties. One of the main advantages of fluorescein is its solubility in water, while it is a red solid, in solution it becomes green. Coupled with its carboxylate moiety, fluorescein can exist in seven prototropic forms in aqueous solution (Scheme 1.2.2); the pKa of its 42 monoanionic/dianionic form is of 6.4.146 The dianionic fluorescein is actually the most fluorescent tautomer with a quantum yield of 0.95 in water. It absorbs at λ= 490 nm and emits at λ= 514 nm with a lifetime of 4 ns. Fluorescein’s optical properties can be tuned by appending several moieties on its core. These molecules can be employed as sensors for a wide range of metal ions or amino acids. Moreover, it allows biomolecules to be attached to fluorescein for specific targeting.147 Anecdotally, fluorescein was used to dye the Chicago River green for St Patrick’s Day.148

Scheme 1.2.2– Prototropic forms of fluorescein146

Rhodamine is an analogue of fluorescein with N-alkyl substituents. The tetramethyl-rhodamine absorbs at λ= 540 nm and emits at λ= 565 nm with a quantum yield of 0.68. Unlike fluorescein, it has low pH sensitivity and higher photostability, yet 43 both compounds have similar applications. Early rhodamine dyes were utilized in histology mainly as mitochondria indicators. With the attachment of biomolecules and other moieties, rhodamines application expanded to laser dyes, chemosensors, single- molecule imaging and pigments in the industry.143,149,150

Coumarin dyes comprise a class of near-UV fluorophores (λmax ~ 360 nm). The simplest coumarin is colorless and emits in the blue region; yet substituted coumarin have often an orange/yellow color and emit in the green region. They have moderate quantum yield (~ 0.65) and photostability. Substitution at the 7 position of the coumarin core affects its polarity, hydrophobicity and acidity making them versatile fluorophores. For example, 7-amino-4-methyl-coumarin is pH inert and lipophilic whereas 7-hydroxy analogue has a pH dependent fluorescence and will only emit in its anionic form (pKa ~

7.5)151 Coumarin dyes are employed as biological indicators especially for enzyme substrates such as hydrolase, protease and deacetylase.141,142

Metalated phthalocyanines are also used as pigments and dyes. They absorb and emit at longer wavelengths (λ> 600 nm) which allow them to be used for near-IR photostable fluorophores. For example, ZnPc absorbs at λ= 670 nm and emits at λ= 681 nm with a quantum yield of emission of 0.30.152 Usually, biomolecules-appended and metal modified versions of this macrocycle are employed as they are more water soluble and fluorescent than their unmodified free base counterpart.152–154

BODIPY

4,4-Difluoro-4-borata-3a-azonia-4a-aza-s-indacene also known as BODIPY or

BOron-DIPYrromethene was first reported in 1968 by German chemists Treibs and

155 Kreuzer. The reaction of dipyrromethene with BF3Et2O in the presence of a base gave fluorescent boron-based complexes. BODIPY is a BF2-complex dipyrromethene; structurally it is considered as a rigidified monomethine cyanine dye as illustrated in

Scheme 1.2.3. Yet, the boron atom stabilizes the ligand by coordination and allows the π- system to be planar hence enhancing conjugation and charge transfer along dipyrromethene core.156

Scheme 1.2.3 – Structure of BODIPY and related compounds

Although it was first discovered in the late 60s, the crystal structure of the parent

BODIPY was only reported in 2009 by three different groups (Figure 1.2.3).157–159

BODIPY is nearly planar, the boron atom deviates a 4.3° angle from the dipyrromethene plane. The bond lengths support the single and double character of the C-C bonds, and confirm the strong π-electron delocalization within the dipyrromethene core. The molecule is nearly symmetric as both B-N and B-F bonds differ with 0.005 Å. The differences can be attributed to the zwitterionic character of BODIPY and the polarization of the B-F due to the stacking of four molecules in each unit cell.158

Figure 1.2.3 – Structure of the parent BODIPY – hydrogen atoms have been omitted. Dark grey, blue, light pink and yellow colors represent C, N, B and F atoms respectively.157

BODIPY’s popularity as a fluorophore is due to its numerous outstanding features. These compounds strongly absorb and emit in the visible spectral region (λmax between 470 and 530 nm) with high molar absorption coefficients (> 80,000 M-1cm-1) and excellent quantum yields (ΦF > 0.6). Furthermore, BODIPYs are stable to a variety of conditions (pH, light, temperature and solvent polarity). They are also easily prepared and modified with good yield and reproducibilities.

The absorption spectra of BODIPYs contain narrow spectral bands with two maxima in the visible region (Figure 1.2.4).160 The intense narrow band is assigned to the

S0-S1 transition (π-π*) with a λmax between 500 - 530 nm. A shoulder is observed at ~ 480 nm; it corresponds to the 0-1 vibrational transition. The weak broader band is found at a lower wavelength (~350 nm) and is attributed to the S0-S2 transition (π-π*). Upon excitation, the electron relaxes by emitting at about 530-560 nm, that corresponds to S1-

S0 transition. The emission and absorption spectra are symmetric, agreeing with Kasha’s rule. It is implied that there is negligible non-radiative decay since the fluorescence quantum yield is high which can be explained by the rigid planar structure of BODIPY dyes.161,162

In 1989, a report introduced BODIPY as an alternative fluorophore to fluorescein and rhodamine as biological markers.163 While these fluorophores strongly emit at the same region of BODIPYs, their solubility issues, pH dependences and difficult syntheses made them less favorable.156,164 Since this publication, the number of reports on substituted BODIPY has exponentially increased; in the first 6 months of 2014, 303 papers and patents were published describing the various applications of BODIPY.164–166

The synthesis of BODIPY is simple and can be done in two or three steps, depending on the method, when starting from pyrroles (Scheme 1.2.4).

Dipyrrometha(e)nes share a similar synthetic pathway to porphyrin precursors, which is why BODIPY is considered to be the “little sister” of porphyrin.156 Dipyrromethanes are prepared from the acid-catalyzed condensation of a pyrrole with aldehydes, acid chlorides or anhydrides. Asymmetric BODIPY can be prepared by the reaction of a keto- or aldo- pyrrole with another substituted pyrrole.167 Dipyrromethenes are obtained from the 47 oxidation of the dipyrromethanes with DDQ or p-chloranil. Finally, the reaction of the resultant dippyromethenes with BF3.Et2O in presence of a base (Et3N is commonly used) yields to BODIPYs.164 The last two steps are commonly performed as a one-pot reaction to improve the overall yield of reaction.

Scheme 1.2.4 – Synthetic routes to symmetric and asymmetric BODIPYs

Despite the facile synthesis of substituted BODIPYs, the parent BODIPY was first reported in 2009, due to the instability of the unsubstituted dipyrromethene precursor. Three different synthetic methods were employed to circumvent the preparation of dipyrromethene intermediate. 157–159 First, an one-pot synthesis from pyrrole was employed to obtain the parent compound, but it was produced in poor yield

(8%).158 The second publication reports the Pd-catalyzed reaction of 8- thiomethylBODIPY with triethylsilane.157 Finally the third one employed a one-pot

159 synthesis from the unsubstituted dipyrromethane with DDQ, DBU and BF3.Et2O. The parent BODIPY absorbs at ~ 500 nm; in dichloromethane158 the molar absorptivity (ɛ) is

50,000 M-1 cm-1 whereas in methanol159 it increases to 64,000 M-1 cm-1. Its emission varies from 511 to 535 nm depending on the solvent. The parent BODIPY quantum yield 48 was measured to be of 90% in water and it varies from 70 to 93 % depending on the solvent polarity.

The optical properties of BODIPY can be easily tuned by substituting on the meso carbon, pyrrole moiety or at the boron center (Scheme 1.2.5). Electrophiles are easily introduced and are readily available for post functionalization with biological molecules for example.156,164

Scheme 1.2.5 – Modification centers of BODIPY

Halogenated BODIPYs can be prepared via several routes. The halogen can be introduced at the starting pyrrole, dipyrromethene or the final BODIPY core, depending on the desired position of the substitution. In 2005, Boens et al. developed the first synthesis of 3,5-dichloroBODIPY, by reacting the dipyrromethene with N-

168 chlorosuccinimide (NCS) before BF2 complexation. The 3,5-dibromo and diiodo

169 170 171 analogs can be prepared with NBS or Br2 and I2 respectively. The introduction of iodo and bromo substituents causes a red-shift on both absorption and emission of the

BODIPYs. Due to the heavy atom effect, the fluorescence is quenched (ΦF <1%) yet it allows singlet to triplet intersystem crossing. The spin change also permits BODIPYs to be used as photosensitizers.172

Of the halogenated adducts, chloroBODIPYs are the most employed for functionalization (Scheme 1.2.6). The first example was reported in 2005 when an

49 azacrown ether (aza-18-crown-6) was appended to a chloroBODIPY via nucleophilic substitution.173 The BODIPY-linked azacrown has a high selectivity for K+ over Li+, Na+ or Cs+. The compound is poorly fluorescent with a quantum yield of 0.6%. Upon the binding of K+ to the azacrown, the absorption of the BODIPY-complex blue shifts (529 to

505 nm) and the emission is similarly shifted. The fluorescence increased upon metal complexation with the quantum yield of the complex rose to 4%. As expected, no change in absorption and emission was recorded during the titration of the azacrown complex with other alkali cations. Other nucleophiles can be used such as amines, alcohols and biomolecules to yield novel fluorescent sensors, dyes and materials.161,167,174–178

Scheme 1.2.6 – General procedure for BODIPY functionalization

2,6-Dinitro and sulfonic BODIPYs can be prepared via the reaction of the unsubstituted BODIPYs with nitric acid and chlorosulfonic acid respectively (Scheme

1.2.7).155 While sulfonation does not alter the optical properties of the dye, the nitrated compounds show a reduced fluorescence quantum yield. Also, sulfonation is found to increase BODIPY’s solubility in water. However, few reports were published on the synthesis and applications of these compounds.164,170,179

Scheme 1.2.7 – Nitration and sulfonation of BODIPYs

BODIPY dyes can be functionalized via palladium catalyzed reactions (Stille,

Heck, Suzuki and Sonogashira).156,161,164,167 Aryl, ethynyl, vinyl or heteroaromatic moieties can be introduced either on a pyrrole,180 3,5-dihalogenated BODIPY181 or directly on the BODIPY core182,183 under mild conditions (Scheme 1.2.8).

Scheme 1.2.8 – Functionalization of BODIPY dyes via Pd-catalyzed coupling reactions.

These moieties extend the π-conjugation which causes a bathochromic shift in the absorbance and emission to far-red and near IR regions (λmax > 600 nm). Mono- substituted dyes are less fluorescent than the di-substituted counterparts (Scheme 1.2.9).

In addition, direct arylation of the BODIPY core decreases the fluorescence intensity due to non-radiative decay via rotation of the aryl group. Considering this issue, more rigid systems were prepared. Aromatic rings such as benzene, naphthalene and norbornane

51 were fused to pyrroles. The indole-BODIPY absorption was red-shifted (~ 600 nm), and its quantum yield efficiency varied from 0.2 to 0.9 depending on the identity of the meso substituents.

Scheme 1.2.9 – π-extended BODIPY dyes

The nature of the meso- substituent has a significant influence on the emission/absorption, quantum yield and lifetime of the BODIPY.184 However, contrary to pyrrole substitution, the addition of an aryl group at the meso carbon has a weak effect on the fluorescence. Indeed, the aromatic ring and the BODIPY core are perpendicular to each other; as a result there is no electronic interaction between these two moieties. The meso substituent is introduced to the BODIPY core via reaction of pyrrole with a

52 substituted aldehyde/ketone or anhydride; or via the reaction of a ketopyrrole with another pyrrole for the formation of asymmetric BODIPYs.164 Yet, the aryl substitution at the meso position can influence the polarity of the dye, making it more lipophilic or hydrophilic.185 The meso- substitution with an alkyne moiety extends the π-conjugation and will red shift the optical properties. Heteroatoms (halogens, O, N and S) can be introduced as well. Recent studies show that 8-N BODIPYs are weakly fluorescent and cause a bathochromic shift in the absorption and emission spectra. 8-HaloBODIPY fluorophores see their quantum yields of emission decrease as we go down the periodic table.184 They are also useful for post-functionalization to introduce various ligands and biomolecules which widen the application area of BODIPY dyes. These meso- functionalized BODIPY are employed as sensors for redox active molecules, pH probes, metal chelators and biological labels.162,167,168,186–190

More recently, the substitution of fluorine atoms in the BF2 groups have been reported (Scheme 1.2.10). These atoms are replaced by alkoxy, alkyl, aryl moieties or chlorine atoms. These replacements are done either via the reaction of organolithium or

Grignard reagents in the case of alkyl and aryl moieties.191–193 Alkoxy groups are introduced using sodium alkoxides or hydroxides in the presence of a strong Lewis acid.194,195 The replacement of the fluorine does not alter the BODIPY dyes properties, proving that the fluorine had little effect on the absorbance and fluorescence properties.

The novel BODIPYs possess an increased Stokes shift however.156,166 Furthermore, water-soluble BODIPY can be obtained via that route as well as novel light harvesting compounds increasing BODIPYs multiple utilities.177,196 In 2012, two examples of the replacement of fluorine by chlorine were reported; the F-BODIPY reacted with BCl3 in

CH2Cl2 for an hour to yield the Cl-BODIPY. However, the optical properties of these novel compounds have not yet been studied.197,198

Scheme 1.2.10 – Modification at the boron center of BODIPY molecules.

Aza-BODIPY

Aza-BODIPY is a modified BODIPY where the meso carbon is replaced by a nitrogen atom (Figure 1.2.5). The free base, azadipyrromethene, was first reported in the

199,200 early 1940s by Roger et al. The first BF2-complex was prepared in 1993 as the tetraphenyl aza-BODIPY.201 The chemistry of these dyes was not actively pursued until

2002. Aza-BODIPY fluorophores have similar properties to BODIPY. They both strongly absorb and emit light (high ε and ΦF) with a λmax > 650 nm. Aza-BODIPY dyes are insensitive to solvent polarity and exhibits minimal aggregation. It was found that the

1 strong absorbance of these dyes facilitates O2 generation, which makes aza-BODIPY dyes excellent candidates for photodynamic therapy.164,172

Figure 1.2.5 – Structure of tetraphenyl-aza-BODIPY – hydrogen atoms have been omitted for clarity. Dark grey, blue, light pink and yellow colors represent C, N, B and F atoms respectively.202

In spite of their advantages, the synthesis of aza-BODIPY fluorophores can be somewhat problematic. Indeed, the precursor’s synthesis (azadipyrromethene) requires difficult reaction conditions (time, solvent, poor yields), which could be the reason why these dyes have not been extensively explored. Three methods are reported for the synthesis of azadipyrromethenes. The first method was developed in the 1940s by Roger et al. The tetraphenyl-azadipyrromethene was prepared via the reaction of γ-nitro-β- phenyl-butyrophenone with either ammonium formate or ammonium formamide

(Scheme 1.2.11).199,200 The nitro-ketone was obtained from the Michael reaction of a chalcone with nitromethane. O’Shea and coworkers optimized the reaction by replacing

55 ammonium formate by the acetate salts, and by using alcoholic solvents to increase the yield and purity of the products.203,204

Scheme 1.2.11 – Synthesis of azadipyrromethene from chalcones

The second method consists in converting 2,4-diarylpyrroles into their 5-nitroso derivatives followed by acid-catalyzed condensation with a second diarylpyrrole (Scheme

1.2.12). Both symmetric and asymmetric dyes can be formed using this method.205 More recently, Kobayashi and Luk’yanets groups have developed a facile and practical method.

The reaction of phthalonitrile with an aryl Grignard reagent produces azadipyrromethenes in moderate yields (Scheme 1.2.13). This method is mostly used for the formation of benzannulated aza-BODIPY dyes.206–209

Scheme 1.2.12 – Synthesis of azadipyrromethene from nitroso derivatives

Scheme 1.2.13 – Synthesis of azadipyrromethene from phthalonitriles

Similar to BODIPY dyes, substitutions on the pyrrole and aryl moieties of aza-

BODIPY cause a bathochromic shift of both absorbance and emission to near-IR region.161,164 The introduction of electron-donating groups such as methoxy or alkylamine at the para position of the aryl moiety results in red-shift of nearly 100 nm.210–212 The phenyl moiety can also be replaced by heteroaromatic rings such as pyridine and thiophene to lead to changes in properties.213–216 However the position of the substitution is important; only 3,5-positions substitutions result in significant change of optical properties.213,214

Extension of the conjugation and conformationally restricted systems also red- shift the absorbance and emission of aza-BODIPY dyes (Scheme 1.2.14). Their extinction coefficients increase as well. The pyrrole moiety can be fused with benzene and naphthalene and other heteroaromatic rings.205,208,209,213–215,217 However, in the case of pyrazine, a hypsochromic shift (comparing to benzofused aza-BODIPY) is noticed; it could be explained by the higher electronegativity of the pyrazine nitrogen atoms.218 The ease of functionalization of aza-BODIPY allows them to be employed as chemosensors, photosensitizers and bio-imaging agents.172,203,210,211,216,219–223

Scheme 1.2.14 – Modified aza-BODIPY dyes

BODIPY Analogues

Despite the numerous advantages of the BODIPY fluorophores, the small Stokes shift and weak emissions in the solid state exhibited by these compounds are problematic.

Indeed, the weak emission is said to be due to self-absorption resulting from narrow

Stokes shifts inducing a strong overlap of the dye absorption and emission spectra.224

New BODIPY analogues have been developed to address these issues.

The first example of a fluorescent BODIPY analogue was reported in 1993 as a

225 biimidazole-BF2 compound. The fluorophore absorbs and emits in the near UV (λmax=

335 nm, λem= 380 nm), has a reasonable Stokes shift and a high quantum yield, ΦF ~

0.95. The bis-benzimidazole analogue was synthesized as well, its absorption and 58 emission are red shifted, due to π-conjugation extension.225 Moreover, the pyridine analogue of BODIPY was reported in the early 1970s but was not fluorescent. However, the presence of a cyanide moiety on the meso carbon allows the compound to fluoresce.226,227 The aza-BODIPY pyridine analogue strongly emits at 422 nm with a quantum yield of 81% (Scheme 1.2.15).

Scheme 1.2.15 – First BODIPY analogues.225–227

Following these results, different analogues of BODIPY were prepared, including naphthypyridines, pyrazoles or indoles to maintain the cyanine-type structure.161,164,224

The complexation with BF2 conformationally locks the structure, reducing radiationless decay. This allows for stronger fluorescence in both the solid state and in solution. These novel dyes possess a larger Stokes shift and excellent photostability, which previous functionalized BODIPY dyes lacked.

The N,N-BF2 complexes can be categorized in two groups, depending on the size

224 of the ring formed after complexation (Scheme 1.2.16). The BF2 group is chelated to two nitrogen atoms that belong either to one or two aromatic rings or to a non-aromatic system. The non-aromatic nitrogen atom can be either a Schiff base (imine, ketamine

(nacnac) or azine) or an amine.228,229 The syntheses of these ligands are somewhat facile; they involve palladium-catalyzed cross-coupling between two heteroaromatic rings or acid-catalyzed condensation of carbonyls with amines or hydrazines. Followed by BF2 coordination, it became simple to prepare a broader range of asymmetric fluorescent compounds.

Scheme 1.2.16 – Examples of BODIPY analogues224

One unique characteristic of these BODIPY analogues is their solid state fluorescence. Indeed, BODIPY dyes only fluoresce in solution and not in the solid state due to their small Stokes shifts and π-π stacking leading to self-quenching.224,230

Although many of the BODIPY analogues exhibit π-π stacking in the solid state, some emit in the solid state; this is due to aggregation-induced emission (AIE).231 For example,

BODIHY (Scheme 1.2.17), a new family of BF2 dyes, exhibited high emission in solid state upon aggregation.230 BODIHY is prepared via the reaction of a naphthyldiazonium salt with a derivitized pyridine ring. Both methyl and cyano BODIHY absorb between

λmax 410-430 nm in THF and are poorly emissive (ΦF ~ 0.07). Yet, crystals and films of these compounds emit light with a quantum yield of 0.24 and 0.52 respectively. Also, the addition of water into the THF solution show increased emission due to molecular 60 aggregation. Water helps forming aggregate that restricts the rotation of the phenyl ring, which prevents loss of energy and therefore increases the emission. By studying the crystal packing of the BODIHY, it was found that the planarity and the lack of extensive

π-π interaction lead to high solid-state quantum yield of emission.230

Recently, Mack et al. revisited Linstead chemistry by reacting oxo-DII (see

Chapter 1) with 2-aminopyridine and other substituted pyridines. The complexation of these ligands with BF3.OEt2 produced novel fluorescent compounds that are structural analogues of aza-BODIPYs (Scheme 1.2.17, 1-phenyl-3-oxo-isoindoline). These compounds are yellow solids and emit blue/green light. Extension of the π-conjugation at the pyridine or isoindoline moieties shift both absorption and emission wavelength in the

139,232 red, as well as increase the extinction coefficient. The isoindolinone-BF2 dyes exhibit both solution and solid-state fluorescence. The latter is explained by the fact that these compounds are asymmetric which limits the π-π stacking in the solid state, therefore enhances the solid state fluorescence.232

Scheme 1.2.17 - Examples of solid-state emitting fluorophores230–233

Several others BODIPY analogues are known to emit in the solid state within the visible region (Scheme 1.2.17).224 The study of the crystal structure of BOPIM shows that despite the planarity of the compound, the π-π stacking is inhibited by the rotation of the

233,234 phenyl ring, which allows solid state emission. Meanwhile the naphthypyridine-BF2 emission is induced by aggregation like BODIHY.231

235 Like BODIPY, the novel BF2 fluorophores are photostable and chemical inert.

With the ease of synthesis of these fluorescent dyes using readily available starting materials and their optimum optical properties, these analogues are becoming an appealing alternative to BODIPY dyes. Finally these novel compounds are aimed to be employed in optoelectronic devices, OLEDs and solid-state lasers.139,224,236

CHAPTER II

2 THE PHTHALOCROWNS: ISOINDOLINE-CROWN ETHER MACROCYCLES

Introduction

The binding and molecular recognition of cations is a significant field in coordination chemistry.237,238 A variety of host molecules (ligands and macrocycles) have been synthesized and the properties of these compounds to selectively bind cations continue to be studied. Two of the most studied metal binding macrocycles are the synthetic dye phthalocyanine12,239 and the cation binding family of polyoxo macrocycles known as the crown ethers.240–242 The crown ethers, first discovered in the 1960s by C.

Pedersen, are known for their affinity to alkali metal ions and charged molecules such as

+ 243 the ammonium cation (NH4 ), and play important roles as phase transfer catalysts.244,245 The phthalocyanines are also important metal binding macrocycles, and are used heavily both as bulk colorants and as components of specialized materials.12,246

Since 2006, we have been investigating the synthetic chemistry of phthalocyanine analogs known as the hemiporphyrazines, where rings other than isoindolines (such as benzene, pyridine or cyclohexane) are introduced into the backbone of the phthalocyanine macrocyle.32,247–249 The text of this chapter is a modified reprint of the material as it appears in: Tamgho, I.-S.; Engle, J. T.; Ziegler, C. J. J. Org. Chem. 2012,

77, 11372–11376.

In this chapter, I present a family of phthalocyanine hybrid molecules produced by using hemiporphyrazine synthetic methods. Specifically, herein I report the family of phthalocyanine/crown ether chimeras I call the phthalocrowns, fusions between these two macrocycles. Four different phthalocrowns were synthesized and characterized, including two which I was able to structurally elucidate. Depending on the number of ether units, either 2:2 or 1:1 macrocycles are formed. Additionally, between the dioxo and trioxo phthalocrowns, I observed significant differences in stability, with the trioxo macrocycle hydrolyzing to form an imino-oxo isoindoline derivative.

In the early 1950s, Linstead and coworkers reported the synthesis of 1,3- diiminoisoindoline (DII, 2)18 as a precursor to the synthesis of phthalocyanines, hemiporphyrazines and related isoindoline-based chelates.18,30,33,71,103,250,251 Compound 2, shown in Scheme 2.1, is synthesized via the reaction of phthalonitrile, 1, with ammonia in a methanol solution in the presence of a small amount of sodium metal.18

Diiminoisoindoline was found to be a precursor for the synthesis of a variety of chelating ligands and macrocycles. For example, compound 2 reacts with 2,6-diaminopyridine to produce hemiporphyrazine and with 2-aminopyridine to afford 1,3-bis(2- pyridylimino)isoindoline. Both hemiporphyrazine and 1,3-bis(2-pyridylimino)isoindoline coordinate to metal ions and exhibit rich transition element chemistry.31,100,106,252 In addition to arylamines, Compound 2 also reacts with aliphatic amines to afford the corresponding substituted diiminoisoindolines.18,65,120 Recently, the Ziegler group synthesized an aliphatic analog of phthalocyanine, cyclohexylcyanine, by reacting 1,3 diaminocyclohexane with compound 2.32 They have surmised that they could extend this chemistry to the synthesis of new isoindoline based macrocycle types, and that they could

generate phthalocyanine/crown ether chimera-type molecules via the reaction of amine terminated polyethers with 2.

Experimental

Experimental Section: All materials were obtained from commercial suppliers and were used without further purification. 1,3-Diiminoisoindoline (DII, 2) was prepared according to Elvidge’s modified procedure.18 1,11-Diamino-3,6,9-trioxaundecane was produced from the corresponding azide using the method reported in the patent by

Nippon Shinyaku Co., Ltd.253 The azide, 1,11-diazido-3,6,9-trioxaundecane, was synthesized using a procedure reported by J.R. Thomas et al.254

Proton (1H) and carbon (13C) NMR spectra were performed on 300 MHz, 400

MHz and 500 MHZ spectrometers. High resolution mass spectrometry experiments were performed on a mass spectrometer equipped with an orthogonal electrospray source (Z- spray) operated in positive ion mode. Sodium iodide was used for mass calibration for a calibration range of m/z 100-2000. Samples were prepared in a solution containing acidified methanol and infused into the electrospray source at a rate of 5-10 μl min-1.

Optimal ESI conditions were: capillary voltage 3000 V, source temperature 110 oC and a cone voltage of 55 V. The ESI gas was nitrogen. Data was acquired in continuum mode until acceptable averaged data was obtained.

X-ray intensity data for the monoclinic form of 4 and compound 6 were measured at 100 K on a CCD-based X-ray diffractometer system equipped with a Mo-target X-ray tube (λ = 0.71073 Å) operated at 2000 W power. The data for the orthorombic form of 3

(using Cu-κα radiation, λ = 1.54178 Å) were collected on a CCD-based diffractometer with dual Cu/Mo ImuS microfocus optics. The crystals were mounted on a cryoloop using Paratone oil and placed under a stream of nitrogen at 100 K. Data were corrected for absorption effects using the multi-scan method. The structures were refined and solved using direct methods until the final anisotropic full-matrix, least squares refinement of F2 converged.

General Procedure for the Syntheses of Phthalocrowns 3-6: DII (1) and the corresponding diamine (2,2’-oxybis(ethylamine), 1,2-bis(2-aminoethoxy)ethane, or 1,11- diamino-3,6,9-trioxaundecane, 1.2 equiv.) were dissolved in 1-butanol. The reaction mixture was refluxed for 16 h, cooled and concentrated. The crude product was either recrystallized or purified by flash chromatography on silica.

Synthesis of 3: 2,2’-Oxybis(ethylamine) (500 mg, 4.80 mmol) and DII (634 mg,

4.36 mol) were refluxed in 1-butanol (100 mL). The solid was recrystallized in

CHCl3/CH3OH/Et2O (49/1/50) to give 2 (657 mg, 1.53 mmol, 32% yield) as an off-white

1 solid: mp 173-175°C; H NMR (500 MHz; CDCl3/CD3OD) δ ppm: 3.2 (bs, 2H), 3.77 (s,

13 8H), 3.94 (s, 8H), 7.39 (s, 4H), 7.84 (s, 4H) C NMR (125 MHz, CDCl3/CD3OD) δ

+ ppm: 46.8, 70.4, 121.0, 130.3, 137.5, 168.6. MS (ESI) Calc. for C24H27N6O2 ([M+H] )

+ 430.5 found 431.2; HR MS (ESI) Calc. for C24H27N6O2 ([M+H] ) 431.2195 found

431.2184, 2.6 ppm.

Synthesis of 4: 1,2-Bis(2-aminoethoxy)ethane (1.23 g, 8.3 mmol) and DII 1 (1.00 g, 6.89 mmol) were refluxed in 1-butanol (150 mL). The crude product was purified by column chromatography on silica gel using 10% CH3OH in CHCl3 to give 4 (200 mg,

0.77 mmol, 11% yield) as a yellow solid. Single crystals of 4 were grown from a vapor

diffusion of hexane into a chloroform solution: mp 138-140°C; 1H NMR (300 MHz,

CDCl3): δ ppm: 3.65 (s, 4H), 3.78 (s, 8H), 7.54 and 7.83 (dd, J = Hz, 4H), 9.99 (b, 2H);

13 C NMR (75 MHz, CDCl3): δ ppm: 50.11, 70.07, 71.38, 121.6, 130.9, 136.3, 155.9; MS

+ (ESI) Calc. for C14H17N3O2 ([M+H] ) 260.3 found 260.2; HRMS (ESI) Calc. for

-1 NaC14H17N3O2 ([M+Na]) 282.1218 found 282.1205, 4.6 ppm; IR (cm ): 3226, 2910,

2864, 1660.

Synthesis of 5: 1,11-diamino-3,6,9-trioxaundecane (200 mg, 1.04 mmol), DII

(126 mg, 0.867 mmol), 1-butanol (50 mL). The crude product was purified by recrystallization in CH2Cl2/Et2O to give 5 (65.1 mg, 0.215 mmol, 25% yield): mp 102-

1 105 °C. H NMR (300 MHz, CDCl3): δ ppm: 3.64 (s, 8H), 3.76 (s, 4H), 3.95 (s, 4H), 7.12

13 (bs, 2H), 7.72 (bs, 2H); C NMR (75 MHz, CDCl3): δ ppm: 46.7. 70.2, 70.5, 70.7, 120.8,

+ 129.9, 137.6, 167.6; MS (ESI) Calc. for C16H21N3O3 ([M ]) 303.4 found 303.6; HRMS

(ESI) Calc. for C16H22N3O3 ([M+H]) 304.1661 found 304.1656, 1.6 ppm

Synthesis of 6: Attempts to purify 5 on silica gel yields the hydrolyzed compound

5. Single crystals of 6 were grown from a vapor diffusion of hexane into a chloroform

1 solution (10 mg, 0.032 mmol, 9% yield): mp 165–169 °C; H NMR (500 MHz, CDCl3): δ ppm: 3.53 - 4.05 (m, 16H), 7.53, 7.63, 7.78 and 7.88 (m, 4H); 13C NMR (125 MHz,

CDCl3): δ ppm: 37.5, 50.2, 67.9, 70.0, 70.1, 70.6, 70.7, 72.1, 123.2, 123.3, 125.7, 131.5,

132.7, 133.9, 151.2, 167.5. HRMS (ESI) Calc. for NaC16H20N2O4 ([M+Na]) 327.1321 found 327.1318, 0.92 ppm

Table 2.1 - Crystal data and structure refinement for 4-mono

Identification code 4-mono

Empirical formula C14H19N3O3 Formula weight 277.32 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1)/n Unit cell dimensions a = 10.461(5) Å α = 90° b = 8.172(4) Å β = 95.244(8)° c = 16.100(7) Å γ = 90° 3 Volume 1370.7(10) Å Z 4 3 Density (calculated) 1.344 Mg/m -1 Absorption coefficient 0.096 mm F(000) 592 3 Crystal size 0.27 x 0.12 x 0.12 mm Theta range for data collection 2.23 to 26.99°. Index ranges -13<=h<=13, -10<=k<=10, -20<=l<=15 Reflections collected 9274 Independent reflections 2873 [R(int) = 0.0343] Completeness to theta = 26.99° 96.2 % Absorption correction Multi-scan Max. and min. transmission 0.9886 and 0.9745 2 Refinement method Full-matrix least-squares on F Data / restraints / parameters 2873 / 0 / 257 2 Goodness-of-fit on F 1.063 Final R indices [I>2sigma(I)] R1 = 0.0484, wR2 = .1205 R indices (all data) R1 = 0.0597, wR2 = .1275 -3 Largest diff. peak and hole 0.252 and -0.175 e.Å

Table 2.2 - Crystal data and structure refinement for 4-ortho

Identification code 4-orthorhombic

Empirical formula C14H17N3O2 Formula weight 259.31 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Orthorhombic Space group P2(1)2(1)2(1) Unit cell dimensions a = 8.9063(3) Å α = 90° b = 10.3310(3) Å β = 90° c = 13.8954(4) Å γ = 90° 3 Volume 1278.53(7) Å Z 4 3 Density (calculated) 1.347 Mg/m -1 Absorption coefficient 0.750 mm F(000) 552 3 Crystal size 0.24 x 0.22 x 0.17 mm Theta range for data collection 5.34 to 66.42°. Index ranges -10<=h<=10, -12<=k<=10, -14<=l<=16 Reflections collected 4825 Independent reflections 2046 [R(int) = 0.0183] Completeness to theta = 66.42° 97.2 % Absorption correction Multi-scan Max. and min. transmission 0.8819 and 0.8423 2 Refinement method Full-matrix least-squares on F Data / restraints / parameters 2046 / 0 / 172 2 Goodness-of-fit on F 0.972 Final R indices [I>2sigma(I)] R1 = 0.0257, wR2 = 0.0734 R indices (all data) R1 = 0.0259, wR2 = 0.0737 -3 Largest diff. peak and hole 0.169 and -0.234 e.Å

Table 2.3 - Crystal data and structure refinement for 6.

Identification code 6

Empirical formula C14H18N2O4 Formula weight 278.30 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1)/n Unit cell dimensions a = 16.086(4) Å α = 90° b = 8.997(2) Å β = 106.238(3)° c = 19.922(5) Å γ = 90° 3 Volume 2768.2(12) Å Z 8 3 Density (calculated) 1.336 Mg/m -1 Absorption coefficient 0.099 mm F(000) 1184 3 Crystal size 0.20 x 0.20 x 0.10 mm Theta range for data collection 1.44 to 25.03°. Index ranges -19<=h<=19, -10<=k<=10, -23<=l<=23 Reflections collected 18391 Independent reflections 4869 [R(int) = 0.0376] Completeness to theta = 25.03° 99.7 % Absorption correction Multi-scan Max. and min. transmission 0.9902 and 0.9805 2 Refinement method Full-matrix least-squares on F Data / restraints / parameters 4869 / 0 / 361 2 Goodness-of-fit on F 1.009 Final R indices [I>2sigma(I)] R1 = 0.0380, wR2 = 0.1193 R indices (all data) R1 = 0.0516, wR2 = 0.1338 -3 Largest diff. peak and hole 0.219 and -0.254 e.Å

Results and Discussion

I reacted diiminoisoindoline 2 with three amine terminated ethers, as shown in

Scheme 2.1. The monooxo species 2,2’-oxybis(ethylamine) and the dioxo precursor 1,2- bis(2-aminoethoxy)ethane are commercially available, and the trioxo compound 1,11- diamino-3,6,9-trioxaundecane was synthesized from the corresponding chloride using the procedure described in a patent by J.R. Thomas.253,254 All three amino ethers were reacted with 2 in a slight excess in refluxing butanol for 16 hours, and we observed two types of product formation depending on the size of the ether chain. In the case of 2,2’- oxybis(ethylamine), condensation with 2 produces a 2+2 product, shown in Scheme 2.1.

The ratio of diamine and isoindoline in the macrocycle formation is most easily observed via mass spectrometry (and not very readily by NMR methods). The mass spectrum clearly shows the presence of a product peak from the reaction of 2 with 2,2’- oxybis(ethylamine) at 431.22 M/z, corresponding to the 2+2 product 3. The 1,2-bis(2- aminoethoxy)ethane and 1,11-diamino-3,6,9-trioxaundecane precursors, however, form

1:1 ratio macrocycles 4 and 5, exhibiting mass spectrometry peaks at 282.12 (M + Na) and 304.16 M/z values respectively. I surmise that the 2+2 product forms upon reaction of 2 with 2,2’-oxybis(ethylamine) due to the steric limitations of a 1+1 macrocycle. I also attempted to synthesize these compounds using a modified Siegl procedure83 with alkali or alkali earth metal cations as templates, but were unsuccessful in isolating any phthalocrowns.

Scheme 2.1 - General synthesis of the phthalocrowns

Compound 3 shows limited solubility, as seen in the related hemiporphyrazines31 and dissolves in DMF, DMSO, high boiling alcohols and a 1:9 solution of methanol:chloroform. Compounds 4 and 5 exhibit increased solubility versus the hemiporphyrazines, dissolving in nearly all solvents with the exception the alkanes, ethers, benzene and acetonitrile. The yields of all three compounds is inversely related to their solubility; compound 3 shows the highest product yield since it is the least soluble of the compounds. For compound 5, I carried out the syntheses under a variety of dilution conditions, but did not observe many differences in yield. All three compounds do not exhibit UV-visible transitions in the visible region of the spectrum, and as expected show UV transitions similar to those seen for diiminoisoindoline.

When I investigated the room temperature 1H NMR spectra of 3 in DMSO, I observed several broad resonances above 7.0 ppm that were indicative of both hydrogen

bonding and dynamic behavior. In CD3OD/CDCl3, I did not observe this behavior due to

H/D exchange with solvent. For the expected AA'BB' spin system of the phenyl ring, the deshielded resonance is split into two broad peaks, and the more shielded resonance is also broad, indicative of a slow exchange process. I postulated that this might result from the presence of the ionizable proton on the external (i.e. Schiff base) nitrogen on the macrocycle rather than the central nitrogen of the isoindoline unit. To further investigate this possibility, I carried out a variable temperature NMR experiment, shown in Figure

2.1. With increasing temperature, the split peak due to the phenyl hydrogen atom immediately adjacent to the imine coalesces and forms a single resonance, due to fast exchange of the ionizable hydrogen atom between external nitrogen atoms. I was able to calculate the ΔG‡ for this ionizable hydrogen atom exchange process as 44.6 kJ/mol (ΔH‡

= 41.8 kJ/mol and ΔS‡ = -75 J/mol·K),255 which is on the order of the energy of a hydrogen bonding type interaction. Also, the ionizable hydrogen resonance broadens and moves from ~8.5 ppm to ~8.2 ppm with increasing temperature. This shifting corresponds to the transfer of the proton, with more rapid exchange, from a more hydrogen bonded state to a less hydrogen bonded, and thus more shielded, state.

Figure 2.1 - Variable temperature 1H NMR spectra of 3 in DMSO showing dynamic proton exchange behavior.

Compound 4 is stable to chromatographic purification on silica

(chloroform/methanol 9:1). I was able to isolate single crystals and elucidate the structure of this compound from two different crystal forms. The compositional difference between the monoclinic and orthorhombic crystal forms is the presence of a water molecule in the monoclinic form, which forms hydrogen bonds between Schiff base nitrogen positions in the solid state. The molecules of 4 in the monoclinic structure form linear arrays of hydrogen bound molecules (via these bridging water molecules) similar to that seen in alkyl substituted diiminosisoindolines in the solid state.134 The structure of 4 from the monoclinic form is shown in Figure 2.2, with non-ionizable hydrogen atoms omitted for clarity. Unlike compound 3, the ionizable proton in 4 is

located inside the macrocycle on the central nitrogen of the isoindoline, and is engaged in a strong hydrogen bond to one of the two ether oxygen atoms, also shown in Figure 2.2.

The length of this hydrogen bond is nearly identical in both structures, with NO distances of ~2.72 and ~2.71 Å for the monoclinic and orthorhombic forms of the macrocycle, respectively. This hydrogen bonding interaction results in a non-planar macrocycle, with planes defined by the two oxygen atoms and the central isoindoline nitrogen at angles of ~52° and ~45° for the monoclinic and orthorhombic forms respectively. For compound 4, we did not observe any dynamic NMR behavior.

Figure 2.2 - Structure of 4 with 35% thermal ellipsoids (left) and the structure of 3 showing the internal hydrogen bond (right). Hydrogen atoms on the thermal ellispoid plot have been omitted for clarity.

Compound 5 also is the product of a 1:1 condensation between the triether diamine precursor and 2, but I observed significant differences between the dioxo macrocycle 4 and compound 5. Whereas compound 4 is highly stable, 5 decomposes much more readily. When I attempted to purify 5 on a silica column, I observed the formation of a partially hydrolyzed product 6, as shown in Scheme 2.1, formed by the addition of H2O and loss of NH3. Compound 6 is a 3-imino-1-oxoisoindoline substituted 75

at the amide nitrogen and the Schiff base nitrogen positions. I was able to structurally characterize this compound by single crystal X-ray methods, as shown in Figure 2.3. The

C-O bond of the acyl group is clearly double in character (C-O: 1.2219(16) Å) and the C-

N bond can be characterized as an imine (C-N: 1.2645(18) Å). As in compound 4, the plane of the isoindoline deviates from that of the crown ether unit to a similar extent,

~40°, as measured by the mean planes of the isoindole and the 11- atom crown fragment.

Figure 2.3 - The structure of compound 6 with 35% thermal ellipsoids. Hydrogen atoms have been omitted for clarity.

In conclusion, I present three crown ether type macrocycles composed of the phthalocyanine subunit molecule isoindoline and the diamines 2,2’-oxybis(ethylamine),

1,2-bis(2-aminoethoxy)ethane and 1,11-diamino-3,6,9-trioxaundecane. These phthalocyanine/crown ether fusion molecules can either form as 2 + 2 condensations, as seen for the monooxo compound 3, or as 1 + 1 products as in 4 and 5. The 1H NMR spectrum of 2 shows dynamic behavior due to proton exchange reactions at the external

Schiff base nitrogen positions. Compound 4 is a highly stable macrocycle, due to the

presence of an internal hydrogen bond between the central isoindoline nitrogen atom and one of the two macrocycle oxygen atoms. In contrast, compound 5 undergoes hydrolysis to form compound 6, a 3-imino-1-oxoisoindoline modified crown ether. The work on these compounds, related macrocycles and their metal adducts is ongoing.

CHAPTER III

3 THE SYNTHESES AND STRUCTURES OF

BIS(ALKYLIMINO)ISOINDOLINES

4 Introduction

The chemistry of isoindolines has been the key for the development of phthalocyanines as well as related macrocycles and chelating ligands.12,256,257 The synthesis of the parent isoindoline, 1,3-diiminoisoindoline (DII, 2) was first reported in the early 1950s.18 Compounds derived from DII exhibit rich metal binding properties.

The metal complexes of the phthalocyanines, for example, show excellent optical properties and are used as synthetic dyes in industry or as potential photosensitizers in medicine.258,259 Additionally, the DII derived hemiporphyrazine family of macrocycles can also bind metal ions and have been used as components for materials applications.31,252 DII can also be used as a precursor of isoindoline-based chelating ligands, in particular the 1,3-bis(pyridylimino)diiminoisoindoline.31,83,99 The first examples of the products were reported following the discovery of DII by Linstead and coworkers.18,71,72 These ligands are the product of the condensation of DII and primary alkyl and arylamines. Later in the 1970s, to avoid the formation of phthalocyanine (self- condensation of DII), CaCl2-catalyzed condensation of phthalonitrile (precursor of DII) with primary arylamines was employed.83

It was then found that the bis(arylimino)isoindolines (where the aryl group is a coordinating base such as pyridine,18,83,100 imidazole116 or thiazole122) can form N/S tridentate and pincer-like isoindoline ligands that can coordinate to an extensive range of transition metal cations. However studies into the reactivity bis(alkylimino)isoindoline were not extended. Since early work in the 1950s only synthesis,23,120,129,132,260 studies on the amino/imino tautomerization65,128 and metal complexes133,134 with lanthanides of these ligands have been reported. The text of this chapter is a modified reprint of the material as it appears in: Tamgho, I.-S.; Engle, J. T.; Ziegler, C. J. Tetrahedron Lett.

2013, 54, 6114–6117.

In this chapter, we are revisiting the synthesis and characterization of several bis(alkylimino)isoindolines, several of which structures were successfully elucidated.

We have examined methods for the preparation of these compounds: the direct reaction of DII with primary amines (method A)18, and the reaction of primary amines with phthalonitrile using Siegl’s conditions (method B)83 as shown in Scheme 3.1. We observed that the condensation of DII with bulky amines and cyclic amines did not lead to high yields of products, and often afforded only the monosubstituted adducts, regardless of reaction time or solvent conditions. Siegl’s method, however, was shown to produce improved yields for bulky and cyclic amines. For non-sterically hindered amines, Siegl’s method did not show increased yields. Structural elucidation of several of the reaction products revealed that the ionizable hydrogen atoms are located at the exocyclic amine position rather than on the isoindoline nitrogen. This is in contrast with the 1H NMR spectra for these compounds, which reveal symmetric structures in solution.

In the solid state, extensive hydrogen bonding was observed. The metal binding of some bis(alkylimino)isoindoline was also investigated, we have observed an unusual binding mode of the bis(benzylimino)isoindoline, 19, where a silver hexamer is formed. While in the case of the bis(ethylimino)isoindoline, 8, we observed the hydrolysis of the ligand and the formation of a silver dimer.

Experimental

Materials and Methods: All reagents were purchased from TCI Chemical, Acros

Organics or Sigma-Aldrich and used as received. 1,3-Diiminoisoindoline (DII, 1) was prepared according to Elvidge’s modified procedure.1 NMR spectroscopy was performed with Varian VXR 300 MHz and 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 for 7, Ag(8)oxo, 9, 10, 16, 18, 19.HCl, Ag(19), 20 and 20•HCl 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. The data for the 8, 14, 15, 19, 21, 22 and 23 (using Cu-κα radiation, λ = 1.54178 Å) were collected on a CCD-based diffractometer with dual

Cu/Mo ImuS microfocus optics. 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.

Synthetic Method A18: DII (100 mg, 0.689 mmol) and primary amine (excess) were refluxed in 10 mL of ethanol for 24 hours. After evaporation of the solvent and unreacted primary amine, the residue was recrystallized from various solvents.

Synthetic Method B83: Phthalonitrile (128 mg, 1.00 mmol), primary amine

(excess) and anhydrous CaCl2 (11 mg, 0.100 mmol) were refluxed in 10 mL of n-butanol for 48 hours. After evaporation of the solvent and unreacted primary amine, the residue was recrystallized from various solvents, or purified by flash chromatography.

1,3-Bis-methyliminoisoindoline (method A), 7: The residue was recrystallized from EtOAc to give 7 as a cream colored solid (93.0 mg, 78%); mp: 168-171 °C. 1H

NMR (300 MHz, CD3OD): δ (ppm) 3.36 (s, 6H), 7.52 and 7.75 (dd, J = 2.93, 5.96 Hz,

13 4H); C NMR (125 MHz, CD3OD): δ (ppm) 37.8, 121.9, 131.9, 138.4, 170.0; MS (ESI)

Calc. for C10H11N3 ([M + H]+) 174.1, found 173.7; HRMS (ESI) Calc. for C10H11N3 ([M

+ H]+) 174.1031, found 174.1035, 2.3 ppm.

1,3-Bis-ethyliminoisoindoline (method A), 8: The residue was recrystallized from

EtOAc to give 8 as a cream colored solid (104 mg, 75%), mp: 156-159 °C. 1H NMR (300

MHz, CD3OD): δ (ppm) 1.34 (t, J = 7.32 Hz, 6H), 3.78 (q, J = 7.32 Hz, 4H), 7.52 (dd, J =

13 2.93, 5.56 Hz, 2H), 7.81 (dd, J = 3.07, 5.71 Hz, 2H); C NMR (125 MHz, CD3OD): δ

+ (ppm) 15.5, 42.1, 121.8, 131.5, 138.7, 168.8; MS (ESI) Calc. for C12H15N3 ([M + H] )

+ 202.1, found 202.1; HRMS (ESI) Calc. for C12H15N3 ([M + H] ) 202.1344, found

202.1347, 1.5 ppm. Single crystals were grown from slow evaporation of an ethanolic solution.

Synthesis of Ag(8)oxo: 8 (20 mg, .099 mmol) dissolved in 2 mL of EtOH was added to a 2 mL ethanolic solution of AgNO3 (16.9 mg, .099 mmol). The reaction was

stirred for 30 min at room temperature. The white precipitate formed was filtered, and the filtrate was layered with Et2O and left in the dark. Colorless crystals formed after 2 days.

1-Cyclopropylimino-3-iminoisoindoline, (method A), 9: After 36 hours of reaction, solvent was evaporated and the product recrystallized from ethyl acetate to give

9 as a cream colored solid (57.4 mg, 45%), mp: 163-165 °C. 1H NMR (300 MHz,

13 CD3OD): δ (ppm) 0.92 (m, 4H), 3.70 (bs, 1H), 7.54 (m, 2H), 7.82 (m, 2H); C NMR (75

MHz, CD3OD): δ (ppm) 9.1, 33.3, 121.7, 122.3, 131.0, 132.4, 135.5, 139.7, 166.4, 170.9;

MS (ESI) Calc. for C11H11N3 ([M + H]+) 186.1, found 186.3. Single crystals were grown from a vapor diffusion of hexane into an ethyl acetate solution.

1,3-Bis-cyclopropyliminoisoindoline, (method B), 10: The product was recrystallized from MeOH/Et2O to give 10 as a cream colored solid (155 mg, 69%), mp:

1 154-156 °C. H NMR (300 MHz, CD3OD) δ (ppm) 0.95 – 1.10 (m, 8H), 3.67 (m, 2H),

13 7.64 and 7.92 (dd, J = 2.93, 5.56 Hz, 4H); C NMR (125 MHz, CD3OD): δ (ppm) 7.03,

7.82, 32.0, 120.4, 121.1, 129.7, 131.1, 4° carbon was not seen. MS (ESI) Calc. for

+ C14H15N3 ([M + H] ) 226.13 found 226.0. Single crystals were grown from a vapor diffusion of THF into a methanolic solution. Anal. Calc. for C14H15N3. 0.75CH3OH.

1.9HCl C: 55.61, H: 6.30, N: 13.19. Found, C: 55.69, H: 6.20, N: 13.19.

1,3-Bis-allyliminoisoindoline, (method A), 11: The residue was purified by column chromatography on silica gel (EtOAc) to give 11 as a red solid (79.2 mg, 51%),

1 mp: 1493-152 °C. H NMR (300 MHz, CDCl3): δ (ppm) 4.42 (d, 4H), 5.19 (d, 2H), 5.33

(d, 2H), 6.09 (m, 2H), 7.45 and 7.70 (dd, J = 3.07, 5.42 Hz, 2H); 13C NMR (125 MHz,

CDCl3): δ (ppm) 49.8, 116.5, 120.4, 130.2, 135.15, 137.4, 167.0; MS (ESI) Calc. for

+ C14H15N3 ([M + H] ) 226.13, found 226.1.

1,3-Bis-propyliminoisoindoline, (method B), 12: The residue was recrystallized

1 from Et2O give 12 as a cream colored solid (107 mg, 69%), mp: 124-125 °C . H NMR

(300 MHz, CD3OD): δ (ppm) 1.02 (t, J = 7.32 Hz, 6H), 1.77 (sxt, J = 7.32 Hz, 4H), 3.71

(t, J = 7.17 Hz, 4H) 7.51 and 7.82 (dd, J = 3.07, 5.42 Hz, 4H); 13C NMR (125 MHz,

CD3OD): δ (ppm) 10.6, 22.7, 121.0, 130.9, 136.4, 169.6; MS (ESI) Calc. for C14H19N3

+ + ([M + H] ) 230.2, found 230.2; HRMS (ESI) Calc. for C14H19N3 ([M + H] ) 230.1657, found 202.1648, 3.9 ppm.

1,3-Bis-n-butyliminoisoindoline, (method A), 13: The residue was purified by flash column chromatography on silica gel (2% CH3OH in CHCl3) to give 13 as a cream

1 colored solid (128 mg, 72%), mp: 131-133 °C. H NMR (300 MHz, CD3OD): δ (ppm)

0.99 (t, J = 7.32 Hz, 6H), 1.46 (sxt, J = 7.90 Hz, 4H), 1.74 (quin, J = 6.73, 14.9 Hz, 4H),

3.75 (t, J = 7.17 Hz, 4H), 7.52 and 7.82 (dd, J = 2.93, 5.56 Hz, 4H); 13C NMR (75 MHz,

CD3OD): δ (ppm) 12.8, 20.1, 31.9, 45.9, 120.4, 130.1, 137.3, 168.0 HRMS (ESI) Calc.

+ for C16H23N3 ([M + H] ) 258.1970, found 258.1970, 0.0 ppm.

1,3-Bis-t-butyliminoisoindoline, (method B), 14: The precipitate was washed with cold chloroform, then recrystallized from MeOH/Et2O to give 14 as a cream colored solid

1 (198 mg, 77%), mp: 137-139°C. H NMR (300 MHz, CD3OD): δ (ppm) 1.61 (s, 18H),

13 7.56 and 7.97 (dd, J= 2.63, 5.56 Hz, 4H); C NMR (75 MHz, CD3OD): δ (ppm) 30.0,

+ 56.7, 123.0, 132.5, 168; MS (ESI) Calc. for C16H23N3 ([M + H] ) 258.2, found 258.1.

Anal. Calc. for C16H23N3. 0.55 CH3OH. 0.3 CHCl3 C, 65.11; H, 8.27; N, 13.52. Found: C,

65.07; H, 8.31; N, 13.66. Single crystals were grown from a vapor diffusion of hexane into a chloroform solution.

1,3-Bis-cyclopentyliminoisoindoline, (method B), 15: The residue was recrystallized from EtOAc/hexanes to give 15 as a cream colored solid (211 mg, 75%),

1 mp: 143-145 °C. H NMR (300 MHz, CD3OD): δ (ppm) 1.68 (m, 8H), 1.85 (m, 4H), 2.09

(m, 4H), 4.66 (m, 2H), 7.49 and 7.87 (dd, J = 3.07, 5.42 Hz, 4H), 13C NMR (75 MHz,

CD3OD): δ (ppm) 25.5, 34.7, 58.8, 122.1, 131.5, 137.8, 167.8 MS (ESI) Calc. for

+ C18H23N3 ([M + H] ) 282.2, found 282.2. Anal. Calc. for C18H23N3. 0.65 CH3OH C;

74.12, H: 8.54, N: 13.9. Found C: 73.81, H: 8.32, N: 14.16. Single crystals were grown from slow evaporation of a methanolic solution.

1,3-Bis-(3-pentylimino)isoindoline, (method B), 16: The precipitate was recrystallized from EtOAc/pentane to give 16 as a cream colored solid (194 mg, 68%),

1 mp: 134-137 °C. H NMR (300 MHz, CD3OD): δ (ppm) 0.92 (t, J = 7.47 Hz, 12H), 1.67

(m, 8H), 4.19 (m, 2H), 7.51 and 7.90 (dd, J = 2.93, 5.56 Hz, 4H); 13C NMR (125 MHz,

CD3OD): δ (ppm) 11.4, 29.5, 60.4, 122.0, 131.5. MS (ESI) Calc. for C18H27N3 ([M +

H]+) 286.2, found 286.2. Single crystals were grown from slow evaporation of an ethyl acetate/pentane solution.

1,3-Bis-n-pentyliminoisoindoline, (method A), 17: The residue was recrystallized from EtOAc/hexanes to give 17 as a cream colored solid (146 mg, 74%), mp: 127 °C. 1H

NMR (300 MHz, CD3OD): δ (ppm) 0.93 (t, J = 7.09 Hz, 6H), 1.40 (m, 8H), 1.75 (quin, J

= 7.28Hz, 4H), 3.73 (t, J = 7.21 Hz, 4H), 7.50 (dd, J = 2.93, 5.62 Hz, 2H), 7.81 (dd, J =

13 3.06, 5.5 Hz, 2H); C NMR (125 MHz, CD3OD): δ (ppm) 13.0, 22.1, 29.2, 29.4, 46.1,

+ 120.5, 130.1, 137.3, 168.1; MS (ESI) Calc. for C18H27N3 ([M + H] ) 286.2, found 286.2.

1,3-Bis-cyclohexyliminoisoindoline, (method B), 18: The residue was recrystallized from MeOH/Et2O to give 18 as a cream colored solid (232 mg, 75%), mp:

1 161-164 °C . H NMR (300 MHz, CD3OD): δ (ppm) 1.48 (m, 8H), 1.86 (m, 8H), 1.98

(m, 8H), 4.19 (bs, 2H), 7.50 and 7.87 (dd, J = 5.6, 2.9 Hz, 4H) ; 13C NMR (125 MHz,

CD3OD): δ (ppm) 26.1, 26.5, 33.8, 56.0, 122.9, 132.8, 137.3, 171.0; MS (ESI) Calc. for

+ C20H27N3 ([M + H] ) 310.2, found 309.9. Single crystals were from slow evaporation of a methanol solution.

1,3-Bis-benzyliminoisoindoline, (method A), 19: The residue was recrystallized from EtOAc/hexanes to give 19 as a cream colored solid (154 mg, 69%), mp: 159-161

1 °C. H NMR (500 MHz, CDCl3): δ (ppm) 4.99 (s, 4H), 7.25-7.43 (m, 12H), 7.61 (bs, 2H)

13 C NMR (125 MHz, CDCl3): δ (ppm) 51.0, 120.4, 127.1, 128.5, 130.1, 137.9, 139.5,

+ 167.4. HR MS (ESI) Calc. for C22H19N3 ([M + H] ) 326.1657 found 326.1657 0.0 ppm.

Single crystals were grown from slow evaporation of ethanolic solution.

Synthesis of Ag(19) : 19 (20 mg, 0.061 mmol) dissolved in 2 mL of EtOH was added to a 2 mL ethanolic solution of AgNO3 (15.7 mg, .092 mmol). The reaction was stirred for 30 min at room temperature. The white precipitate formed was filtered, and the filtrate was layered with Et2O and left in the dark. Colorless crystals formed after 2 days from the diffusion mixture.

1,3-Bis-furfuryliminoisoindoline, (method A), 20: The residue was recrystallized from MeOH/Et2O to give 20 as an orange colored solid (151 mg, 71 %) mp: 148-149 °C.

1 H NMR (300 MHz, CDCl3): δ (ppm) 4.98 (s, 4H), 6.29 (s, 2H), 6.33 (s, 2H), 7.32 (s,

13 2H), 7.63 (m, 2H), 7.86 (m, 2H), 8.62 (bs, 1H). C NMR (75 MHz, CDCl3): δ (ppm)

44.0, 107.7, 110.5, 120.7, 130.3, 137.4, 142.0, 152.4, 165.9 MS (ESI) Calc. for

+ C18H15N3O2 ([M + H] ) 306.1 found 306.0. Single crystals were grown from slow evaporation of methanolic solution.

1,3-Bis-α-napthyliminoisoindoline, (method B), 21: The residue was recrystallized from EtOAc/hexanes to give 21 as a yellow solid (161.55 mg, 59%), mp:

1 110 °C. H NMR (300 MHz, CD3OD): δ (ppm) 6.34 (sd, 1H) 7.10 – 8.25 (m, 24 H). MS

(ESI) Calc. for C28H19N3 ([M + H]+) 398.16 found 398.5. Single crystals were grown from slow evaporation of a EtOAc/hexanes solution.

1-α-Naphthylimino-3-iminoisoindoline, (method B), 22: Single crystals were grown from slow evaporation of ethyl acetate/methanol, after column chromatography

(silica, EtOAc) of 100 mg of 21 to give 22 as a yellow solid (30.7 mg, 45%), mp: 141-

1 142 °C . H NMR (500 MHz, CDCl3): δ (ppm) 6.99 (d, J = 6.85 Hz, 1H), 7.32 (t, J = 7.34

Hz, 1H), 7.36 – 7.44 (m, 2H), 7.53 (t, J = 7.46 Hz, 1H), 7.57 – 7.65 (m, 1H), 7.81 (d, J =

8.31 Hz, 1H), 7.86 (d, J = 8.56 Hz, 1H), 8.04 (d, J = 7.58 Hz, 1H); 13C NMR (125 MHz,

CDCl3): δ (ppm) 105.0, 116.2, 120.2, 122.7, 123.5, 124.1, 125.7, 125.9, 126.3, 127.7,

131.0, 131.9, 134.1; MS (ESI) Calc. for C18H13N3 ([M + H]+) 272.1, found 272.1.

1,3-Bis-adamantyliminoisoindoline, (method B), 23: The residue was purified by recrystallization from MeOH/Et2O to give 23 as a white solid (331 mg, 80%), mp: 159-

1 161 °C. H NMR (300 MHz, CDCl3): δ (ppm) 1.76 (s, 12H), 2.17 (s, 6H), 2.29 (s, 12H),

13 7.39 (dd, J = 3.1, 5.4 Hz, 2H), 7.63 (m, 2H) ; C NMR (125 MHz, CDCl3): δ (ppm) 30.0,

+ 36.8, 42.7, 119.8, 129.4, 164.2; MS (ESI) Calc. for C28H35N3 ([M + H] ) 414.29, found

+ 414.1 HRMS (ESI) Calc. for C28H35N3 ([M + H] ) 414.2909, found 414.2897, 2.9 ppm.

Table 3.1 - Crystal data and structure refinement for 7

Identification code 7

Empirical formula C35H36N6O4 Formula weight 604.70 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1)/m Unit cell dimensions a = 10.2696(5) Å α = 90° b = 9.4501(5) Å β = 101.473(3)° c = 16.4202(8) Å γ = 90° 3 Volume 1561.72(14) Å Z 2 3 Density (calculated) 1.286 Mg/m -1 Absorption coefficient 0.086 mm F(000) 640 3 Crystal size 0.36 x 0.27 x 0.20 mm Theta range for data collection 2.02 to 29.05°. Index ranges -13<=h<=13, -11<=k<=12, -22<=l<=20 Reflections collected 14130 Independent reflections 4322 [R(int) = 0.0417] Completeness to theta = 29.05° 98.0 % Absorption correction Multi-scan Max. and min. transmission 0.9831 and 0.9700 2 Refinement method Full-matrix least-squares on F Data / restraints / parameters 4322 / 0 / 230 2 Goodness-of-fit on F 1.007 Final R indices [I>2sigma(I)] R1 = 0.0833, wR2 = 0.1890 R indices (all data) R1 = 0.1005, wR2 = 0.1984 -3 Largest diff. peak and hole 0.625 and -0.463 e.Å

Table 3.2 - Crystal data and structure refinement for 8

Identification code 8

Empirical formula C12H15N3 Formula weight 201.27 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Monoclinic Space group P2(1)/c Unit cell dimensions a = 13.2741(6) Å α = 90° b = 18.7048(9) Å β = 91.636(4)° c = 9.1265(4) Å γ = 90° Volume 2265.09(18) Å3 Z 8 Density (calculated) 1.180 Mg/m3 Absorption coefficient 0.568 mm-1 F(000) 864 Crystal size 0.21 x 0.14 x 0.08 mm3 Theta range for data collection 3.33 to 65.47°. Index ranges -15<=h<=15, -21<=k<=21, -10<=l<=10 Reflections collected 12166 Independent reflections 3694 [R(int) = 0.0566] Completeness to theta = 65.47° 94.60% Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7527 and 0.5704 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 3694 / 0 / 275 Goodness-of-fit on F2 1.24 Final R indices [I>2sigma(I)] R1 = 0.0873, wR2 = 0.2138 R indices (all data) R1 = 0.1047, wR2 = 0.2217 Largest diff. peak and hole 0.362 and -0.274 e.Å-3

Table 3.3 - Crystal data and structure refinement for Ag(8)oxo

Identification code Ag(8)oxo

Empirical formula C20H18Ag2N6O8 Formula weight 686.14 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1)/c Unit cell dimensions a = 13.557(15) Å α = 90°. b = 10.535(12) Å β = 90.996(14)°. c = 7.791(9) Å γ = 90°. Volume 1113(2) Å3 Z 2 3 Density (calculated) 2.048 Mg/m -1 Absorption coefficient 1.823 mm F(000) 676 3 Crystal size 0.13 x 0.09 x 0.05 mm Theta range for data collection 1.50 to 25.11°. Index ranges -16<=h<=16, -12<=k<=12, -9<=l<=9 Reflections collected 7486 Independent reflections 1978 [R(int) = 0.0810] Completeness to theta = 25.11° 99.3 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9144 and 0.7975 2 Refinement method Full-matrix least-squares on F Data / restraints / parameters 1978 / 0 / 164 2 Goodness-of-fit on F 1.171 Final R indices [I>2sigma(I)] R1 = 0.0875, wR2 = 0.2474 R indices (all data) R1 = 0.1106, wR2 = 0.2575 -3 Largest diff. peak and hole 2.322 and -2.470 e.Å

Table 3.4 - Crystal data and structure refinement for 9

Identification code 9

Empirical formula C11H11N3 Formula weight 185.23 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Tetragonal Space group I4(1)/a Unit cell dimensions a = 14.4428(17) Å α = 90° b = 14.4428(17) Å β = 90° c = 23.947(2) Å γ = 90° Volume 4995.3(10) Å3 Z 16 Density (calculated) 0.985 Mg/m3 Absorption coefficient 0.062 mm-1 F(000) 1568 Crystal size 0.48 x 0.37 x 0.32 mm3 Theta range for data collection 1.65 to 25.06°. Index ranges -17<=h<=10, -16<=k<=17, -28<=l<=28 Reflections collected 18617 Independent reflections 2222 [R(int) = 0.0405] Completeness to theta = 25.06° 99.70% Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9806 and 0.9711 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2222 / 0 / 128 Goodness-of-fit on F2 1.306 Final R indices [I>2sigma(I)] R1 = 0.0501, wR2 = 0.1713 R indices (all data) R1 = 0.0577, wR2 = 0.1759 Largest diff. peak and hole 0.500 and -0.194 e.Å-3

Table 3.5 - Crystal data and structure refinement for 10

Identification code 10

Empirical formula C14H18ClN3O Formula weight 279.76 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1)/n Unit cell dimensions a = 7.828(6) Å α = 90° b = 8.633(6) Å β = 97.893(8)° c = 21.316(16) Å γ = 90° Volume 1426.9(18) Å3 Z 4 Density (calculated) 1.302 Mg/m3 Absorption coefficient 0.264 mm-1 F(000) 592 Crystal size 0.24 x 0.22 x 0.18 mm3 Theta range for data collection 1.93 to 25.39°. Index ranges -9<=h<=9, -10<=k<=10, -25<=l<=25 Reflections collected 9913 Independent reflections 2567 [R(int) = 0.0482] Completeness to theta = 25.39° 97.70% Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9540 and 0.9394 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2567 / 0 / 180 Goodness-of-fit on F2 1.039 Final R indices [I>2sigma(I)] R1 = 0.0382, wR2 = 0.1007 R indices (all data) R1 = 0.0416, wR2 = 0.1045 Largest diff. peak and hole 0.237 and -0.317 e.Å-3

Table 3.6 - Crystal data and structure refinement for 14

Identification code 14

Empirical formula C16H23N3O2 Formula weight 289.37 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Monoclinic Space group C2/c Unit cell dimensions a = 7.1059(3) Å α = 90° b = 19.6672(8) Å β = 91.298(4)° c = 24.2192(12) Å γ = 90° Volume 3383.8(3) Å3 Z 8 Density (calculated) 1.136 Mg/m3 Absorption coefficient 0.610 mm-1 F(000) 1248 Crystal size 0.19 x 0.12 x 0.09 mm3 Theta range for data collection 4.50 to 62.00°. Index ranges -8<=h<=8, -22<=k<=22, -25<=l<=22 Reflections collected 8942 Independent reflections 2528 [R(int) = 0.0444] Completeness to theta = 62.00° 95.10% Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9466 and 0.8913 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2528 / 0 / 197 Goodness-of-fit on F2 1.102 Final R indices [I>2sigma(I)] R1 = 0.0974, wR2 = 0.2689 R indices (all data) R1 = 0.1079, wR2 = 0.2770 Largest diff. peak and hole 0.628 and -0.312 e.Å-3

Table 3.7 - Crystal data and structure refinement for 15

Identification code 15

Empirical formula C38H54N6O2 Formula weight 626.87 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Triclinic Space group P-1 Unit cell dimensions a = 11.3991(4) Å α = 98.9350(10)° b = 11.7440(4) Å β = 97.2670(10)° c = 14.0215(5) Å γ = 106.7470(10)° Volume 1746.31(11) Å3 Z 2 Density (calculated) 1.192 Mg/m3 Absorption coefficient 0.584 mm-1 F(000) 680 Crystal size 0.21 x 0.20 x 0.10 mm3 Theta range for data collection 3.24 to 62.00°. Index ranges -12<=h<=13,-11<=k<=13,-16<=l<=16 Reflections collected 19508 Independent reflections 5319 [R(int) = 0.0216] Completeness to theta = 62.00° 96.90% Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9450 and 0.8882 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 5319 / 2 / 425 Goodness-of-fit on F2 0.951 Final R indices [I>2sigma(I)] R1 = 0.0569, wR2 = 0.1558 R indices (all data) R1 = 0.0594, wR2 = 0.1595 Largest diff. peak and hole 0.933 and -0.433 e.Å-3

Table 3.8 - Crystal data and structure refinement for 16

Identification code 16

Empirical formula C113H174N18 Formula weight 1784.7 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Orthorhombic Space group Pbca Unit cell dimensions a = 24.052(10) Å α = 90° b = 18.354(7) Å β = 90° c = 24.632(10) Å γ = 90° Volume 10874(8) Å3 Z 4 Density (calculated) 1.090 Mg/m3 Absorption coefficient 0.065 mm-1 F(000) 3912 Crystal size 0.20 x 0.15 x 0.15 mm3 Theta range for data collection 1.62 to 25.11°. Index ranges -28<=h<=28, -21<=k<=21, -29<=l<=29 Reflections collected 75624 Independent reflections 9664 [R(int) = 0.0915] Completeness to theta = 25.11° 99.70% Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9903 and 0.9872 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 9664 / 12 / 627 Goodness-of-fit on F2 0.97 Final R indices [I>2sigma(I)] R1 = 0.0745, wR2 = 0.1564 R indices (all data) R1 = 0.1154, wR2 = 0.1812 Largest diff. peak and hole 0.930 and -0.351 e.Å-3

Table 3.9 - Crystal data and structure refinement for 18

Identification code 18

Empirical formula C22H35N3O2 Formula weight 373.53 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1)/c Unit cell dimensions a = 12.835(5) Å α = 90° b = 9.031(3) Å β = 94.465(4)° c = 18.866(7) Å γ = 90° Volume 2180.2(13) Å3 Z 4 Density (calculated) 1.138 Mg/m3 Absorption coefficient 0.073 mm-1 F(000) 816 Crystal size 0.62 x 0.47 x 0.37 mm3 Theta range for data collection 1.59 to 25.00°. Index ranges -15<=h<=15, -10<=k<=10, -22<=l<=22 Reflections collected 14732 Independent reflections 3837 [R(int) = 0.0358] Completeness to theta = 25.00° 99.80% Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9734 and 0.9561 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 3837 / 0 / 248 Goodness-of-fit on F2 1.031 Final R indices [I>2sigma(I)] R1 = 0.0390, wR2 = 0.1047 R indices (all data) R1 = 0.0434, wR2 = 0.1093 Largest diff. peak and hole 0.264 and -0.210 e.Å-3

Table 3.10 - Crystal data and structure refinement for 19

Identification code 19

Empirical formula C22H19N3 Formula weight 325.40 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Orthorhombic Space group Pbca Unit cell dimensions a = 9.0249(2) Å α = 90° b = 13.4108(4) Å β = 90° c = 29.2736(8) Å γ = 90° 3 Volume 3543.02(16) Å Z 8 3 Density (calculated) 1.220 Mg/m -1 Absorption coefficient 0.567 mm F(000) 1376 3 Crystal size 0.26 x 0.25 x 0.13 mm Theta range for data collection 3.02 to 64.00°. Index ranges -8<=h<=10, -14<=k<=15, -31<=l<=33 Reflections collected 11649 Independent reflections 2881 [R(int) = 0.0208] Completeness to theta = 64.00° 98.1 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9279 and 0.8685 2 Refinement method Full-matrix least-squares on F Data / restraints / parameters 2881 / 0 / 226 2 Goodness-of-fit on F 0.902 Final R indices [I>2sigma(I)] R1 = 0.0319, wR2 = 0.0839 R indices (all data) R1 = 0.0369, wR2 = 0.0885 -3 Largest diff. peak and hole 0.205 and -0.294 e.Å

Table 3.11 - Crystal data and structure refinement for 19•HCl

Identification code 19•HCl

Empirical formula C22H22ClN3O Formula weight 379.88 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Triclinic Space group P-1 Unit cell dimensions a = 7.777(2) Å α = 66.017(14)° b = 11.436(2) Å β = 81.293(17)° c = 12.189(4) Å γ = 85.954(17)° 3 Volume 979.1(4) Å Z 2 3 Density (calculated) 1.289 Mg/m -1 Absorption coefficient 0.212 mm F(000) 400 3 Crystal size 0.45 x 0.39 x 0.28 mm Theta range for data collection 1.85 to 25.31°. Index ranges -9<=h<=9, -13<=k<=13, -14<=l<=14 Reflections collected 7031 Independent reflections 3501 [R(int) = 0.0342] Completeness to theta = 25.31° 97.7 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9431 and 0.9108 2 Refinement method Full-matrix least-squares on F Data / restraints / parameters 3501 / 2 / 252 2 Goodness-of-fit on F 1.209 Final R indices [I>2sigma(I)] R1 = 0.0484, wR2 = 0.1508 R indices (all data) R1 = 0.0545, wR2 = 0.1593 -3 Largest diff. peak and hole 0.507 and -0.270 e.Å

Table 3.12 - Crystal data and structure refinement for Ag(19)

Identification code Ag(19)

Empirical formula C22H18Ag1.62N3.62 O2.25 Formula weight 544.44 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Triclinic Space group P1 Unit cell dimensions a = 14.425(5) Å = 90.901(4)° b = 15.775(6) Å = 91.788(4)° c = 20.298(8) Å  = 116.745(4)° Volume 4121(3) Å3 Z 8 Density (calculated) 1.755 Mg/m3 Absorption coefficient 1.581 mm-1 F(000) 2158 Crystal size 0.23 x 0.21 x 0.16 mm3 Theta range for data collection 1.58 to 25.05°. Index ranges -17<=h<=16, -18<=k<=18, -24<=l<=24 Reflections collected 28301 Independent reflections 25838 [R(int) = 0.0351] Completeness to theta = 25.05° 99.0 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7452 and 0.6289 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 25838 / 4 / 2126 Goodness-of-fit on F2 1.085 Final R indices [I>2sigma(I)] R1 = 0.0516, wR2 = 0.1482 R indices (all data) R1 = 0.0532, wR2 = 0.1511 Largest diff. peak and hole 2.524 and -1.198 e.Å-3

Table 3.13 - Crystal data and structure refinement for 20

Identification code 20

Empirical formula C18H15N3O2 Formula weight 305.33 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Orthorhombic Space group Pbca Unit cell dimensions a = 9.896(11) Å α = 90° b = 12.359(13) Å β = 90° c = 24.40(3) Å γ = 90° 3 Volume 2984(5) Å Z 8 3 Density (calculated) 1.359 Mg/m -1 Absorption coefficient 0.091 mm F(000) 1280 3 Crystal size 0.41 x 0.32 x 0.26 mm Theta range for data collection 1.67 to 25.03°. Index ranges -11<=h<=11, -14<=k<=14, -28<=l<=28 Reflections collected 18124 Independent reflections 2635 [R(int) = 0.0723] Completeness to theta = 25.03° 99.8 % Absorption correction multi- scan Max. and min. transmission 0.9767 and 0.9636 2 Refinement method Full-matrix least-squares on F Data / restraints / parameters 2635 / 0 / 208 2 Goodness-of-fit on F 0.956 Final R indices [I>2sigma(I)] R1 = 0.0435, wR2 = 0.1143 R indices (all data) R1 = 0.0562, wR2 = 0.1270 -3 Largest diff. peak and hole 0.274 and -0.224 e.Å

Table 3.14 - Crystal data and structure refinement for 20•HCl

Identification code 20•HCl

Empirical formula C18H16ClN3O2 Formula weight 341.79 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group C2/c Unit cell dimensions a = 25.2066(12) Å α = 90° b = 9.5283(4) Å β = 115.460(2)° c = 15.0380(7) Å γ = 90° 3 Volume 3261.0(3) Å Z 8 3 Density (calculated) 1.392 Mg/m -1 Absorption coefficient 0.250 mm F(000) 1424 3 Crystal size 0.13 x 0.13 x 0.07 mm Theta range for data collection 1.79 to 25.09°. Index ranges -30<=h<=26, -8<=k<=11, -17<=l<=17 Reflections collected 10783 Independent reflections 2901 [R(int) = 0.0333] Completeness to theta = 25.09° 99.9 % Absorption correction SADABS Max. and min. transmission 0.9820 and 0.9682 2 Refinement method Full-matrix least-squares on F Data / restraints / parameters 2901 / 0 / 217 2 Goodness-of-fit on F 1.059 Final R indices [I>2sigma(I)] R1 = 0.0421, wR2 = 0.1307 R indices (all data) R1 = 0.0575, wR2 = 0.1506 -3 Largest diff. peak and hole 0.353 and -0.349 e.Å

100

Table 3.15 - Crystal data and structure refinement for 21

Identification code 21

Empirical formula C41H35N4 Formula weight 583.73 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Triclinic Space group P-1 Unit cell dimensions a = 11.7309(6) Å α = 72.332(2)° b = 12.0944(7) Å β = 79.761(2)° c = 12.2826(7) Å γ = 71.485(2)° Volume 1568.09(15) Å3 Z 2 Density (calculated) 1.236 Mg/m3 Absorption coefficient 0.561 mm-1 F(000) 618 Crystal size 0.35 x 0.24 x 0.14 mm3 Theta range for data collection 3.79 to 61.00°. Index ranges -13<=h<=13, -13<=k<=13, -11<=l<=13 Reflections collected 17200 Independent reflections 4441 [R(int) = 0.0189] Completeness to theta = 61.00° 92.60% Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7528 and 0.6885 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 4441 / 5 / 458 Goodness-of-fit on F2 1.995 Final R indices [I>2sigma(I)] R1 = 0.0499, wR2 = 0.2067 R indices (all data) R1 = 0.0520, wR2 = 0.2118 Largest diff. peak and hole 0.427 and -0.426 e.Å-3

101

Table 3.16 - Crystal data and structure refinement for 22

Identification code 22

Empirical formula C18H13N3 Formula weight 271.31 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Orthorhombic Space group Pccn Unit cell dimensions a = 13.1281(7) Å α = 90° b = 24.3397(12) Å β = 90° c = 8.4553(5) Å γ = 90° Volume 2701.8(3) Å3 Z 8 Density (calculated) 1.334 Mg/m3 Absorption coefficient 0.635 mm-1 F(000) 1136 Crystal size 0.27 x 0.10 x 0.06 mm3 Theta range for data collection 3.83 to 60.99°. Index ranges -14<=h<=14, -26<=k<=27, -9<=l<=5 Reflections collected 7025 Independent reflections 1987 [R(int) = 0.0388] Completeness to theta = 60.99° 96.10% Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7526 and 0.6113 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 1987 / 0 / 190 Goodness-of-fit on F2 1.073 Final R indices [I>2sigma(I)] R1 = 0.0444, wR2 = 0.1178 R indices (all data) R1 = 0.0588, wR2 = 0.1297 Largest diff. peak and hole 0.278 and -0.208 e.Å-3

102

Table 3.17 - Crystal data and structure refinement for 23

Identification code 23

Empirical formula C45.75H61N4.50O Formula weight 689.99 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Tetragonal Space group P4(2)/mbc Unit cell dimensions a = 21.3626(6) Å α = 90° b = 21.3626(6) Å β = 90° c = 36.2078(13) Å γ = 90° Volume 16523.8(9) Å3 Z 16 Density (calculated) 1.109 Mg/m3 Absorption coefficient 0.507 mm-1 F(000) 6000 Crystal size 0.19 x 0.13 x 0.08 mm3 Theta range for data collection 2.44 to 66.65°. Index ranges -23<=h<=25, -24<=k<=20, -41<=l<=43 Reflections collected 54069 Independent reflections 7412 [R(int) = 0.0647] Completeness to theta = 66.65° 99.60% Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.9620 and 0.9098 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 7412 / 0 / 485 Goodness-of-fit on F2 1.047 Final R indices [I>2sigma(I)] R1 = 0.0662, wR2 = 0.1866 R indices (all data) R1 = 0.0886, wR2 = 0.2053 Largest diff. peak and hole 1.115 and -0.521 e.Å-3

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Results and Discussion

A series of seventeen substituted diiminoindolines have been synthesized in this study. Several of them have been previously reported (R= methyl,23,65,71,120,132 ethyl,72 propyl,132 butyl23,71,132 and cyclohexyl23,120) but have not been fully characterized. Two methods were employed for the synthesis of the substituted isoindolines. The first one was the procedure used by Linstead and coworkers; refluxing diiminoisoindoline 2 with two equivalents of an alkyl amine in ethanol for 24 hours.18 The second method was

Siegl’s procedure; phthalonitrile 1 was reacted with two equivalents of alky amine

83 refluxing in n-butanol for 48 hours, catalyzed by CaCl2. In both cases, evolution of ammonia was observed. Compound 1 also reacted with ammonia in a sodium methylate solution to form compound 2. The bis(imino)isoindoline yields ranged between 45 to

80% after purification either by flash chromatography or recrystallization from various solvents. The compounds produced in this study listed by method of preparation and yields are shown in Table 3.18.

The optimal method for the syntheses of these compounds varied based on the identity of the primary amine. For the non-sterically hindered amines, such as methyl, ethyl, propyl, butyl and pentyl amines, direct reaction with DII afforded the desired bis- substituted product in good yield. However, for the bulker amines and cycloalkyl amines, Siegl's alternative method more efficiently produced the desired bis-substituted amines. One exception is seen with the naphthylamine reaction, where both the bis substituted isoindoline and the monofunctionalized 1-amino-3-aminoisoindoline are produced. Additionally, when DII is used as a starting material for cyclopropylamine,

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only the monofunctional adduct, 1-cyclopropylimino-3-iminoisoindoline, is produced. In contrast, for the less bulky amines, Siegl’s method from phthalonitrile provided no advantages in yield versus direct reaction with DII. All of the resultant compounds were fully characterized, including by NMR spectroscopy and mass spectrometry.

Scheme 3.1 - General synthesis of bis(alkylimino)isoindolines

I was able to structurally elucidate several of the bis-substituted isoindolines as well as two examples of the monosubstituted compounds. The data collection and structure parameters for the crystal structures presented in this report are presented in

Tables 3.1-3.17. Figure 3.1 and Figure 3.2 show the structures of several of the bis- substituted compounds (7, 8, 10, 14-16, 18-21 and 23) and Figure 3.7 shows the structures for two of the monofunctionalized compounds (9 and 22). All of the compounds were isolated and structurally characterized as neutral species with the exception of 7 and 10, which were elucidated as a co-crystal and the HCl salt respectively.

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Table 3.18 - The syntheses and yields of substituted isoindolines 7-23

Yield Compound Name R1 R2 Method (%)

7 1,3- bis-methyliminoisoindoline CH3 CH3 A 78

8 1,3- bis-ethyliminoisoindoline C2H5 C2H5 A 75 1-cyclopropylimino-3- 9 C H H A 45 iminoisoindoline 3 5 1,3-bis- 10 C H C H B 69 cyclopropyliminoisoindoline 3 5 3 5

11 1,3-bis-allyliminoisoindoline C3H5 C3H5 A 51

12 1,3-bis-n-propyliminoisoindoline C3H7 C3H7 A 68

13 1,3-bis-n-butyliminoisoindoline C4H9 C4H9 A 72

14 1,3-bis-t-butyliminoisoindoline C4H9 C4H9 B 77 1,3-bis- 15 C H C H B 75 cyclopentyliminoisoindoline 5 9 5 9 1,3-bis-(3- 16 C H C H B 68 pentylimino)isoindoline 5 11 5 11

17 1,3-bis-pentyliminoisoindoline C5H11 C5H11 A 74 1,3-bis- 18 C H C H B 75 cyclohexyliminoisoindoline 6 11 6 11

19 1,3-bis-benzyliminoisoindoline C7H7 C7H7 A 68

20 1,3-bis-furfuryliminoisoindoline C5H5O C5H5O A 71 1,3-bis-α- 21 C H C H B 59 naphthyliminoisoindoline 10 7 10 7 1-α-naphthylimino-3- 22 C H H B 45 iminoisoindoline 10 7 1,3-bis- 23 C H C H B 80 adamantyliminoisoindoline 10 15 10 15

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Figure 3.1 - Structures of bis-substituted diiminoisoindolines with 35% thermal ellipsoids. Non-ionizable hydrogen atoms and the chloride anion for compound 10 have been omitted for clarity. Grey, blue and green ellipsoids represent C, N, and H atoms respectively.

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Figure 3.2 - Structures of bis-substituted diiminoisoindolines with 35% thermal ellipsoids. Non-ionizable hydrogen atoms have been omitted for clarity. Grey, blue, green and red ellipsoids represent C, N, H, and O atoms respectively.

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For the bis-substituted isoindolines, I was able to make two important structural observations from the single crystal data. First, the group on the imines in these compounds can be oriented either toward the isoindoline ring (a syn conformation) or away from the ring (an anti conformation).27,135 In all of the cases with the exception of the bis-napthyl compound 21, the alkyl groups adopt an anti conformation. The prevalence of this structure results from two factors: the steric bulk of the imine substituents, and the presence of stabilizing hydrogen bonds. A second structural aspect that can be observed in the bis substituted isoindolines is the tautomerization of the ionizable hydrogen atom. These compounds can tautomerize between protonation at the central nitrogen atom position and protonation at one of the two imine positions.

Inspection of the difference map, the length of the imine C-N bonds and the presence of hydrogen bonding all indicate that the protons typically reside on the external imine bond positions rather than the central isoindoline nitrogen atom. Once again, the only exception is observed in the bis-naphthyl species, which has the ionizable hydrogen atom on the central isoindoline nitrogen atom position.

Previously, Negrebetiskii et al. published a study on the E-Z isomerization of the imine bonds on the bis-methyl substituted diiminoisoindoline.65 These experiments were carried out in 3:1 chloroform/acetone using a 90 MHz NMR instrument. We investigated the temperature dependent 1H NMR of compound 13 in two solvent systems: DMSO and

3:1 chloroform/acetone. Although I did observe sharpening of peaks from the butyl group, some coalescence of the phenyl AA'BB' spin system, and downfield shifts for the ionizable protons (see Figures 3.3–3.6), I was not able to freeze out a proton localized

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form of 13. However, my observations were consistent with the room temperature fast exchange of H+ between the nitrogen atoms in 13 (Scheme 3.2).

Scheme 3.2 – Proton exchange observed in bis(alkylimino)isoindolines.

Figure 3.3 - Variable temperature 1H NMR spectra of 13 (aromatic protons) in DMSO showing dynamic proton exchange behavior.

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Figure 3.4 - Variable temperature 1H NMR spectra of 13 (aromatic protons) in 3:1 chloroform/acetone showing dynamic proton exchange behavior. The scale has been shifted for clarity purposes

Figure 3.5 - Variable temperature 1H NMR spectra of 13 in 3:1 chloroform/acetone showing dynamic proton exchange behavior.

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Figure 3.6 - Variable temperature 1H NMR spectra of 13 in 3:1 chloroform/acetone showing dynamic proton exchange behavior.

In two reactions, I observed the formation of a monofunctionalized adduct. For cyclopropylamine, the identity of the product depended on the method of synthesis.

Method A, reaction of DII with the amine, only resulted in the monofunctionalized product, 1-cyclopropylimino-3-iminoisoindoline. In the case of the monofunctionalized naphthalene product, the route to the product was slightly more complex. Initially, the bis-substituted product was produced via Siegl's method, however I observed the presence of an additional equivalent of naphthylamine in the product, which was confirmed by X-ray crystallography. When I attempted to remove this equivalent of naphthylamine via chromatography, I isolated 1-α-naphthylimino-3-iminoisoindoline instead.

The structures of both compounds are shown in Figure 3.7. Both compounds show similar structural features. In particular, I observe a longer bond distance to the unsubstituted exocyclic nitrogen than in the modified one; there is some multiple bond 112

delocalization between the C-NH2 and C-Ncentral atoms. Additionally, I located both N- bound hydrogen atoms at the terminal unsubstituted imine nitrogen atom rather than at the central isoindoline nitrogen atom. This is readily confirmed via inspection of the hydrogen bonding in the solid. Both substances form hydrogen bonded dimers, where one of the terminal imine hydrogen atoms forms a complimentary hydrogen bond with the central nitrogen atom from a neighboring equivalent (see Figure 3.8). 1-

Cyclopropylimino-3-iminoisoindoline forms an additional hydrogen bond between the second unsubstituted imino hydrogen atom and a substituted imine nitrogen atom on a neighboring equivalent, forming one dimensional hydrogen bonded chains in the solid state. This same interaction is not present in the 1-α-naphthylimino-3-iminoisoindoline compound as the steric bulk of the naphthyl group prevents the formation of a 1D hydrogen bonded network.

Figure 3.7 - Structures of mono-substituted diiminoisoindolines 9 and 22 with 35% thermal ellipsoids. Non-ionizable hydrogen atoms have been omitted for clarity. Grey, blue and green ellipsoids represent C, N, and H atoms respectively.

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Figure 3.8 - Hydrogen bonding interactions observed in the structure of 9 (left) and 22 (right). Non-ionizable hydrogen atoms have been omitted for clarity. Grey, blue and green ellipsoids represent C, N, and H atoms respectively.

The metal binding chemistry of bis(alkylimino)isoindolines has not been fully explored. Recently Russian chemists isolated three complexes of bis(isopropylimino)isoindolines with lanthanides metal cation.133 The structures of these complexes were elucidated, and it was observed that in the case of yttrium and dysprosium, the metal cation was coordinated by three deprotonated ligands. In the case of cerium, an unusual dimeric structure is observed with six bis(methylimino)isoindolines binding two Ce3+ ions. In both cases, the ligands bind in a η2 fashion involving the deprotonated isoindoline and adjacent imine nitrogen atoms.133 Costa and Ziegler reported the unusual binding of silver to cyclohexylcyanine, where the silver cation would only bind to the meso nitrogen of the macrocycle.32 I decided to investigate the metal binding of these bis(alkylimino)isoindolines with silver as well. Several ligands (8,

10, 13, 14 and 19) were reacted with one equivalent of silver nitrate in ethanol. Two structures of the silver complexes were structurally elucidated. I noticed different binding modes of the silver cation.

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In the case of 8, the crystal structure revealed the formation of a dimeric structure,

Ag(8)oxo, and the hydrolysis of the ligand as seen in Figure 3.9. The complex crystallizes in the monoclinic space group P21/c. Each asymmetric unit contains 2 unit cells which consist of a hydrolyzed ligand molecule, a silver cation and a nitrate anion.

The ligand hydrolyzed and rearranged itself to form a 1-oxo-N-ethyliminoisoindoline, while losing a molecule of ethylamine. Also, each silver is coordinated linearly to an imine nitrogen and a nitrate anion. It also interacts with another silver cation. The Ag-Ag bond length is of 3.118(3) Å which is longer than the one found in metallic silver (2.89

Å) but smaller than the sum of two Van der Waals radii (3.54 Å). The Ag-Nimine bond measures 2.092(15) Å which is consistent with N-donor Ag(I) complexes bond lengths.261,262 The ligand is neutral, indicating that the exocyclic imine nitrogen is not bound to the silver cation but donates electron density from its lone pair of electrons.

The presence of a hydrogen bond was observed between the carbonyl and the imine moieties; the bond length NH...O measures 2.916 Å.

Figure 3.9 – Crystal structure of Ag(8)oxo with 35% thermal ellipsoids. Non-ionizable hydrogen atoms have been omitted for clarity. Grey, blue, red and purple ellipsoids represent C, N, O and Ag atoms respectively.

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The metalation of 19 with AgNO3 formed yellow crystals which crystallized in a triclinic system (Figure 3.10). The silver cations form a six-membered metallacycle in a twisted boat conformation (Figure 3.11). Another example of a silver hexamer was reported in 2008 by Kempe et al. but we observed the first one involving isoindolines and derivates.263 The silver metallacycle is surrounded by four ligands with Ag(I) cations having different coordination modes. Ag(1) and Ag(4) are tetracoordinate where each is coordinated to two imine nitrogen of facing ligands at both axial positions and to two adjacent silver cations. Ag (2) (3) (5) and (6) are pentacoordinate; where they are coordinated to three silver cations (two adjacent and one facing cations), an imine nitrogen and an isoindoline nitrogen of two facing ligands. The average length of neighboring and opposite Ag...Ag ions is 2.871 Å and 3.111 Å respectively. Each ligand acts as a tridentate monoanionic and two nitrate anions are found in the unit cell to balance the charge. The Nisoindoline-Ag length varies from 2.093 to 2.207 Å, and the Nimine-

Ag distances range from 2.090 to 2.163 Å. These values agree with the distances reported in similar complexes.248,262,264,265

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Figure 3.10 – Crystal structure of Ag(19). Non-ionizable hydrogen atoms have been omitted for clarity. Grey, blue, and purple sticks represent C, N, and Ag atoms respectively.

Figure 3.11 – Configuration of the silver hexamer with 35% thermal ellipsoids.

In conclusion, I have revisited the synthesis of bis-substituted diiminoisoindolines. Both the original method developed by Linstead and the more recent procedure presented by Siegl can be used to generate these compounds. For cyclic and bulky amines, Siegl's method provides more complete reactions and higher yields of product. The structures of these compounds presented herein reveal the conformational

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and protonation states of these substituted isoindolines. The metalation of some bis(alkylimino)isoindolines with Ag(I) cation resulted in the formation of two different binding modes of the ligands as we observed both a silver dimer and hexamer. The

Ziegler’s group is continuing their work on the fundamental chemistry of diiminoisoindoline and related compounds.

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CHAPTER IV

4 A NEW HIGHLY FLUORESCENT AND SYMMETRIC PYRROLE-BF2

CHROMOPHORE: BOPHY

Introduction

Fluorescent chromophores have become essential to modern chemical investigations. Chromophores with high quantum yields of emission, such as fluorescein, coumarin and arylmethine dyes, have been used in applications ranging from biological imaging and sensing to light harvesting.140,143,266–270 Some of the more successful fluorophores in the literature belong to BODIPY family of compounds.156,164,166,167,172,221

These dyes, which are comprised of a dipyrromethene bound to a central BF2 unit, have several optimal characteristics, including a large molar absorbtivity, a high quantum yield of emission, and a reasonably sized Stokes shift. The success of the BODIPY dyes and related compounds has spurred investigations into similar systems, such as the nitrogen substituted aza-BODIPY variants.156,164,166,167,211,271–273

In this chapter, I present the new pyrrole-BF2 based fluorophore BOPHY

(bis(difluoroBOron)1,2-bis((1H-Pyrrol-2-yl)methylene) HYdrazine), which can be produced via a simple, two step procedure. The resulting chromophore is a symmetric, highly fluorescent compound with two BF2 units bridged by a coupled pair of Schiff bases. The text of this chapter is a modified reprint of the material as it appears in:

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Tamgho, I.-S.; Hasheminasab, A.; Engle, J. T.; Nemykin, V. N.; Ziegler, C. J. J. Am.

Chem. Soc. 2014, 136, 5623-5626

Experimental

General Information: All reagents and starting materials were purchased from commercial vendors and used without further purification. Column chromatography was performed on silica gel (Dynamic Adsorbents, Inc, 63-200 μm). Deuterated solvents were purchased from Cambridge Isotope Laboratories and used as received. NMR spectra were recorded on 300, 400 and 500 MHz Varian spectrometers. Chemical shifts were given in ppm relative to residual solvent resonances (1H, 13C NMR spectra) or to external

11 standards (BF3.Et2O for B). High resolution mass spectrometry experiments were performed on a Micromass ESI-Tof™ II (Micromass, Wythenshawe, UK) mass spectrometer equipped with an orthogonal electrospray source (Z-spray) operated in positive ion mode. Sodium iodide was used for mass calibration for a calibration range of m/z 100-2000. Samples were prepared in a solution containing acidified methanol and infused into the electrospray source at a rate of 5-10 μL min-1. Optimal ESI conditions were: capillary voltage 3000 V, source temperature 110oC and a cone voltage of 55 V.

The ESI gas was nitrogen. Data was acquired in continuum mode until acceptable averaged data was obtained.

X-ray intensity data were measured on a Bruker CCD-based diffractometer with dual Cu/Mo ImuS microfocus optics (Cu Kα radiation, λ = 1.54178 Å, Mo Kα radiation,

λ =0.71073 Å). Crystals were mounted on a cryoloop using Paratone oil and placed under

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a steam of nitrogen at 100 K (Oxford Cryosystems). The detector was placed at a distance of 4.00 cm from the crystal. 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.

UV-Vis spectra were recorded on a Hitachi UV-Vis spectrophotometer (U-3010).

Fluorescence excitation and emission data in solution were recorded on a Horiba Jobin-

Yvon FluoroMax-4 fluorescence spectrophotometer using Coumarin 540 in methanol as a standard.144 All slit widths were held constant at 2 nm. The quantum yields in solution

were calculated using the following equation: ; ηx = 1.424, ηst =

1.329; Φst = 0.46 and Grad the gradient from the plot of integrated fluorescence intensity vs absorbance274

Cyclic voltammograms were obtained using a standard three electrode cell and

Electrochemical analyser BAS 100B from Bioanalytical systems and were recorded at

298 K under the following conditions: 10-3 M samples in dried tetrahydrofuran(THF) in the presence of 0.1 M tetrabu-tylammonium hexafluorophosphate (TBAPF6) as a supporting electrolyte, Ag/Ag+ reference electrode, 0.79 mm2 gold working electrode, and platinum wire auxiliary electrode. The working electrode was polished first with 3

µm fine diamond, then 0.05 µm alumina. The electrode was rinsed with ethanol and deionized water after each polishing and wiped with a Kimwipe. The non-aqueous

Ag/Ag+ reference was prepared by soaking the silver wire in the degassed and dried THF solution of 5% Acetonitrile: 0.01M AgClO4: 0.1M TBAPF6. At a 0.10 V/s sweep rate, the

+ Fc/Fc occurs at 0.060 ±0.005 V (∆Ep = 119mV; ipa/ipc = 0.99).

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Computational Aspects: All computations were performed using Gaussian 09 software running under Windows or UNIX OS.S2 Molecular orbital contributions were compiled from single point calculations using the VMOdes program.S3 In all calculations, TPSSh hybrid (10% of Hartree-Fock exchange)275 exchange correlation functional was used because it was found in a set of model gas-phase calculations that it is superior over standard GGA (BP86)276 and hybrid B3LYP277 exchange-correlation functionals. In all calculations, 6-311G(d) basis set277 was employed. Solvent effects

278–280 were modeled using PCM approach. Geometry optimizations in C2h symmetry using all three tested exchange-correlation functionals for both molecules result in the presence of two imaginary frequencies. One leads to C2 geometry (both boron atoms deviate from the molecular plane to the same direction) and the second one to Cs geometry (boron atoms deviate from the molecular plane to opposite directions). Further geometry optimization in C2 and Cs point groups result in all calculated frequencies to be positive thus representing energy minima. In all TDDFT calculations, the lowest 30 excited states were calculated in order to cover experimentally observed transitions in

UV-visible region.

Synthesis of 24: This compound was prepared as previously described in the literature.281 Pyrrole-2-carbaldehyde (1.00 g, 10.5 mmol) and hydrazine hydrate (300 mg,

6 mmol) were dissolved in 30 mL of ethanol. Few drops of acetic acid were added, the solution became yellow. After a few seconds, a yellow precipitate formed and the reaction mixture was stirredat room temperature for an hour. The yellow precipitate was collected by filtration and rinsed with cold ethanol (2 x 10 mL) and dried under vacuum to afford a yellow solid (0.612 mg, 56 % yield). The spectroscopic characteristics were in

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good agreement with those found in the literature.281 1H NMR (DMSO-d6, 300 MHz): δ

(ppm) 6.20 (s, 2H), 6.61 (s, 2H), 6.99 (s, 2H), 8.39 (s, 2H), 11.54 (bs, 2H). 13C (DMSO- d6, 75 MHz): δ (ppm) 109.6, 114.7, 123.2, 127.3, 150.5.

Synthesis of 26: The compound was synthesized in a similar manner as described above for 24 using 3,5-dimethylpyrrole-2-carboxaldehyde to afford 26 as a yellow powder with a yield of 65%. Crystals suitable for single-crystal X-ray diffraction were

1 grown by slow evaporation of a solution of 26 in dichloromethane. H NMR (CDCl3, 300

MHz): δ (ppm) 2.18 (s, 6H), 2.27 (s, 6H), 5.81 (s, 2H), 8.37 (s, 2H), 8.62 (bs, 2H). 13C

(CDCl3, 75 MHz): δ (ppm) 10.65, 13.12, 110.6, 123.4, 127.0, 132.8, 147.7. ESI MS Calc.

+ for C14H18N4 m/z 242.15, found [M+H] m/z 243.1.

Synthesis of 25: DIPEA (2.00 mL, 1.48 g, 11.5 mmol) was added to a solution of

24 (200 mg, 1.07 mmol) in DCM (10.0 mL). BF3•Et2O (1.70 mL, 1.94 g, 13.6 mmol) was then added dropwise. The reaction mixture was stirred at room temperature overnight.

The reaction mixture was quenched with water and extracted by DCM. The organic layer was washed with water (3 x 10 mL) and dried over magnesium sulfate. After solvent concentration, pure product can be obtained via column chromatography on silica gel using 100% DCM to give 25 as a yellow solid (125 mg, 42%). The product was recrystallized from methylene chloride/hexanes. Crystals suitable for single-crystal X-ray diffraction were grown by slow evaporation of a solution of 25 in dichloromethane. 1H

NMR ((CD3)2CO, 300 MHz): δ (ppm) 6.64 (dd, 2H), 7.32 (d, 2H), 7.74 (s, 2H), 8.26 (s,

13 19 2H); C NMR ((CD3)2CO, 125 MHz): δ (ppm) 117.4, 128.5, 137.7, 141.8; F (CDCl3,

470 MHz): δ (ppm) -144.44 (q, JB-F = 25.67 Hz); 11B ((CD3)2CO, 128 MHz) δ (ppm)

0.27 (t, JB-F = 26.11 Hz) ; HR-MS (ESI): m/z Calc. for C10H8N4B2F4Na 304.0805, found

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3 -1 -1 304.0809. mp = 251-253°C. UV/Vis (CH2Cl2): λ (nm) - 300 (ε = 4.9 x10 M .cm ); 424

(ε = 40.9 x103 M-1.cm-1); 442 (ε = 38.6 x103 M-1.cm-1). Emission (excitation at 424 nm):

λem (1) = 465 nm; λem (2) = 493 nm.

Synthesis of 27: The compound was synthesized in a similar manner as described above for 25 using 26 to afford 27 as a yellow powder with a yield of 38%. The product was recrystallized from methylene chloride/hexanes. Crystals suitable for single-crystal

X-ray diffraction were grown by slow evaporation of a solution of 27 in chloroform. 1H

NMR (CDCl3, 300 MHz): δ (ppm) 2.33 (s, 6H), 2.50 (s, 6H), 6.18 (s, 2H), 7.94 (s, 2H);

13 19 C NMR (CDCl3, 100 MHz): δ (ppm) 11.0, 14.1, 118, 123, 134, 141, 151; F (CDCl3,

11 470 MHz): δ (ppm) -142.45 (q, JB-F= 27.6 Hz); B (CDCl3, 128 MHz): δ (ppm) 0.58 (t,

JB-F = 29.32 Hz) ; HR-MS (ESI): m/z Calc. for C14H16N4B2F4Na 361.1395, found

3 -1 -1 361.1415. mp = 243-246°C. UV/Vis (CH2Cl2): λ (nm) - 312 (ε = 4.0 x10 M .cm ); 444

(ε = 37.5 x103 M-1.cm-1); 467 (ε = 37.4 x103 M-1.cm-1). Emission (excitation at 444 nm):

λem (1) = 485 nm; λem (2) = 518 nm.

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Table 4.1 - Crystal data and structure refinement for 25.

Identification code 25

Empirical formula C5H4BF2N2 Formula weight 140.91 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Monoclinic Space group C2/m a = 12.1963(16) Å α = 90° Unit cell dimensions b = 6.6666(12) Å β = 105.850(10)° c = 7.0140(11) Å γ = 90° 3 Volume 548.61(15) Å Z 4 3 Density (calculated) 1.706 Mg/m -1 Absorption coefficient 1.338 mm F(000) 284 3 Crystal size 0.47 x 0.26 x 0.17 mm Theta range for data collection 6.56 to 59.96°. Index ranges -13<=h<=12, -5<=k<=7, -7<=l<=7 Reflections collected 1345 Independent reflections 418 [R(int) = 0.0332] Completeness to theta = 59.96° 93.1 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.8005 and 0.5750 2 Refinement method Full-matrix least-squares on F Data / restraints / parameters 418 / 0 / 58 2 Goodness-of-fit on F 1.276 Final R indices [I>2sigma(I)] R1 = 0.0508, wR2 = 0.1556 R indices (all data) R1 = 0.0528, wR2 = 0.1578 -3 Largest diff. peak and hole 0.567 and -0.235 e.Å

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Table 4.2 - Crystal data and structure refinement for 26.

Identification code 26

Empirical formula C14 H20 N4 Formula weight 244.34 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Triclinic Space group P-1 Unit cell dimensions a = 8.9665(5) Å α = 89.782(3)° b = 9.2535(5) Å β = 82.210(3)° c = 9.3048(5) Å γ = 70.804(2)° Volume 721.69(7) Å3 Z 2 Density (calculated) 1.124 Mg/m3 Absorption coefficient 0.070 mm-1 F(000) 264 Crystal size 0.43 x 0.36 x 0.22 mm3 Theta range for data collection 2.21 to 25.02°. Index ranges -10<=h<=10, -10<=k<=11, -11<=l<=11 Reflections collected 10571 Independent reflections 2549 [R(int) = 0.0207] Completeness to theta = 25.02° 99.7 % Absorption correction SADABS Max. and min. transmission 0.9848 and 0.9705 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2549 / 0 / 167 Goodness-of-fit on F2 1.039 Final R indices [I>2sigma(I)] R1 = 0.0408, wR2 = 0.1064 R indices (all data) R1 = 0.0469, wR2 = 0.1112 Largest diff. peak and hole 0.195 and -0.185 e.Å-3

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Table 4.3 - Crystal data and structure refinement for 27.

Identification code 27

Empirical formula C14H16B2F4N4 Formula weight 337.93 Temperature 100(2) K Wavelength 1.54178 Å Crystal system Monoclinic Space group P2(1)/c a = 9.1674(3) Å α = 90° Unit cell dimensions b = 11.8374(4) Å β = 109.091(2)° c = 7.2745(3) Å γ = 90° 3 Volume 746.00(5) Å Z 2 3 Density (calculated) 1.504 Mg/m -1 Absorption coefficient 1.082 mm F(000) 348 3 Crystal size 0.24 x 0.22 x 0.20 mm Theta range for data collection 5.11 to 66.19°. Index ranges 0<=h<=10, -14<=k<=0, -8<=l<=7 Reflections collected 1247 Independent reflections 1247 [R(int) = 0.0000] Completeness to theta = 66.19° 95.6 % Absorption correction SADABS Max. and min. transmission 0.8119 and 0.7782 2 Refinement method Full-matrix least-squares on F Data / restraints / parameters 1247 / 0 / 111 2 Goodness-of-fit on F 1.059 Final R indices [I>2sigma(I)] R1 = 0.0325, wR2 = 0.0948 R indices (all data) R1 = 0.0349, wR2 = 0.0969 -3 Largest diff. peak and hole 0.258 and -0.177 e.Å

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Results and Discussion

For several years, Ziegler and coworkers have been investigating the chemistry of

282–286 Schiff base chelates as part of our work on the chemistry of Re(CO)3 compounds.

They have also been working with hydrazine as a reagent for the synthesis of phthalazines and phthalazine chelates.29 The reaction of aldehydes with hydrazine results in dimeric Schiff base structures, and pyrrole-2-carboxaldehyde readily reacts with hydrazine to form the pyrrole-imine dimeric chelate 24, shown in Scheme 4.1.281 This compound reacts readily with BF3 to form the BOPHY chromophore 25. I can also produce the tetramethyl substituted BOPHY analog (Me4BOPHY, 27) via the same two step procedure starting with the dimethyl substituted pyrrole-2-carboxylaldehyde via the intermediate 3. Compounds 25 and 27 can be readily purified via column chromatography using silica as the solid phase and methylene chloride as the eluent.

Subsequent evaporation of volatile components affords pure crystals of 25 and 27.

Scheme 4.1 - General synthesis of BOPHYs

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I elucidated the structure of BOPHY and Me4BOPHY via single crystal X-ray diffraction and the structures of the two compounds are shown in Figure 4.1. The structure of the free ligands (as seen in the case of the tetramethyl variant 26 shown in

Figure 4.1) led us to expect a five membered chelate ring with BF2, which has been seen upon metal ion coordination.287–289 However, I observe six member ring chelate formation, resulting in a molecule that has an inversion center (C2h symmetry). The chromophore is thus comprised of four rings, with two pyrrole units at the periphery and two six membered rings incorporating two BF2 groups. In the solid state, both 25 and 27 are rigidly planar, with only the fluorine atoms and the methyl hydrogen atoms in 27 deviating from the plane of the tetracycle. In 25 and 27, the bond lengths in the pyrrole units are similar to those seen in BODIPY type compounds and are indicative of aromaticity on the peripheral pyrrole units at the edge.157–159 The hydrazine-Schiff base moieties retain double and single bond character, although the C-N double bonds slightly increase in length in 25 and 27 by approximately 0.016 and 0.03 Å respectively versus the free ligands. This indicates that these compounds do not have aromaticity extended across the tetracycles. Several compounds have been recently reported that have features

290 similar to 25 and 27, including a bis-naphthyridine BF2 dimer and a series of isoindoline-based BF2 chromophores, however these are the first examples of a

139,224,230,236,291 hydrazine-based pyrrole-BF2 dimer.

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Figure 4.1 - The structures of 25, 26 and 27 with 35% thermal ellipsoids. Hydrogen atoms have been omitted for clarity. Grey, blue, orange and green ellipsoids represent C, N, B and F atoms respectively.

The absorption and emission spectra of 25 and 27 are shown in Figure 4.2. The unsubstituted BOPHY molecule 25 exhibits absorption maxima at 424 and 442 nm, with extinction coefficients of 4.09 x 104 M-1 cm-1 and 3.86 x 104 M-1 cm-1. The tetramethyl substituted variant 27 exhibits red shifted absorption bands, with absorbances at 444

(3.75 x 104 M-1 cm-1) and 467 nm (3.74 x 104 M-1 cm-1). Both compounds are strongly emissive and the quantum yields of emission in CH2Cl2 were close to unity, with values of 95 and 92% for 25 and 27 respectively. Both chromophores exhibit two emission bands, at 465 and 493 nm for 25 and 485 and 518 nm for compound 27. Like the

BODIPY fluorophores,156,164,166,167,185,292–294 both compounds 25 and 27 are stable in a variety of organic solvents; we observed a slight solvatochromism as their maximum

130

absorbance shifts of only 5-6 nm depending on the identity of the solvent (Figure 4.3 and

4.5). Moreover, the concentration-dependent absorbance of the dyes was measured in dichloromethane and we did not see any aggregation effect as no changes in the absorbance have been noted (Figure 4.4 and 4.6). To extend the comparison with

BODIPY dyes, the photostability of BOPHYs were studied. We observed that solutions of 25 and 27 are stable to light and air for days, as well as to extended UV irradiation

(365 nm, Figure 4.7). There are a couple of notable features in the absorption and emission spectra of both fluorophores. First, I observe a difference in the relative intensities of the absorption bands between these two compounds, with compound 25 having more intense absorption in the high energy band, whereas 27 has nearly equal absorptivity for both bands. Second, the emission profile is not the mirror image of the absorption and the higher energy emission is more intense than the lower energy emission in both 25 and 27. This is in apparent contradiction to Kasha’s rule, as will be discussed below.

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25, Abs 27, Abs 4 1 25, Em. 27, Em. 0.8

1) - 0.6 1.cm

- 2 M 4 0.4 (x10

ε 1 Normalized Intensity 0.2

0 0 300 350 400 450 500 550 600 650 λ (nm)

Figure 4.2 - Absorption and emission spectra for 25 and 27 in CH2Cl2

Ethyl Acetate 430 Toluene 1 420 DCM Acetone (nm)

DMF λ 410

0.8 MeCN 400 THF 0 0.1 0.2 0.3 0.4 0.5 Hexanes Relative Polarity 0.6

0.4 Normalized Normalized absorbance

0.2

0 350 400 450 500 λ (nm) Figure 4.3 - Normalized absorbance spectra of compound 25 in different solvents.

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1.2 19.2 uM 20.1 uM 22.0 uM 23.0 uM 1 24.9 uM 26.8 uM 27.8 uM 28.7 uM 0.8

0.6 Absorbance 0.4

0.2

0 280 320 360 400 440 480 λ (nm) Figure 4.4 - UV-Vis spectra of 25 in dichloromethane at different concentrations.

460 MeCN 450 DMF

1 440 EtOAc 430 (nm) Hexanes λ 420 Toluene 0.8 410 400 DCM 0 0.1 0.2 0.3 0.4 0.5 Relative Polarity 0.6

0.4 Normalized Normalized absorbance 0.2

0 350 400 450 500 λ (nm)

Figure 4.5 - Normalized absorbance spectra of compound 27 in different solvents

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32.5 μM 29.5 μM 1 27.1 μM 25.0 μM 23.2 μM 21.7 μM 0.8 20.3 μM 19.1 μM

0.6

0.4 Absorbance

0.2

0 300 350 400 450 500 λ (nm)

Figure 4.6 - UV-Vis spectra of 27 in dichloromethane at different concentrations.

0.9

0.8 27

0.7

0.6 Normalized Absorbance Normalized 0.5 0 100 200 300 400 500 Irradiation Time (min) Figure 4.7 - Change of optical density of 25 and 27 in toluene at the absorption maximum wavelength with the irradiation at 365 nm (4 W). Solutions were not degassed.

134

I also investigated the cyclic voltammetry of compounds 24-27, which can be seen in Figure 4.8. Cyclic voltammetry experiments were carried out in THF using tetrabutylammonium hexafluorophosate as the electrolyte. The free ligands show

+ irreversible reductions close to -0.5 V versus Ag /AgCl. Upon formation of the BF2 adducts, the reductions shift to lower potentials at approximately -0.90 and -0.80 V for 25 and 27. Compound 27 exhibits what appears to be a second irreversible reduction at about -1.05 V. These shifts to lower potentials were expected, due to the binding of the electron deficient BF2 unit, and correlate well with the red shift of the absorption bands of

24 and 26 to 25 and 27 respectively.

5 μA

27 25 26 24

1.5 1 0.5 0 -0.5 -1 -1.5 -2 + potential (V) vs Ag/Ag Figure 4.8 - Cyclic voltammograms of 24-27 in THF.

135

In order to explain absorption and emission spectra of 25 and 27, I have conducted density functional theory (DFT) and time-dependent DFT (TDDFT)

275–280 calculations on these systems. DFT calculations suggest that C2h geometries in 25 and 27 does not represent an energy minimum (Figure 4.9), while C2-symmetry (both boron atoms deviate from planarity toward one side) and Ci-symmetry (boron atoms deviate from planarity toward different sides) symmetries are the stationary points on the potential energy surfaces. The energy differences between C2 and Ci geometries are small

(1.3 - 1.6 kcal/mol) and the corresponding orbital energies and compositions are also very similar to each other (see Figure 4.9). The HOMOs in 25 and 27 are a π-type MO ~70% delocalized between the two pyrrole fragments with ~30% contribution from the N-N bridge, while LUMO is a π*-type MO and has ~90% pyrrolic and ~10% N-N bridge character as seen in the graphical representations of the frontier MOs in Figure 4.10 and

Figure 4.11 for 25 and 27 respectively. Both the HOMO and LUMO in 27 have higher energies than those in 25, reflecting electron-donating nature of the methyl groups.

HOMO in 27 undergoes larger degree of destabilization (~0.4 eV) than LUMO (~0.3 eV), which leads to its smaller HOMO-LUMO gap. The HOMO and HOMO-1 as well as the LUMO and LUMO+1 in 25 and 27 are energetically well-separated from each other

(~1 eV), which in turn (taking into consideration of the nature of C2h, C2, and Ci point groups) should result in the presence of only one low-energy band in their absorption spectra. Indeed, TDDFT-predicted absorption spectra of 25 and 27 in C2 and Ci symmetries (Figure 4.12) are in excellent agreement with the experimental data and clearly suggest that the strong band observed in a visible range for 25 and 27 is dominated by HOMO to LUMO excitation. TDDFT predicted ~25 nm red shift for the

136

first excited state in 27 compared to 25 in excellent agreement with the experimental data. In agreement with their electronic structure, the TDDFT-predicted energy of the second excited state is ~1 eV higher than the first excited state in 25 and 27 and correlates well with their experimentally observed band at ~320 nm. Thus, on the basis of their electronic structures and TDDFT calculations, it should be suggested that, similar to the other polycyclic systems, two low energy clear bands and the shoulder observed in the absorption spectra of 25 and 27 belong to the vibronic progression of the same excited state rather than to the different excited states. In agreement with this hypothesis, some structural reorganization in the excited state of 25 or 27 can result in slight change in the displacement (the relative intensities across the main vibronic progression) in the emission spectra of 25 and 27 compared to their absorption spectra (Figure 4.2).

Figure 4.9 - DFT predicted orbital energies for 25 and 27 with pictorial representation of the frontier MOs.

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90 N2 Pyrr-2 85 Pyrr-1 BF2-2 80 BF2-1

70 MO

60 Occupied Virtual

55 C2 0 10 20 30 40 50 60 70 80 90 100 Composition, % 90 N2_2 Pyrr_2 85 Pyrr_1 BF2_2 80 BF2_1

70 MO

65 Occupied Virtual 60

55 Ci 0 10 20 30 40 50 60 70 80 90 100 Comosition, % Figure 4.10 - PCM-DFT calculated (TPSSh/6-311G(d)) MO compositions of compound 25 in C2 (top) and Cs (bottom) symmetry

138

105 N2 Pyrr2 100 Pyrr1 BF2_2 95 BF2_1

85 MO number 80 Occupied Virtual

70 C2 Me4

0 10 20 30 40 50 60 70 80 90 100 Composition, %

105 N2 Pyrr2 100 Pyrr1 BF2_2 95 BF2_1

85 MO number 80 Occupied Virtual

70 Ci Me4

0 10 20 30 40 50 60 70 80 90 100 Composition, % Figure 4.11 - PCM-DFT calculated (TPSSh/6-311G(d)) MO compositions of compound 27 in C2 (top) and Cs (bottom) symmetry.

139

Figure 4.12 - Experimental (top) and TDDFT predicted (middle and bottom) absorption spectra of 25 and 27 in DCM.

C2 symmetry Ci symmetry

LUMO+1

LUMO

HOMO

HOMO+1

Figure 4.13 - PCM-DFT calculated (TPSSh/6-311G(d)) frontier MOs of compound 25.

140

C2 symmetry Ci symmetry

LUMO+1

LUMO

HOMO

HOMO+1

Figure 4.14 - PCM-DFT calculated (TPSSh/6-311G(d)) frontier MOs of compound 27.

In conclusion, the BOPHY architecture represents a new structural motif for highly fluorescent compounds. Compounds 25 and 27 have unusual absorption and emission properties that are not intuitive from their orbital configurations; we hypothesize that structural reorganization, such as vibronic coupling, may be involved.

141

Additionally, the BOPHY structural motif is an attractive target for functionalization at a variety of positions on the periphery, and we have investigated the methylated variant.

The Ziegler’s group is continuing their work on characterizing the photophysical properties of 25 and 27 as well as synthesizing structural variants.

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CHAPTER V

SUMMARY

Since the serendipitous discovery of phthalocyanines and 1,3-diiminoisoindoline

(DII) in the first half of the 20th century, the chemistry of these compounds and analogues

(ligands and macrocycles) have flourished and are now employed as photosensitizers, dyes and catalysts. However, the synthesis and chemistry of the simple derivatives of DII was left unexplored.

Following Linstead’s and Siegl’s methods, we were able to synthesize a series of bis(alkylimino)isoindolines and a novel macrocycle, the phthalocrown which are studied in the first part of this dissertation.

A phthalocrown is a chimera molecule, fusion of a phthalocyanine and a crown ether. Three different phthalocrowns were synthesized from the condensation of 1,3- diiminoisoindoline with an amino-ether. The first phthalocrown is a hemiporphyrazine analogue, product of the 2+2 condensation of DII and the mono-oxo diamine. 1H VT-

NMR study of the macrocycle shows the dynamic behavior of a proton between the isoindole nitrogen and the adjacent Schiff-base. The di- and trioxo diamine condense with DII in a 1+1 fashion. Both compounds were characterized by NMR and high resolution mass spectrometry. In the case of the di-oxo phthalocrown, two forms of crystal structures were obtained. In both cases, we observed the presence of an inter- and intra-molecular hydrogen bonding.

143

The tri-oxo phthalocrown is less stable than the previous studied. Indeed, it is sensitive to acid as it hydrolyzes to an oxo-phthalocrown which structure was elucidated.

The phthalocrowns are analogous to azacrowns, their metal chemistry ought to be similar, it is surmised that phthalocrowns would bind metal cations such as alkaline earth, transition and main-group metals and be used as phase-transfer catalysts like other DII- ligands and crown ether.

The third chapter of this dissertation focuses on bis(alkylimino)isoindolines. A series of seventeen compounds were synthesized and fully characterized by NMR, mass spectrometry and by X-ray crystallography. The study of these compounds in solution and solid states show that they have different conformations. In solution, 1H and 13C

NMR spectra suggest that these ligands are symmetric; however the study of the bond lengths in the crystal structure indicates an asymmetric conformation as the ionizable hydrogen is located on an external nitrogen atom. The reaction of AgNO3 with the benzyl and ethyl DII resulted to the formation of two different unusual complexes. The ethyl DII hydrolyzed and formed a silver dimer with an oxo-ethyl DII, while four benzyl DII chelate to a hexamer of silver cations.

In the last part of this dissertation, I continued working with Schiff-bases compounds. In this case, the condensation of pyrrole-2-carbaldehyde with hydrazine yielded to a conjugated symmetric ligand. By analogy with BODIPY, this ligand and its tetramethyl congener were reacted with BF3•Et2O to form a bis-BF2 pyrrolic complex, called BOPHYs. They are highly fluorescent with a quantum yield close to unity and stable in a variety of solvents and light. The photophysical properties of these compounds were studied and are found to be similar to BODIPYs. The advantage of BOPHYs is their

144

facile synthesis (Schiff-base condensation) with readily available starting materials.

Future research on these compounds will involve functionalization of the core similar to what it is being done with BODIPYs, in order to turn them into efficient fluorescent probes.

145

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