Preface

This book is both a review of current research and an undergraduate textbook for inorganic chemistry at university level. In university undergraduate lectures, basic concepts are main‐ ly explained and added examples of frontier research are optional. However, in many cases, frontier research is more interesting for students than basic studies. This book is aimed at undergraduates in inorganic chemistry. Each author introduces or reviews "frontier re‐ search topics" of inorganic coordination chemistry. Their application examples are indicated with "basic concepts" as found in textbooks on this subject. The chapters' topics are struc‐ tured as "frontier research topics" but also "related items" or concept in a typical standard textbook of inorganic chemistry.

> **Takashiro Akitsu** Department of Chemistry Faculty of Science Tokyo University of Science, Japan

**Chapter 1**

**Provisional chapter**

**Introductory Chapter: Concepts in Textbook and a**

**Introductory Chapter: Concepts in Textbook and a** 

DOI: 10.5772/intechopen.81684

The reason to propose the concept of this book is that some graduate students could not think their own researches in laboratory with related things learned in undergraduate textbooks. In order to overcome this issue, chapters in this book mention basic things of inorganic chemis-

In a conference [1], for example, we have recently reported the results of Z-scan NLO measurements for the analogous achiral organic ligands and metal complexes shown in **Figure 1**. As a promising renewable energy, a dye-sensitized solar cell (DSSC) is developing to improve performance of each materials and systems. From the view point of dye of metal complexes (or extended organic compounds), we have reported chiral Schiff base (salen-type) metal complexes. Induced CD from chiral Schiff base metal complexes containing azo-group has been also investigated for Au or TiO2 nanoparticles using their optical interaction so far.

Probably, the disagreement between researches and textbook may come from deviation (explained in brackets) from typical cases of definition (description) of terms (bold fonts). In

*Four-coordinated complexes (coordination numbers)*: A complex of four-coordinated coordination structure adopts two structures, tetrahedral type and square planar type. In tetrahedral type, metal atoms are steric repulsion such as large ligand is larger than electron factor (The com-

*Multidentate (chelate) ligands*: Ligands in which two or more atoms can simultaneously form two electrons (lone-pair) donor bonding to the same metal ion are called "multidentate" ligands in contrast to monodentate ligand. These ligands are also called as "chelate" ligands

this case, related things in basic inorganic chemistry are as follows:

plex in **Figure 1** is a square planar one having chelate ligand.)

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

**Study on Schiff Base Metal Complexes**

**Study on Schiff Base Metal Complexes**

Additional information is available at the end of the chapter

try as well as frontier research topics on purpose.

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.81684

Takashiro Akitsu

Takashiro Akitsu

**1. Introduction**

#### **Introductory Chapter: Concepts in Textbook and a Study on Schiff Base Metal Complexes Introductory Chapter: Concepts in Textbook and a Study on Schiff Base Metal Complexes**

DOI: 10.5772/intechopen.81684

Takashiro Akitsu Takashiro Akitsu

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.81684

## **1. Introduction**

The reason to propose the concept of this book is that some graduate students could not think their own researches in laboratory with related things learned in undergraduate textbooks. In order to overcome this issue, chapters in this book mention basic things of inorganic chemistry as well as frontier research topics on purpose.

In a conference [1], for example, we have recently reported the results of Z-scan NLO measurements for the analogous achiral organic ligands and metal complexes shown in **Figure 1**. As a promising renewable energy, a dye-sensitized solar cell (DSSC) is developing to improve performance of each materials and systems. From the view point of dye of metal complexes (or extended organic compounds), we have reported chiral Schiff base (salen-type) metal complexes. Induced CD from chiral Schiff base metal complexes containing azo-group has been also investigated for Au or TiO2 nanoparticles using their optical interaction so far.

Probably, the disagreement between researches and textbook may come from deviation (explained in brackets) from typical cases of definition (description) of terms (bold fonts). In this case, related things in basic inorganic chemistry are as follows:

*Four-coordinated complexes (coordination numbers)*: A complex of four-coordinated coordination structure adopts two structures, tetrahedral type and square planar type. In tetrahedral type, metal atoms are steric repulsion such as large ligand is larger than electron factor (The complex in **Figure 1** is a square planar one having chelate ligand.)

*Multidentate (chelate) ligands*: Ligands in which two or more atoms can simultaneously form two electrons (lone-pair) donor bonding to the same metal ion are called "multidentate" ligands in contrast to monodentate ligand. These ligands are also called as "chelate" ligands

**References**

[1] Akitsu T, Sato H, Kunitake F, Beppu I, Haraguchi T, Joe IH. Z-scan NLO of Schiff base metal complexes having azobenzene. In: 8th International Science Conference; 21-23

Introductory Chapter: Concepts in Textbook and a Study on Schiff Base Metal Complexes

http://dx.doi.org/10.5772/intechopen.81684

3

[2] Akitsu T. Lecture Notes: D,f-Block Inorganic Chemistry. Riga, Latvia: Scholars' Press;

[3] Akitsu T, editor. Integrating Approach to Photofunctional Hybrid Materials for Energy and the Environment. NY, USA: Nova Science Publishers, Inc.; 2013. ISBN:

[4] Akitsu T, editor. Descriptive Inorganic Chemistry Researches of Metal Compounds.

[5] Akitsu T, editor. Symmetry (Group Theory) and Mathematical Treatment in Chemistry.

November 2018; India: Jadavpur University

Rijeka, Croatia: InTech; 2017. ISBN: 978-953-51-3397-1

Rijeka, Croatia: InTech; 2018. ISBN: 978-1-78923-315-5

2018. ISBN: 978-620-2-30609-6

978-1-62417-638-8

**Figure 1.** (a) Molecular structure, (b) simulated UV-vis spectrum (DFT), (c) IR spectrum, and (d) diffuse reflectance UV-vis spectrum of a Schiff base Cu(II) complex.

and include bidentate, tridentate, tetradentate, etc. and various coordination sites. For example, ethylenediamine has (N,N) coordination atoms (The complex in **Figure 1** has a tetradentate (N,N,O,O) Schiff base ligand.)

*Electronic spectra (d-d transition)*: In order for the electronic state of a molecule to cause optical transition between d orbitals, the following "selection rule" exists. The d-d transitions occurring according to the selection rule are called allowed transitions, and the rest ones are called forbidden transitions. However, even for forbidden transitions, transitions may occur due to perturbation by vibration modes within the molecule. In **Figure 1**, UV-vis and IR spectra are exhibited. However, the intense bands in UV-vis spectrum are π-π\* band due to organic ligands.

In this way, it is a wish of the editor to master basic concepts [2] in advanced researches [3–5] mainly for graduate students.

### **Author details**

Takashiro Akitsu

Address all correspondence to: akitsu@rs.kagu.tus.ac.jp

Department of Chemistry, Faculty of Science, Tokyo University of Science, Tokyo, Japan

### **References**

and include bidentate, tridentate, tetradentate, etc. and various coordination sites. For example, ethylenediamine has (N,N) coordination atoms (The complex in **Figure 1** has a tetraden-

**Figure 1.** (a) Molecular structure, (b) simulated UV-vis spectrum (DFT), (c) IR spectrum, and (d) diffuse reflectance

*Electronic spectra (d-d transition)*: In order for the electronic state of a molecule to cause optical transition between d orbitals, the following "selection rule" exists. The d-d transitions occurring according to the selection rule are called allowed transitions, and the rest ones are called forbidden transitions. However, even for forbidden transitions, transitions may occur due to perturbation by vibration modes within the molecule. In **Figure 1**, UV-vis and IR spectra are exhibited. However, the intense bands in UV-vis spectrum are π-π\* band due

In this way, it is a wish of the editor to master basic concepts [2] in advanced researches [3–5]

Department of Chemistry, Faculty of Science, Tokyo University of Science, Tokyo, Japan

tate (N,N,O,O) Schiff base ligand.)

UV-vis spectrum of a Schiff base Cu(II) complex.

2 Basic Concepts Viewed from Frontier in Inorganic Coordination Chemistry

to organic ligands.

**Author details**

Takashiro Akitsu

mainly for graduate students.

Address all correspondence to: akitsu@rs.kagu.tus.ac.jp


**Chapter 2**

H5 ) 4 ;

(C<sup>5</sup> H5 ) <sup>−</sup>; and

**Provisional chapter**

**Modern Techniques in Synthesis of Organometallic**

**Modern Techniques in Synthesis of Organometallic** 

Germanium is one of the most significant semiconductors to be used for electronic devices due to small bandgap and high intrinsic mobility of holes and electrons. Germanium has received a large attention due to its extraordinary reactivity and properties. It is commonly used in fluorescent lamps and as catalyst as well to produce various types of plastic. Germanium nanomaterials have broad range of applications from photovoltaic devices to phase-change memory materials. Germanium forms complexes by reacting with numerous elements such as carbon, oxygen, nitrogen, hydrogen, and phosphorous as a part of several organic compounds. Germanium coordinates with these elements by single, double, and triple linkages. Interestingly, all such reactions occur at ambient temperature usually in tetrahydrofuran under vacuum. Germanium may also react directly with primary and secondary nitrogen in the presence of a suitable base, whereas with tertiary nitrogen, it may react directly even in the absence of a base. Nevertheless, this chapter describes the

modern techniques in synthesis of organometallic compounds of germanium. **Keywords:** germylene, organometallic germanium, germanium coordination

> -C<sup>5</sup> H5 ) 2

Organometallic compounds may be defined as *the compounds having at least one metal-carbon bond in a molecule*. This bond may be covalent in nature as in tetraethyl lead, Pb(C<sup>2</sup>

more interestingly, coordinate covalent as in silver(I)-*N*-heterocyclic carbene, Ag(NHC)<sup>2</sup> (**Figure 1**). However, the mentioned definition is not limited to metal-carbon bond only; there are several other examples where metal-nitrogen, metal-boron, metal-hydrogen, metal-oxygen,

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

; ionic as in potassium cyclopentadienyl, K<sup>+</sup>

DOI: 10.5772/intechopen.79985

**Compounds of Germanium**

**Compounds of Germanium**

http://dx.doi.org/10.5772/intechopen.79985

**Abstract**

**1. Introduction**

pi-dative as in chromocene, Cr(η<sup>5</sup>

Hina Hayat and Muhammad Adnan Iqbal

Hina Hayat and Muhammad Adnan Iqbal

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

#### **Modern Techniques in Synthesis of Organometallic Compounds of Germanium Modern Techniques in Synthesis of Organometallic Compounds of Germanium**

DOI: 10.5772/intechopen.79985

Hina Hayat and Muhammad Adnan Iqbal Hina Hayat and Muhammad Adnan Iqbal

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.79985

### **Abstract**

Germanium is one of the most significant semiconductors to be used for electronic devices due to small bandgap and high intrinsic mobility of holes and electrons. Germanium has received a large attention due to its extraordinary reactivity and properties. It is commonly used in fluorescent lamps and as catalyst as well to produce various types of plastic. Germanium nanomaterials have broad range of applications from photovoltaic devices to phase-change memory materials. Germanium forms complexes by reacting with numerous elements such as carbon, oxygen, nitrogen, hydrogen, and phosphorous as a part of several organic compounds. Germanium coordinates with these elements by single, double, and triple linkages. Interestingly, all such reactions occur at ambient temperature usually in tetrahydrofuran under vacuum. Germanium may also react directly with primary and secondary nitrogen in the presence of a suitable base, whereas with tertiary nitrogen, it may react directly even in the absence of a base. Nevertheless, this chapter describes the modern techniques in synthesis of organometallic compounds of germanium.

**Keywords:** germylene, organometallic germanium, germanium coordination

### **1. Introduction**

Organometallic compounds may be defined as *the compounds having at least one metal-carbon bond in a molecule*. This bond may be covalent in nature as in tetraethyl lead, Pb(C<sup>2</sup> H5 ) 4 ; pi-dative as in chromocene, Cr(η<sup>5</sup> -C<sup>5</sup> H5 ) 2 ; ionic as in potassium cyclopentadienyl, K<sup>+</sup> (C<sup>5</sup> H5 ) <sup>−</sup>; and more interestingly, coordinate covalent as in silver(I)-*N*-heterocyclic carbene, Ag(NHC)<sup>2</sup> (**Figure 1**). However, the mentioned definition is not limited to metal-carbon bond only; there are several other examples where metal-nitrogen, metal-boron, metal-hydrogen, metal-oxygen,

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Germanium monocations may demonstrate both nucleophilic and electrophilic properties. Aminotroponiminate GeII monocation was synthesized by elimination of chloride from par-

tions may demonstrate both nucleophilic and electrophilic properties. Aminotroponiminate GeII monocation was synthesized by elimination of chloride from particular chlorogermylene

**C1** (cholorogermyliumylidene) was obtained by reacting 1 equivalent of **L1** (a free bis-NHC)

sphere (**Scheme 1**). The reaction mixture was stirred overnight to isolate **C1** as white precipitates. Single crystals of **C1** were grown by slow evaporation at 4°C in acetonitrile. NHC-Ge bond was confirmed by 13C NMR by obtaining a chemical shift at δ166.3 ppm. **C1** was further reacted with a dark green solution of sodium naphthalene in THF very carefully. According to the reported procedure, 1 equivalent of naphthalene was stirred in THF overnight with 1 equivalent of sodium metal to obtain sodium naphthalenide. A suspension of half equivalent of **C2** in THF (at −30°C) was added to the sodium naphthalenide solution at −30°C, and the

mixture was stirred to bring the reaction mixture temperature up to 0°C in about 3 h.

The volatilities were removed under vacuum, and the residue was washed with cold THF during filtration. Single dark red-colored crystals, suitable for X-ray crystallography, of **C2** were


as a halide scavenger [7]. Germanium monoca-

http://dx.doi.org/10.5772/intechopen.79985

7

Modern Techniques in Synthesis of Organometallic Compounds of Germanium

in THF at −20°C (cooling method). The formation


as a halide scavenger [7].

**2. Germanium complexes involving bonding through carbon (C)**

ticular chlorogermylene using (η<sup>5</sup>

obtained by a concentrated solution of C<sup>2</sup>

**Scheme 1.** Synthesis of Ge compounds involving bonding through carbon.

using (η<sup>5</sup>

with GeCl<sup>2</sup>


**Figure 1.** Different types of organometallic compounds having metal-carbon bonds.

metal-sulfur, etc. bonds are also included in organometallic chemistry. Nevertheless, their bonding way is uniquely different than in coordination compounds, which makes them organometallic compounds instead of coordination compounds. For instance, just keep in mind that metal-carbon bond-containing compounds are organometallic in nature.

The current chapter describes organometallic compounds of germanium. Germanium was exposed by Clemens Winkler in 1886, and its initial wide application was in the formation of point-contact Schottky diodes for radar response during WWII. Germanium is a conventional electronic material. The history of element germanium is at the closely same era as the story of transition from physics of dirt to beginning of recent semiconductor physics. The revelation of point-contact transistor of germanium by J. Bardeen and W. Brattain on Christmas Eve 1947 was followed by the discovery of germanium junction transistor by W. Shockley that represents the establishment of semiconductor age. The years succeeding the findings of germanium did not show any main scientific conclusion and technological applications for this expensive, brittle, rare, and metal-like element. F.W. Aston found three reasonably stable isotopes, namely, 70Ge, 72Ge, and 74Ge in 1923. In the 1930s, germanium was supposed to be a bad conducting metal [1].

Germanium is one of the most significant semiconductors used for electronics due to small bandgap and high intrinsic mobility of holes and electrons. Germanium oxides are hygroscopic and water soluble. GeO<sup>2</sup> is thermally unstable and it is transformed into volatile germanium monoxide (GeO) [2]. Germanium compounds have great importance due to their distinctive applications in electronic field. Geranium films also gained attention due to their use in phase-change random access memory (PRAM) devices. They have fascinating great deal of interest due to high endurance, nonvolatility, and higher programming speed. GST (Ge<sup>2</sup> Sb<sup>2</sup> Te<sup>5</sup> ) mainly is a well-liked phase-change substance for phase-change random access memory devices [3]. Group 14 elements have extensive variety of application from photovoltaic devices to PRAM material [4].

Group 14 elements usually have wide significance because of their unusual properties. In recent times, surprising application of alkoxy germylenes has been described. Alkoxy germylene has been used as precursors of nanomaterials. Hypermetallyl germylenes may be appropriate for the preparation of nanomaterial alloys because hypermetallyl germylenes contain good leaving substituent and a low coordinate atom of group 14. Hypergermyl ligands demonstrate limitations of steric shielding for stabilization of low coordinate species [5].

In earlier period, germylene compounds were used for transition metals as ligands due to their potential. Germylenes have been paying interest in organic chemistry. Germylenes are highly reactive derivatives and can be stabilized by sterically challenging substituent [6]. Germanium monocations may demonstrate both nucleophilic and electrophilic properties. Aminotroponiminate GeII monocation was synthesized by elimination of chloride from particular chlorogermylene using (η<sup>5</sup> -C<sup>5</sup> H5 ) ZrCl3 as a halide scavenger [7]. Germanium monocations may demonstrate both nucleophilic and electrophilic properties. Aminotroponiminate GeII monocation was synthesized by elimination of chloride from particular chlorogermylene using (η<sup>5</sup> -C<sup>5</sup> H5 ) ZrCl3 as a halide scavenger [7].

### **2. Germanium complexes involving bonding through carbon (C)**

metal-sulfur, etc. bonds are also included in organometallic chemistry. Nevertheless, their bonding way is uniquely different than in coordination compounds, which makes them organometallic compounds instead of coordination compounds. For instance, just keep in

The current chapter describes organometallic compounds of germanium. Germanium was exposed by Clemens Winkler in 1886, and its initial wide application was in the formation of point-contact Schottky diodes for radar response during WWII. Germanium is a conventional electronic material. The history of element germanium is at the closely same era as the story of transition from physics of dirt to beginning of recent semiconductor physics. The revelation of point-contact transistor of germanium by J. Bardeen and W. Brattain on Christmas Eve 1947 was followed by the discovery of germanium junction transistor by W. Shockley that represents the establishment of semiconductor age. The years succeeding the findings of germanium did not show any main scientific conclusion and technological applications for this expensive, brittle, rare, and metal-like element. F.W. Aston found three reasonably stable isotopes, namely, 70Ge, 72Ge, and 74Ge in 1923. In the 1930s, germanium was supposed to be a

Germanium is one of the most significant semiconductors used for electronics due to small bandgap and high intrinsic mobility of holes and electrons. Germanium oxides are hygro-

manium monoxide (GeO) [2]. Germanium compounds have great importance due to their distinctive applications in electronic field. Geranium films also gained attention due to their use in phase-change random access memory (PRAM) devices. They have fascinating great deal of interest due to high endurance, nonvolatility, and higher programming speed. GST

memory devices [3]. Group 14 elements have extensive variety of application from photovol-

Group 14 elements usually have wide significance because of their unusual properties. In recent times, surprising application of alkoxy germylenes has been described. Alkoxy germylene has been used as precursors of nanomaterials. Hypermetallyl germylenes may be appropriate for the preparation of nanomaterial alloys because hypermetallyl germylenes contain good leaving substituent and a low coordinate atom of group 14. Hypergermyl ligands dem-

In earlier period, germylene compounds were used for transition metals as ligands due to their potential. Germylenes have been paying interest in organic chemistry. Germylenes are highly reactive derivatives and can be stabilized by sterically challenging substituent [6].

onstrate limitations of steric shielding for stabilization of low coordinate species [5].

) mainly is a well-liked phase-change substance for phase-change random access

is thermally unstable and it is transformed into volatile ger-

mind that metal-carbon bond-containing compounds are organometallic in nature.

**Figure 1.** Different types of organometallic compounds having metal-carbon bonds.

6 Basic Concepts Viewed from Frontier in Inorganic Coordination Chemistry

bad conducting metal [1].

(Ge<sup>2</sup> Sb<sup>2</sup> Te<sup>5</sup>

scopic and water soluble. GeO<sup>2</sup>

taic devices to PRAM material [4].

**C1** (cholorogermyliumylidene) was obtained by reacting 1 equivalent of **L1** (a free bis-NHC) with GeCl<sup>2</sup> -dioxane in dry tetrahydrofuran (THF) at room temperature under an inert atmosphere (**Scheme 1**). The reaction mixture was stirred overnight to isolate **C1** as white precipitates. Single crystals of **C1** were grown by slow evaporation at 4°C in acetonitrile. NHC-Ge bond was confirmed by 13C NMR by obtaining a chemical shift at δ166.3 ppm. **C1** was further reacted with a dark green solution of sodium naphthalene in THF very carefully. According to the reported procedure, 1 equivalent of naphthalene was stirred in THF overnight with 1 equivalent of sodium metal to obtain sodium naphthalenide. A suspension of half equivalent of **C2** in THF (at −30°C) was added to the sodium naphthalenide solution at −30°C, and the mixture was stirred to bring the reaction mixture temperature up to 0°C in about 3 h.

The volatilities were removed under vacuum, and the residue was washed with cold THF during filtration. Single dark red-colored crystals, suitable for X-ray crystallography, of **C2** were obtained by a concentrated solution of C<sup>2</sup> in THF at −20°C (cooling method). The formation

**Scheme 1.** Synthesis of Ge compounds involving bonding through carbon.

of NHC-Ge bond was confirmed by 13C NMR where the respective chemical shift appeared at δ 196.1 ppm, which is interestingly much downfield compared to **C1** [8]. Compound **C3** can be prepared through *in situ* path, adding 1 equivalent of GaCl3 in a solution of **C2** in THF at room temperature and stirring the reaction mixture for about 2 h. The volatilities are removed under vacuum, and the product can be extracted by THF. The single crystals of **C3** suitable for X-ray crystallography were obtained by cooling a concentrated solution of it in acetonitrile to 4°C. The 13C NMR showed chemical shift of NHC-Ge at δ 174.16 ppm. This upfield movement of chemical shift might be because of electron drift from gallium toward NHC.

Synthesis of another NHC-Ge adduct **C4** was achieved by adding a dropwise solution of 1 equivalent of **L2** (NHC-GeCl<sup>2</sup> ) in 1 equivalent of Mg[Ge(SiCH3 ) 3 ]2 .2THF in THF at −60°C (**Scheme 2**). The solution was then stirred at room temperature for 2 days to obtain the required product as precipitates. At the end, volatile components were removed under reduced pressure to obtain red residue, washed with pentane, and orange red product was isolated in 45% yield. 13C NMR indicated the formation of NHC-Ge bond by showing a chemical shift at δ 173.9 ppm for the bonded carbene carbon [5]. The synthesis of derivative **C5** from **L2** can be achieved by adding a THF solution of 1 equivalent of Mg[Sn(SiCH3 )3 ] 2 .2THF into a THF solution of **L2** at −78°C, and the mixture is slowly warmed to room temperature in 12 h with consistent stirring. The solvent and other volatilities were removed from the reaction mixture under vacuum, and the residue was extracted with pentane, which was filtered and the filtrate was evaporated to obtain **C5** as orange red powder. Single crystals of orange color were obtained by slow evaporation of saturated solution of **C5** in pentane at −24°C. 13C NMR indicated the NHC-Ge chemical shift at δ 175.5 ppm, whereas 119Sn NMR indicated the chemical shift for bonded tin at δ −589.7 ppm [5].

and then red. The product was obtained with hexane and the extract was stored at −30°C for 16 h. At −30°C, mother liquor was removed by filtration of mixture. At room temperature, precipitate was dried in vacuum for 1 h. End product was extracted as orange red crystalline material in 73% yield. Melting point of the extracted product was 85°C. Production of **C7**

complex, **C7**.

**C6** at room temperature. The solution color changed from red orange to red brown during

under vacuum, and the residue was dissolved in toluene-hexane mixture for the purpose of extracting the required material. The extract was concentrated and few drops of n-hexane were added on it, and then it was cooled to −60°C and stored for 16 h at the same temperature

**C8** (chlorogermyliumylidene) was formed by reacting **L4** (1,8-bis (tributylphosphazenyl)-

dioxane into a solution of **L8** in toluene at ambient temperature generates white precipitates

**C9** [(ButNacnac)Ge:] was obtained by mixing **L5** solution in toluene with [(MesNacnac)Mg]<sup>2</sup>

toluene at −80°C for 5 min (**Scheme 5**). The mixture was then warmed slowly for 6 h at 0°C, and during this period of time, the mixture turned deep red colored. The residue was extracted into cold hexane at 0°C, and volatiles were removed in vacuum. The product was stored at −30°C overnight. At the end, purple-red crystals were formed in 38% isolated yield [11].

to isolate the red-brown crystals of **C7** from mother liquor in 69% yield [9].

Mo·GeC(SiCH3

)3

**3. Germanium complexes involving bonding through nitrogen (N)**

of the desired ionic species, which can be filtered from the reaction medium [8, 10].

(tetramethyl imidazolium salt) solution was added slowly in

Modern Techniques in Synthesis of Organometallic Compounds of Germanium

http://dx.doi.org/10.5772/intechopen.79985

9

. Solution was stirred continuously for 30 min. All volatiles were removed



in

was achieved when an Im-Me<sup>4</sup>

**Scheme 3.** Synthesis of [Cp(CO)<sup>2</sup>

addition of Im-Me<sup>4</sup>

naphthalene) with GeCl<sup>2</sup>

**C6** was formed by dissolving **L3** to a solution of GeCl<sup>2</sup> at 0°C. After stirring the reaction mixture at 0°C for 15 min, the cooling bath was removed and mixture was kept stirred continuously at room temperature for 1 h. Yellow solid was obtained after removing all solvent in vacuum. The mixture (yellow solid) was treated with precooled toluene at 0°C with the addition of Li[CpMo(CO)3 ] and again stirred continuously for next 2.5 h (**Scheme 3**). The mixture was warmed at room temperature and solution color changed from yellow to brown

**Scheme 2.** Synthesis of NHC-stabilized hypermetallyl germylene.

Modern Techniques in Synthesis of Organometallic Compounds of Germanium http://dx.doi.org/10.5772/intechopen.79985 9

**Scheme 3.** Synthesis of [Cp(CO)<sup>2</sup> Mo·GeC(SiCH3 )3 complex, **C7**.

of NHC-Ge bond was confirmed by 13C NMR where the respective chemical shift appeared at δ 196.1 ppm, which is interestingly much downfield compared to **C1** [8]. Compound **C3** can

room temperature and stirring the reaction mixture for about 2 h. The volatilities are removed under vacuum, and the product can be extracted by THF. The single crystals of **C3** suitable for X-ray crystallography were obtained by cooling a concentrated solution of it in acetonitrile to 4°C. The 13C NMR showed chemical shift of NHC-Ge at δ 174.16 ppm. This upfield movement

Synthesis of another NHC-Ge adduct **C4** was achieved by adding a dropwise solution of

(**Scheme 2**). The solution was then stirred at room temperature for 2 days to obtain the required product as precipitates. At the end, volatile components were removed under reduced pressure to obtain red residue, washed with pentane, and orange red product was isolated in 45% yield. 13C NMR indicated the formation of NHC-Ge bond by showing a chemical shift at δ 173.9 ppm for the bonded carbene carbon [5]. The synthesis of derivative **C5** from

a THF solution of **L2** at −78°C, and the mixture is slowly warmed to room temperature in 12 h with consistent stirring. The solvent and other volatilities were removed from the reaction mixture under vacuum, and the residue was extracted with pentane, which was filtered and the filtrate was evaporated to obtain **C5** as orange red powder. Single crystals of orange color were obtained by slow evaporation of saturated solution of **C5** in pentane at −24°C. 13C NMR indicated the NHC-Ge chemical shift at δ 175.5 ppm, whereas 119Sn NMR indicated the

mixture at 0°C for 15 min, the cooling bath was removed and mixture was kept stirred continuously at room temperature for 1 h. Yellow solid was obtained after removing all solvent in vacuum. The mixture (yellow solid) was treated with precooled toluene at 0°C with the

mixture was warmed at room temperature and solution color changed from yellow to brown

] and again stirred continuously for next 2.5 h (**Scheme 3**). The

) in 1 equivalent of Mg[Ge(SiCH3

of chemical shift might be because of electron drift from gallium toward NHC.

**L2** can be achieved by adding a THF solution of 1 equivalent of Mg[Sn(SiCH3

in a solution of **C2** in THF at

.2THF in THF at −60°C

) 3 ]2

at 0°C. After stirring the reaction

.2THF into

) 3 ]2

be prepared through *in situ* path, adding 1 equivalent of GaCl3

8 Basic Concepts Viewed from Frontier in Inorganic Coordination Chemistry

1 equivalent of **L2** (NHC-GeCl<sup>2</sup>

addition of Li[CpMo(CO)3

chemical shift for bonded tin at δ −589.7 ppm [5].

**Scheme 2.** Synthesis of NHC-stabilized hypermetallyl germylene.

**C6** was formed by dissolving **L3** to a solution of GeCl<sup>2</sup>

and then red. The product was obtained with hexane and the extract was stored at −30°C for 16 h. At −30°C, mother liquor was removed by filtration of mixture. At room temperature, precipitate was dried in vacuum for 1 h. End product was extracted as orange red crystalline material in 73% yield. Melting point of the extracted product was 85°C. Production of **C7** was achieved when an Im-Me<sup>4</sup> (tetramethyl imidazolium salt) solution was added slowly in **C6** at room temperature. The solution color changed from red orange to red brown during addition of Im-Me<sup>4</sup> . Solution was stirred continuously for 30 min. All volatiles were removed under vacuum, and the residue was dissolved in toluene-hexane mixture for the purpose of extracting the required material. The extract was concentrated and few drops of n-hexane were added on it, and then it was cooled to −60°C and stored for 16 h at the same temperature to isolate the red-brown crystals of **C7** from mother liquor in 69% yield [9].

### **3. Germanium complexes involving bonding through nitrogen (N)**

**C8** (chlorogermyliumylidene) was formed by reacting **L4** (1,8-bis (tributylphosphazenyl) naphthalene) with GeCl<sup>2</sup> -dioxane in 60% isolated yield (**Scheme 4**). The addition of GeCl<sup>2</sup> dioxane into a solution of **L8** in toluene at ambient temperature generates white precipitates of the desired ionic species, which can be filtered from the reaction medium [8, 10].

**C9** [(ButNacnac)Ge:] was obtained by mixing **L5** solution in toluene with [(MesNacnac)Mg]<sup>2</sup> in toluene at −80°C for 5 min (**Scheme 5**). The mixture was then warmed slowly for 6 h at 0°C, and during this period of time, the mixture turned deep red colored. The residue was extracted into cold hexane at 0°C, and volatiles were removed in vacuum. The product was stored at −30°C overnight. At the end, purple-red crystals were formed in 38% isolated yield [11].

**Scheme 4.** Synthesis of β-diketiminate germanium complex.

**Scheme 5.** Synthesis of [(ButNacnac)Ge:] complex.

**C10** was formed when a colored solution of **L6** in diethyl ether was added into [RhCl(cod)]<sup>2</sup> solution in diethylether at −78°C (**Scheme 6**). The solution was placed at room temperature for 45 min. Then, the solution was stirred continuously for another 45 min. After filtration, the solvent was concentrated under reduced pressure. Yellow crystals were obtained in 49% isolated yield. Melting point of the product was 91°C. Reaction was occurred in dry and oxygenfree atmosphere of argon by using glove box techniques. Synthesis of **C11** was carried out in NMR tube. A solution of **C10** in deuterated tetrahydrofuran was contacted with carbon monoxide atmosphere at −80°C. The ligand exchange reaction was completed in less than 10 min as per monitoring by 1 H NMR [12].

The resulting product was separated as yellow crystals in 67.5% isolated yield. Melting point

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**C14** was formed when slurry of tellurium suspended in toluene was added dropwise in 1-Cy solution (**Scheme 9**). Mixture was continuously stirred at ambient temperature for 24 h, meanwhile mixture color changed from purple to red. After filtration, the reaction mixture was concentrated under vacuum. Mixture was stored for 24 h at −27°C to obtain red crystals

of the resulting product was 206.5°C [13].

**Scheme 6.** Synthesis of the germylenedicarbonylrhodium(I) complex, **C11**.

of the product [4].

**C12**.[BF<sup>4</sup> ] was formed by reacting amino(imino)germylene in toluene with BF3 ·OEt<sup>2</sup> at −78°C (**Scheme 7**). The reaction mixture was stirred for 12 h, and during this course of time, it was allowed to slowly warm to the room temperature. Evaporation of solvent and washing residual material with diethyl ether provided the required compound as a yellow powder, which in turn provided compound as colorless crystals suitable for X-ray diffraction on recrystallization by THF. **C12** was formed via the intermediate fluorogermylene dimer [FGeNIPr]<sup>2</sup> as suggested by DFT calculations. The boron tetrafluoride played the role of fluorination reagent as well as fluoride abstraction agent. Multinuclear NMR spectroscopy was used to confirm the formulation of **C12** [BF<sup>4</sup> ]. The researchers found a highly disordered germanium-bonded fluorine atom by single crystal X-ray structure analysis, which possesses 50% site occupancy factor at each of the two germanium atoms [7].

**C13** was formed when a dark green solution of **L13** was added to a suspension of selenium powder in THF at 0°C (**Scheme 8**). Reaction can occur in the absence of light. A yellow solution was formed when mixture was stirred continuously at room temperature for 2 days. The residue was extracted with toluene and hexane, and volatiles were removed under vacuum. Modern Techniques in Synthesis of Organometallic Compounds of Germanium http://dx.doi.org/10.5772/intechopen.79985 11

**Scheme 6.** Synthesis of the germylenedicarbonylrhodium(I) complex, **C11**.

**C10** was formed when a colored solution of **L6** in diethyl ether was added into [RhCl(cod)]<sup>2</sup> solution in diethylether at −78°C (**Scheme 6**). The solution was placed at room temperature for 45 min. Then, the solution was stirred continuously for another 45 min. After filtration, the solvent was concentrated under reduced pressure. Yellow crystals were obtained in 49% isolated yield. Melting point of the product was 91°C. Reaction was occurred in dry and oxygenfree atmosphere of argon by using glove box techniques. Synthesis of **C11** was carried out in NMR tube. A solution of **C10** in deuterated tetrahydrofuran was contacted with carbon monoxide atmosphere at −80°C. The ligand exchange reaction was completed in less than

H NMR [12].

] was formed by reacting amino(imino)germylene in toluene with BF3

(**Scheme 7**). The reaction mixture was stirred for 12 h, and during this course of time, it was allowed to slowly warm to the room temperature. Evaporation of solvent and washing residual material with diethyl ether provided the required compound as a yellow powder, which in turn provided compound as colorless crystals suitable for X-ray diffraction on recrystallization by THF. **C12** was formed via the intermediate fluorogermylene dimer [FGeNIPr]<sup>2</sup>

suggested by DFT calculations. The boron tetrafluoride played the role of fluorination reagent as well as fluoride abstraction agent. Multinuclear NMR spectroscopy was used to confirm

fluorine atom by single crystal X-ray structure analysis, which possesses 50% site occupancy

**C13** was formed when a dark green solution of **L13** was added to a suspension of selenium powder in THF at 0°C (**Scheme 8**). Reaction can occur in the absence of light. A yellow solution was formed when mixture was stirred continuously at room temperature for 2 days. The residue was extracted with toluene and hexane, and volatiles were removed under vacuum.

]. The researchers found a highly disordered germanium-bonded

·OEt<sup>2</sup>

at −78°C

as

10 min as per monitoring by 1

**Scheme 5.** Synthesis of [(ButNacnac)Ge:] complex.

**Scheme 4.** Synthesis of β-diketiminate germanium complex.

10 Basic Concepts Viewed from Frontier in Inorganic Coordination Chemistry

the formulation of **C12** [BF<sup>4</sup>

factor at each of the two germanium atoms [7].

**C12**.[BF<sup>4</sup>

The resulting product was separated as yellow crystals in 67.5% isolated yield. Melting point of the resulting product was 206.5°C [13].

**C14** was formed when slurry of tellurium suspended in toluene was added dropwise in 1-Cy solution (**Scheme 9**). Mixture was continuously stirred at ambient temperature for 24 h, meanwhile mixture color changed from purple to red. After filtration, the reaction mixture was concentrated under vacuum. Mixture was stored for 24 h at −27°C to obtain red crystals of the product [4].

**Scheme 7.** Synthesis of germyliumylidene salt **C12**.[BF<sup>4</sup> ].

**4. Germanium complexes involving bonding through carbon and** 

**Scheme 9.** β-Diketiminate germylene-supported pentafluorophenylcopper(I) and -silver(I) complexes.

F5 )4

toluene using a glove box with a consistent stirring. A quick color change was observed from orange red to light yellow. The mixture was further stirred continuously for next 2 h. After filtration, the filtrate was kept unattended at −20°C. After 5 days, crystals grew and the mixture was filtered and light yellow crystals of **C15** were obtained in 81% isolated yield. The X-ray crystallography showed that complex carries two toluene molecules packed during crystal growth. Melting point of the crystal was 206°C [14]. One more product was formed

hour, the mixture was stirred and toluene was continuously added until all solids dissolved. After filtration, the filtrate was overlayered with n-hexane and placed unattended at −20°C for 2 days. After 48 h, light yellow crystals of **C16** were collected by filtration in 71% isolated

**C17** was synthesized by mixing n-butyl lithium dropwise to a solution of **L11** in THF at −78°C

−78°C. The resulting product was reddish brown. The reddish brown solution was warmed gradually at room temperature and stirred overnight. The residue was extracted with dichloromethane, and solvent was removed under vacuum. Lithium chloride was filtered off, and the filtrate was concentrated. Orange crystals of **C17** were obtained in 47% isolated yield.

in toluene was added to a solution of **L10** in

·dioxane was added to reaction mixture at

CN in a brown vial in the presence of toluene. For half an

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**nitrogen (C, N)**

by mixing **L10** with AgC6

**C15** was formed when a solution of (CuC6

F5 ·CH3

yield. Melting point of the crystals was 156°C [14].

(**Scheme 10**). After 3 h stirring of mixture, GeCl<sup>2</sup>

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**Scheme 9.** β-Diketiminate germylene-supported pentafluorophenylcopper(I) and -silver(I) complexes.

### **4. Germanium complexes involving bonding through carbon and nitrogen (C, N)**

**C15** was formed when a solution of (CuC6 F5 ) 4 in toluene was added to a solution of **L10** in toluene using a glove box with a consistent stirring. A quick color change was observed from orange red to light yellow. The mixture was further stirred continuously for next 2 h. After filtration, the filtrate was kept unattended at −20°C. After 5 days, crystals grew and the mixture was filtered and light yellow crystals of **C15** were obtained in 81% isolated yield. The X-ray crystallography showed that complex carries two toluene molecules packed during crystal growth. Melting point of the crystal was 206°C [14]. One more product was formed by mixing **L10** with AgC6 F5 ·CH3 CN in a brown vial in the presence of toluene. For half an hour, the mixture was stirred and toluene was continuously added until all solids dissolved. After filtration, the filtrate was overlayered with n-hexane and placed unattended at −20°C for 2 days. After 48 h, light yellow crystals of **C16** were collected by filtration in 71% isolated yield. Melting point of the crystals was 156°C [14].

**C17** was synthesized by mixing n-butyl lithium dropwise to a solution of **L11** in THF at −78°C (**Scheme 10**). After 3 h stirring of mixture, GeCl<sup>2</sup> ·dioxane was added to reaction mixture at −78°C. The resulting product was reddish brown. The reddish brown solution was warmed gradually at room temperature and stirred overnight. The residue was extracted with dichloromethane, and solvent was removed under vacuum. Lithium chloride was filtered off, and the filtrate was concentrated. Orange crystals of **C17** were obtained in 47% isolated yield.

**Scheme 8.** Synthesis of bis(germylene)selenide.

**Scheme 7.** Synthesis of germyliumylidene salt **C12**.[BF<sup>4</sup>

12 Basic Concepts Viewed from Frontier in Inorganic Coordination Chemistry

].

**Scheme 10.** Preparation of a germylidenide anion from the C▬C bond activation of a bis(germylene).

Melting point of the product was 163°C [15]. **C18** was formed when THF was added to a mixture of **C17** and Li metal at 0°C. The resulting mixture was warmed at room temperature and stirred for 15 h. The dark green residue was extracted with diethyl ether, and lithium chloride was filtered off. The resulting green solution was stirred at room temperature for 2 h. After filtration, the solution was concentrated affording dark green crystals of **C18** in 49% isolated yield. Melting point of the product was 218°C [15]. **C18** was further used to synthesize **C19** by adding THF into **C18** mixture and Li granules at 0°C. Dark green solution was formed when resulting red mixture was warmed at room temperature and stirred continuously for 15 h. The end product was obtained after removing the solvent under vacuum [15].

**C20** was formed when in a solution of **L12** in THF was added sodium cyclopentadienyl in THF dropwise at 0°C (**Scheme 11**). Yellowish orange solution was obtained, which was warmed at room temperature with continuous stirring for 12 h. The mixture was extracted with diethyl ether, and volatiles were removed under reduced pressure. At the last, yellow crystals were extracted in 74% isolated yield. Melting point of the product was 128°C [16].

**C21** was prepared by adding dropwise a solution of [RhCl(cod)<sup>2</sup> Cl]<sup>2</sup> in THF in a stirred solution of **L13** in THF at room temperature (**Scheme 12**). The mixture was filtered after 16 h stirring. Dark purple crystals were obtained by concentrating the mixture. Melting point of the end product was 194°C [17]. **C22** was prepared by adding [RhCl(cod)]<sup>2</sup> solution dropwise in a stirred solution of **L22** in toluene at room temperature. After 16 h stirring, the reaction mixture was filtered and then concentrated. At the end, the resulting product was obtained as an orange-colored transparent crystalline solid in 85.7% yield. Melting point of the end product was 225°C [17].

**C23** was formed by reacting **L15** with P ≡ CBu<sup>t</sup>

**Scheme 12.** Synthesis of germanium(I) dimer.

**Scheme 11.** Metallogermylenes, Cp-substituted germylene.

mixture was warmed at 35°C and stirred continuously for 15 h. During stirring, the color of reaction mixture was changed into deep red. The residue was extracted by using hexane. All

at 20°C in toluene (**Scheme 13**). The reaction

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**Scheme 11.** Metallogermylenes, Cp-substituted germylene.

**Scheme 12.** Synthesis of germanium(I) dimer.

Melting point of the product was 163°C [15]. **C18** was formed when THF was added to a mixture of **C17** and Li metal at 0°C. The resulting mixture was warmed at room temperature and stirred for 15 h. The dark green residue was extracted with diethyl ether, and lithium chloride was filtered off. The resulting green solution was stirred at room temperature for 2 h. After filtration, the solution was concentrated affording dark green crystals of **C18** in 49% isolated yield. Melting point of the product was 218°C [15]. **C18** was further used to synthesize **C19** by adding THF into **C18** mixture and Li granules at 0°C. Dark green solution was formed when resulting red mixture was warmed at room temperature and stirred continuously for 15 h.

**C20** was formed when in a solution of **L12** in THF was added sodium cyclopentadienyl in THF dropwise at 0°C (**Scheme 11**). Yellowish orange solution was obtained, which was warmed at room temperature with continuous stirring for 12 h. The mixture was extracted with diethyl ether, and volatiles were removed under reduced pressure. At the last, yellow crystals were

of **L13** in THF at room temperature (**Scheme 12**). The mixture was filtered after 16 h stirring. Dark purple crystals were obtained by concentrating the mixture. Melting point of the end product

tion of **L22** in toluene at room temperature. After 16 h stirring, the reaction mixture was filtered and then concentrated. At the end, the resulting product was obtained as an orange-colored transparent crystalline solid in 85.7% yield. Melting point of the end product was 225°C [17].

Cl]<sup>2</sup>

in THF in a stirred solution

solution dropwise in a stirred solu-

The end product was obtained after removing the solvent under vacuum [15].

**Scheme 10.** Preparation of a germylidenide anion from the C▬C bond activation of a bis(germylene).

14 Basic Concepts Viewed from Frontier in Inorganic Coordination Chemistry

extracted in 74% isolated yield. Melting point of the product was 128°C [16].

**C21** was prepared by adding dropwise a solution of [RhCl(cod)<sup>2</sup>

was 194°C [17]. **C22** was prepared by adding [RhCl(cod)]<sup>2</sup>

**C23** was formed by reacting **L15** with P ≡ CBu<sup>t</sup> at 20°C in toluene (**Scheme 13**). The reaction mixture was warmed at 35°C and stirred continuously for 15 h. During stirring, the color of reaction mixture was changed into deep red. The residue was extracted by using hexane. All

**Scheme 13.** Synthesis of *N*-heterocyclic germanium(II) hydride.

volatiles were removed in vacuum. After filtration, the filtrate was stored at 30°C overnight. The end product was obtained as dark red crystals in 67% isolated yield. Melting point of the end product was 142°C [18].

**Scheme 14.** Synthesis of germylene complexes from diaryl germylene complexes.

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**Scheme 15.** Synthesis of digermylene complexes with a Ge▬Ge single bond.

### **5. Germanium complexes involving bonding through nitrogen and hydrogen (N, H)**

Three products were prepared from **L16** (diarylgermylene) by addition of different compounds such as hydrazoic acid, hydrogen cyanide, and anhydrous hydrazine in presence of toluene at room temperature (**Scheme 14**). First, an ethereal solution of hydrazoic acid was formed when methanol was added into [(CH3 )3 Si]N3 solution in diethyl ether. After stirring of solution for 5 min, this colorless solution was added to a stirred solution of **L16** at room temperature. Purple solution became colorless when reaction mixture was stirred continuously overnight. The resulting product (white solid) was washed with pentane and mixed with small amount of hot hexane. Then, the solution was slowly cooled to 6°C and temperature was sustained overnight. **C24** was obtained as colorless blocks in 79% isolated yield [19]. These colorless blocks were suitable for single X-ray diffraction. Melting point of the end product was 177–183°C. Second, hydrogen cyanide was prepared by adding methanolic solution of (CH3 Si)CN in diethyl ether. Colorless solution was stirred for 30 min. After stirring, it was added to stirred Ge(ArMe6)2 solution in toluene at room temperature. The purple solution became colorless when solution was stirred continuously overnight. **C25** was obtained as white solid product, which was washed with small amount of pentane, and all volatile materials were removed under reduced pressure. Third, **C26** was formed when stoichiometric amount of anhydrous hydrazine was added to a stirred solution of **L16** in toluene. The mixture was stirred continuously overnight, and deep purple color changed to colorless during stirring. The resulting microcrystalline white solid was washed by using small amount of hexane and dried under reduced pressure. The microcrystalline solid was stored at 20°C for 1 week after dissolving the solid in toluene. The colorless end product was obtained in 86% isolated yield [20].

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**Scheme 14.** Synthesis of germylene complexes from diaryl germylene complexes.

volatiles were removed in vacuum. After filtration, the filtrate was stored at 30°C overnight. The end product was obtained as dark red crystals in 67% isolated yield. Melting point of the

Three products were prepared from **L16** (diarylgermylene) by addition of different compounds such as hydrazoic acid, hydrogen cyanide, and anhydrous hydrazine in presence of toluene at room temperature (**Scheme 14**). First, an ethereal solution of hydrazoic acid was

> )3 Si]N3

solution for 5 min, this colorless solution was added to a stirred solution of **L16** at room temperature. Purple solution became colorless when reaction mixture was stirred continuously overnight. The resulting product (white solid) was washed with pentane and mixed with small amount of hot hexane. Then, the solution was slowly cooled to 6°C and temperature was sustained overnight. **C24** was obtained as colorless blocks in 79% isolated yield [19]. These colorless blocks were suitable for single X-ray diffraction. Melting point of the end product was 177–183°C. Second, hydrogen cyanide was prepared by adding methanolic solu-

tion became colorless when solution was stirred continuously overnight. **C25** was obtained as white solid product, which was washed with small amount of pentane, and all volatile materials were removed under reduced pressure. Third, **C26** was formed when stoichiometric amount of anhydrous hydrazine was added to a stirred solution of **L16** in toluene. The mixture was stirred continuously overnight, and deep purple color changed to colorless during stirring. The resulting microcrystalline white solid was washed by using small amount of hexane and dried under reduced pressure. The microcrystalline solid was stored at 20°C for 1 week after dissolving the solid in toluene. The colorless end product was obtained in 86%

Si)CN in diethyl ether. Colorless solution was stirred for 30 min. After stirring,

solution in toluene at room temperature. The purple solu-

solution in diethyl ether. After stirring of

**5. Germanium complexes involving bonding through nitrogen and** 

end product was 142°C [18].

formed when methanol was added into [(CH3

**Scheme 13.** Synthesis of *N*-heterocyclic germanium(II) hydride.

16 Basic Concepts Viewed from Frontier in Inorganic Coordination Chemistry

**hydrogen (N, H)**

tion of (CH3

isolated yield [20].

it was added to stirred Ge(ArMe6)2

**Scheme 15.** Synthesis of digermylene complexes with a Ge▬Ge single bond.

**C27** was formed when a solution of **L17** in toluene left in Youngs Schlenk flask at 20°C under 1 atmospheric pressure of highly pure H<sup>2</sup> (**Scheme 15**). The reaction mixture was stirred continuously for 30 min. All volatiles were removed under vacuum. Pale orange solid was obtained as end product. By recrystallization, solid single crystals of complex were obtained from minimum volume of diethyl ether, which remained suitable for X-ray crystallography. Melting point of the end product was 190–194°C [21].

### **6. Germanium complexes involving bonding through carbon and oxygen (C, O)**

**C28** was formed when n-butyl lithium was added slowly to a solution of **L18** (bis-sulfone) in toluene at 40°C (**Scheme 16**). The solution color changed into deep red, and this solution was further stirred continuously for 20 min at 40°C. Then, the reaction mixture was added over a suspension of GeCl<sup>2</sup> -dioxane in toluene at 0°C. The reaction mixture was heated to room temperature and stirred for 18 h. After stirring, all volatiles were removed and the residue was washed with CH<sup>2</sup> Cl<sup>2</sup> . White solid was obtained in 58% isolated yield. Melting point of the white solid was 260°C. Colorless crystals of **C28** were obtained by slow diffusion of pentane in CH<sup>2</sup> Cl<sup>2</sup> . **C29** was formed by adding a solution of Fe<sup>2</sup> (CO)9 into germylene solution in THF at −20°C. Then, the mixture was warmed slowly at room temperature and stirred for 24 h. All volatiles were evaporated. The product was extracted with diethyl ether. Colorless product was obtained at room temperature for X-ray crystallographic analysis [22].

**C30** was formed when a solution of **L19** in hexane was dissolved into acetone (**Scheme 17**). The reaction mixture was stirred continuously at room temperature for 1 h. All volatiles were removed under vacuum. The end product was obtained as a greasy solid. Pure red crystals were obtained by recrystallization of the greasy solid in hexane at 30°C in 42% isolated yield [23].

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continuously (**Scheme 18**). The color of reaction mixture changed immediately into yellow.

away with n-pentane. Colorless crystals of **C31a** were obtained in THF solutions at −20°C in

] in THF at room temperature and stirred

C]<sup>+</sup> [B(C6 F5 )4

stabilized by a bis(NHC) borate ligand.

, the by-product, was removed

]− and toluene

**7. Germanium complexes involving bonding through carbon and** 

**hydrogen (C, H)**

A red solution of **L20** was added into K[HB(s-Bu)3

**Scheme 18.** Synthesis of germyliumylidene hydride [:GeH]<sup>+</sup>

After 1 h, all volatiles were removed under vacuum. B(s-Bu)3

**Scheme 17.** Synthesis of iron germylene complex having Fe-H and Ge-H bonds.

91% isolated yield. Melting point of the end product was 270°C. [Ph3

**Scheme 16.** Synthesis of bis-sulfonyl O,C,O-chelated germylenes.

**Scheme 17.** Synthesis of iron germylene complex having Fe-H and Ge-H bonds.

**C27** was formed when a solution of **L17** in toluene left in Youngs Schlenk flask at 20°C under

continuously for 30 min. All volatiles were removed under vacuum. Pale orange solid was obtained as end product. By recrystallization, solid single crystals of complex were obtained from minimum volume of diethyl ether, which remained suitable for X-ray crystallography.

**C28** was formed when n-butyl lithium was added slowly to a solution of **L18** (bis-sulfone) in toluene at 40°C (**Scheme 16**). The solution color changed into deep red, and this solution was further stirred continuously for 20 min at 40°C. Then, the reaction mixture was added over

temperature and stirred for 18 h. After stirring, all volatiles were removed and the residue

white solid was 260°C. Colorless crystals of **C28** were obtained by slow diffusion of pentane

at −20°C. Then, the mixture was warmed slowly at room temperature and stirred for 24 h. All


. White solid was obtained in 58% isolated yield. Melting point of the

into germylene solution in THF

Colorless product

(CO)9

**6. Germanium complexes involving bonding through carbon and** 

(**Scheme 15**). The reaction mixture was stirred

1 atmospheric pressure of highly pure H<sup>2</sup>

**oxygen (C, O)**

a suspension of GeCl<sup>2</sup>

was washed with CH<sup>2</sup>

Cl<sup>2</sup>

in CH<sup>2</sup>

Melting point of the end product was 190–194°C [21].

18 Basic Concepts Viewed from Frontier in Inorganic Coordination Chemistry

Cl<sup>2</sup>

**Scheme 16.** Synthesis of bis-sulfonyl O,C,O-chelated germylenes.

. **C29** was formed by adding a solution of Fe<sup>2</sup>

volatiles were evaporated. The product was extracted with diethyl ether.

was obtained at room temperature for X-ray crystallographic analysis [22].

**C30** was formed when a solution of **L19** in hexane was dissolved into acetone (**Scheme 17**). The reaction mixture was stirred continuously at room temperature for 1 h. All volatiles were removed under vacuum. The end product was obtained as a greasy solid. Pure red crystals were obtained by recrystallization of the greasy solid in hexane at 30°C in 42% isolated yield [23].

### **7. Germanium complexes involving bonding through carbon and hydrogen (C, H)**

A red solution of **L20** was added into K[HB(s-Bu)3 ] in THF at room temperature and stirred continuously (**Scheme 18**). The color of reaction mixture changed immediately into yellow. After 1 h, all volatiles were removed under vacuum. B(s-Bu)3 , the by-product, was removed away with n-pentane. Colorless crystals of **C31a** were obtained in THF solutions at −20°C in 91% isolated yield. Melting point of the end product was 270°C. [Ph3 C]<sup>+</sup> [B(C6 F5 )4 ]− and toluene

**Scheme 18.** Synthesis of germyliumylidene hydride [:GeH]<sup>+</sup> stabilized by a bis(NHC) borate ligand.

were added into **C31a** at room temperature and the mixture was stirred. Two phases were formed immediately when the mixture was stirred continuously. After 3 h, 1 H NMR indicated the formation of **C32** and HCPh3 (a by-product). The formation of the by-product was indicated by a singlet at δ = 5.58 ppm for HCPh3 . All volatiles were removed under vacuum. Ph3 CH, a by-product, was removed by using n-pentane. The residue was dissolved in acetonitrile, and **C32** was first crystallized in the form of yellowish rods at 4°C in 57% isolated yield. When the solution was further concentrated, the yellowish product changed into orange rods and was collected in 25% isolated yield. Melting point of the end product was 201°C [24].

### **8. Germanium complexes involving bonding through nitrogen and oxygen (N, O)**

**C33** was prepared by mixing a solution of **L21** in toluene at −80°C and was placed under an atmosphere of dry CO<sup>2</sup> gas (**Scheme 19**). The orange red reaction mixture was allowed to heat toward ambient temperature with consistent stirring. At about −30°C, the reaction mixture turned colorless. However, it was allowed to heat till room temperature. The resulting reaction mixture was concentrated toward saturation using rotary evaporator. The saturated solution was layered with n-hexane. Colorless crystals of **C34** were obtained in 75% isolated yield. Melting point of the product was 175–178°C [18].

**C34** was formed by dissolving diethyl ether and Ge[N(SiCH3 ) 2 ] 2 in **L22** (**Scheme 20**). In reaction mixture, n-pentane was added slowly. Then, mixture was stirred at ambient temperature for 5 min. After filtration of reaction mixture, a solid material was obtained and was dried in vacuum to obtain colorless crystalline solid. The product was recrystallized to obtain colorless crystals of **C34** in 85% isolated yield [25].

concentrated in vacuum and hence finally gave solids, which were crystallized from an appropriate solvent. The end product was obtained in 82% isolated yield. For single X-ray

and refluxed for 96 h (**Scheme 23**). All volatiles were removed under low pressure. The residue was extracted three times by pentane. The pentane solution was concentrated and was kept in glove box at −40°C overnight. The white solid was washed with cold n-pentane, and the product was dried in vacuum. The end product was obtained as white powder in 65% isolated yield [27].

and stirred for 10 min at room temperature. After removing solvent from reaction mixture, the

·dioxane solution in THF at ambient temperature (**Scheme 22**). The reaction mixture was stirred for 3 days at ambient temperature. All volatiles were removed using rotary evaporator. The orange crude product was extracted with toluene, and the solution was filtered through celite 545. The filtered material was evaporated to obtain a solid. Recrystallization of this solid was carried out by n-hexane through an overnight period at −27°C. The end product

Pr, *<sup>t</sup>* Bu, <sup>s</sup>

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Bu) was added into

in THF was stirred

.(THF) was mixed

)2 ]4

diffraction, colorless crystal was grown from n-hexane at 18°C [25].

**Scheme 21.** Synthesis of spirocyclic compounds of germanium bonded through "N" and "O".

**C36a**–**C36c** were formed when a suspension of KOR (R = *<sup>i</sup>*

**Scheme 20.** Synthesis of amido alkoxide of germanium.

was obtained as orange crystals in 76% isolated yield [26].

**C37** was formed when solution of sodium bis(trimethylsilyl)amide and GeCl<sup>4</sup>

Synthesis of **C38** was carried out when a solution of **L26** and Ge[N(SiCH3

GeCl<sup>4</sup>

Spirocyclic compounds (**C35a**–**C35c**) were synthesized by adding n-butyl lithium in n-hexane into a solution of 2-(phenylaminomethyl)phenol in diethyl ether (**Scheme 21**). The reaction mixture was stirred at ambient temperature for 2 h. After filtration, the reaction mixture was washed with n-pentane and was then dried under low pressure. The solid was dispersed in toluene and GeCl<sup>4</sup> was added dropwise with the help of syringe. Then, the solution was stirred at ambient temperature for 16 h. The solution was filtered using celite 545 and was

**Scheme 19.** Synthesis of *N*-heterocyclic germanium(II) hydride.

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were added into **C31a** at room temperature and the mixture was stirred. Two phases were

CH, a by-product, was removed by using n-pentane. The residue was dissolved in acetonitrile, and **C32** was first crystallized in the form of yellowish rods at 4°C in 57% isolated yield. When the solution was further concentrated, the yellowish product changed into orange rods and was collected in 25% isolated yield. Melting point of the end product was 201°C [24].

H NMR indi-

(a by-product). The formation of the by-product was

. All volatiles were removed under vacuum.

formed immediately when the mixture was stirred continuously. After 3 h, 1

**8. Germanium complexes involving bonding through nitrogen and** 

**C33** was prepared by mixing a solution of **L21** in toluene at −80°C and was placed under an

heat toward ambient temperature with consistent stirring. At about −30°C, the reaction mixture turned colorless. However, it was allowed to heat till room temperature. The resulting reaction mixture was concentrated toward saturation using rotary evaporator. The saturated solution was layered with n-hexane. Colorless crystals of **C34** were obtained in 75% isolated

tion mixture, n-pentane was added slowly. Then, mixture was stirred at ambient temperature for 5 min. After filtration of reaction mixture, a solid material was obtained and was dried in vacuum to obtain colorless crystalline solid. The product was recrystallized to obtain colorless

Spirocyclic compounds (**C35a**–**C35c**) were synthesized by adding n-butyl lithium in n-hexane into a solution of 2-(phenylaminomethyl)phenol in diethyl ether (**Scheme 21**). The reaction mixture was stirred at ambient temperature for 2 h. After filtration, the reaction mixture was washed with n-pentane and was then dried under low pressure. The solid was dispersed

stirred at ambient temperature for 16 h. The solution was filtered using celite 545 and was

gas (**Scheme 19**). The orange red reaction mixture was allowed to

) 2 ] 2

was added dropwise with the help of syringe. Then, the solution was

in **L22** (**Scheme 20**). In reac-

cated the formation of **C32** and HCPh3

Ph3

**oxygen (N, O)**

atmosphere of dry CO<sup>2</sup>

in toluene and GeCl<sup>4</sup>

indicated by a singlet at δ = 5.58 ppm for HCPh3

20 Basic Concepts Viewed from Frontier in Inorganic Coordination Chemistry

yield. Melting point of the product was 175–178°C [18].

crystals of **C34** in 85% isolated yield [25].

**Scheme 19.** Synthesis of *N*-heterocyclic germanium(II) hydride.

**C34** was formed by dissolving diethyl ether and Ge[N(SiCH3

**Scheme 20.** Synthesis of amido alkoxide of germanium.

**Scheme 21.** Synthesis of spirocyclic compounds of germanium bonded through "N" and "O".

concentrated in vacuum and hence finally gave solids, which were crystallized from an appropriate solvent. The end product was obtained in 82% isolated yield. For single X-ray diffraction, colorless crystal was grown from n-hexane at 18°C [25].

**C36a**–**C36c** were formed when a suspension of KOR (R = *<sup>i</sup>* Pr, *<sup>t</sup>* Bu, <sup>s</sup> Bu) was added into GeCl<sup>4</sup> ·dioxane solution in THF at ambient temperature (**Scheme 22**). The reaction mixture was stirred for 3 days at ambient temperature. All volatiles were removed using rotary evaporator. The orange crude product was extracted with toluene, and the solution was filtered through celite 545. The filtered material was evaporated to obtain a solid. Recrystallization of this solid was carried out by n-hexane through an overnight period at −27°C. The end product was obtained as orange crystals in 76% isolated yield [26].

**C37** was formed when solution of sodium bis(trimethylsilyl)amide and GeCl<sup>4</sup> in THF was stirred and refluxed for 96 h (**Scheme 23**). All volatiles were removed under low pressure. The residue was extracted three times by pentane. The pentane solution was concentrated and was kept in glove box at −40°C overnight. The white solid was washed with cold n-pentane, and the product was dried in vacuum. The end product was obtained as white powder in 65% isolated yield [27].

Synthesis of **C38** was carried out when a solution of **L26** and Ge[N(SiCH3 )2 ]4 .(THF) was mixed and stirred for 10 min at room temperature. After removing solvent from reaction mixture, the

solid residue was dissolved in n-pentane. Then, n-pentane solution was kept in a glove box at −40°C overnight. A white crystalline solid was extracted out from solution and was washed with clean and cold n-pentane. The extracted product was dried in vacuum. The end product was obtained as white powder in 90% isolated yield [27]. Similarly, **C39** was formed when

The reaction mixture was stirred for 10 min at room temperature. All volatiles were removed under vacuum. The extracted residue was washed several times by n-pentane and was dried under vacuum. The end product was obtained as white powder in 85% isolated yield [27].

into a solution of Na(dmamp), where dmamp = 1-dimethylamino-2-methyl-2-propanolate, in THF. The reaction mixture was stirred continuously at room temperature overnight. The reaction mixture was filtered to remove sodium chloride salt as by-product. After filtration,

product was obtained as colorless liquid by distillation in 81% isolated yield. Sulfur powder

stirred at room temperature overnight. **C40** was obtained as a white solid after removing all the volatiles from the reaction mixture. Recrystallization of the crude product from an

(**Scheme 25**). The reaction mixture was stirred at room temperature for 12 h. After filtration, hexane was removed and **C41** was obtained as red solid in 97% isolated yield. Melting point of the end product was 78°C. **C42** was formed when elemental sulfur was added into **L28** solution in THF at room temperature. The reaction mixture was stirred at room temperature for 2 h. All volatiles were removed under reduced pressure. The residue was washed with n-hexane and was dried to get the product as yellow solid in 98% isolated yield. Single

Bu was formed by adding **L29** solution in hexane into KO*<sup>t</sup>*

) 2 ]4 .(THF)<sup>2</sup>

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·dioxane was added slowly

as crude product. The end

Bu at −40°C

in toluene. The reaction mixture was

**L27** was added to a stirred solution of Ge[N(SiCH3

**C40** was synthesized in two steps (**Scheme 24**). Firstly, GeCl<sup>2</sup>

the filtrate was concentrated in vacuum to obtain Ge(dmamp)<sup>2</sup>

ethereal solution of it gave the pure product as colorless crystals in 82% [28].

was then added slowly into a solution of Ge(dmamp)<sup>2</sup>

**Scheme 24.** Synthesis of germanium complex containing Ge〓S double bond.

**C41** [(*<sup>t</sup>*

Bu)<sup>2</sup>

ATI]GeO*<sup>t</sup>*

**Scheme 23.** Synthesis of germanium complexes involving bonding through "N" and "O".

solid residue was dissolved in n-pentane. Then, n-pentane solution was kept in a glove box at −40°C overnight. A white crystalline solid was extracted out from solution and was washed with clean and cold n-pentane. The extracted product was dried in vacuum. The end product was obtained as white powder in 90% isolated yield [27]. Similarly, **C39** was formed when **L27** was added to a stirred solution of Ge[N(SiCH3 ) 2 ]4 .(THF)<sup>2</sup> in toluene at room temperature. The reaction mixture was stirred for 10 min at room temperature. All volatiles were removed under vacuum. The extracted residue was washed several times by n-pentane and was dried under vacuum. The end product was obtained as white powder in 85% isolated yield [27].

**C40** was synthesized in two steps (**Scheme 24**). Firstly, GeCl<sup>2</sup> ·dioxane was added slowly into a solution of Na(dmamp), where dmamp = 1-dimethylamino-2-methyl-2-propanolate, in THF. The reaction mixture was stirred continuously at room temperature overnight. The reaction mixture was filtered to remove sodium chloride salt as by-product. After filtration, the filtrate was concentrated in vacuum to obtain Ge(dmamp)<sup>2</sup> as crude product. The end product was obtained as colorless liquid by distillation in 81% isolated yield. Sulfur powder was then added slowly into a solution of Ge(dmamp)<sup>2</sup> in toluene. The reaction mixture was stirred at room temperature overnight. **C40** was obtained as a white solid after removing all the volatiles from the reaction mixture. Recrystallization of the crude product from an ethereal solution of it gave the pure product as colorless crystals in 82% [28].

**Scheme 22.** Synthesis of germanium alkoxide complexes.

22 Basic Concepts Viewed from Frontier in Inorganic Coordination Chemistry

**Scheme 23.** Synthesis of germanium complexes involving bonding through "N" and "O".

**C41** [(*<sup>t</sup>* Bu)<sup>2</sup> ATI]GeO*<sup>t</sup>* Bu was formed by adding **L29** solution in hexane into KO*<sup>t</sup>* Bu at −40°C (**Scheme 25**). The reaction mixture was stirred at room temperature for 12 h. After filtration, hexane was removed and **C41** was obtained as red solid in 97% isolated yield. Melting point of the end product was 78°C. **C42** was formed when elemental sulfur was added into **L28** solution in THF at room temperature. The reaction mixture was stirred at room temperature for 2 h. All volatiles were removed under reduced pressure. The residue was washed with n-hexane and was dried to get the product as yellow solid in 98% isolated yield. Single

**Scheme 24.** Synthesis of germanium complex containing Ge〓S double bond.

to the crystallization of product overnight. Product was dried in vacuum for 2 h. The end

stirred for 1 h at ambient temperature. After filtration, the filtrate was placed in Schlenk tube

ture at 0°C. After stirring of solution for 25 min at same temperature, the reaction mixture was warmed at room temperature for another 1 h and was concentrated under reduced pressure.

residue was redissolved in pentane and was concentrated to remove uncoordinated THF. The

**C45** was synthesized when iodine was added to a solution of **L32** (**Scheme 28**). Pale yellow precipitates were formed when the reaction mixture was stirred for a period of 12 h. Then, precipitates were washed several times with n-pentane and the end product was obtained as a dark orange powder in 92% isolated yield. Dark red crystals were produced by storing the

stirred for 4 h at ambient temperature. All volatiles were removed using rotary evaporator. Yellow solid product was washed with toluene and was dried in vacuum. Single crystals of **C46** were grown from its hot acetonitrile solution for X-ray diffraction studies. The end product was obtained as yellow solid in 94% isolated yield. Melting point of the end product was 152°C [32]. **C47** was synthesized when a solution of **L34** was transferred into GeCl<sup>2</sup>

tion in THF at room temperature, and the reaction mixture was stirred for 4 h. All volatiles were removed using rotary evaporator. The yellow solid was washed with n-hexane and was

F mixture at −27°C for 7 days [26].

in THF (**Scheme 29**). The reaction mixture was

with **L31** (**Scheme 27**). The solution was

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was added dropwise in the reaction mix-

O.

The resulting

solu-

product was obtained as yellowish crystalline product in 83% isolated yield [30].

The residue was filtered through syringe filter in a glove box by using Et<sup>2</sup>

**9.1. Germanium complexes involving bonding through carbon, nitrogen, and** 

H5

end product was obtained as green solid in 98% isolated yield [31].

**C44** was synthesized by mixing NaH and GeCl<sup>4</sup>

**Scheme 27.** Synthesis of salophene-like germanium complex.

and the tube was taken outside the glove box. GeCl<sup>4</sup>

**9. Three linkages**

saturated solution of **C45** in THF/C6

**C46** was formed by mixing **L33** with ZnCl<sup>2</sup>

**oxygen (C, N, O)**

**Scheme 25.** Synthesis of aminotroponiminatogermylenealkoxide complexes.

crystals of **C42** were obtained by the slow evaporation of solvent from its chloroform solution. Crystals of **C42** were remained suitable for X-ray crystallographic studies. Melting point of the end product was 178°C [29].

n-BuLi was added into a cold solution of 4,6-di-ter-butylresorcinol of dry diethyl ether at −30°C (**Scheme 26**). After mixing, immediately a milky solid suspension was observed. Cooling bath was removed and reaction material was again stirred for 3 h at ambient temperature. The reaction mixture was then cooled and N,N-di-tert-butylchloro(phenylamidinate) germanium(II) was added dropwise in the reaction mixture. After complete addition, the reaction mixture was maintained at ambient temperature overnight. All volatile solvents were removed in vacuum. **C43** was extracted with the addition of hot hexane in reaction mixture *via* cannula filtration. The reaction mixture was concentrated and cooled at −3°C, which led

**Scheme 26.** Synthesis of GeCaromaticGe-type pincer for further coordination with iridium.

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**Scheme 27.** Synthesis of salophene-like germanium complex.

to the crystallization of product overnight. Product was dried in vacuum for 2 h. The end product was obtained as yellowish crystalline product in 83% isolated yield [30].

**C44** was synthesized by mixing NaH and GeCl<sup>4</sup> with **L31** (**Scheme 27**). The solution was stirred for 1 h at ambient temperature. After filtration, the filtrate was placed in Schlenk tube and the tube was taken outside the glove box. GeCl<sup>4</sup> was added dropwise in the reaction mixture at 0°C. After stirring of solution for 25 min at same temperature, the reaction mixture was warmed at room temperature for another 1 h and was concentrated under reduced pressure. The residue was filtered through syringe filter in a glove box by using Et<sup>2</sup> O. The resulting residue was redissolved in pentane and was concentrated to remove uncoordinated THF. The end product was obtained as green solid in 98% isolated yield [31].

### **9. Three linkages**

crystals of **C42** were obtained by the slow evaporation of solvent from its chloroform solution. Crystals of **C42** were remained suitable for X-ray crystallographic studies. Melting point of

n-BuLi was added into a cold solution of 4,6-di-ter-butylresorcinol of dry diethyl ether at −30°C (**Scheme 26**). After mixing, immediately a milky solid suspension was observed. Cooling bath was removed and reaction material was again stirred for 3 h at ambient temperature. The reaction mixture was then cooled and N,N-di-tert-butylchloro(phenylamidinate) germanium(II) was added dropwise in the reaction mixture. After complete addition, the reaction mixture was maintained at ambient temperature overnight. All volatile solvents were removed in vacuum. **C43** was extracted with the addition of hot hexane in reaction mixture *via* cannula filtration. The reaction mixture was concentrated and cooled at −3°C, which led

the end product was 178°C [29].

**Scheme 25.** Synthesis of aminotroponiminatogermylenealkoxide complexes.

24 Basic Concepts Viewed from Frontier in Inorganic Coordination Chemistry

**Scheme 26.** Synthesis of GeCaromaticGe-type pincer for further coordination with iridium.

### **9.1. Germanium complexes involving bonding through carbon, nitrogen, and oxygen (C, N, O)**

**C45** was synthesized when iodine was added to a solution of **L32** (**Scheme 28**). Pale yellow precipitates were formed when the reaction mixture was stirred for a period of 12 h. Then, precipitates were washed several times with n-pentane and the end product was obtained as a dark orange powder in 92% isolated yield. Dark red crystals were produced by storing the saturated solution of **C45** in THF/C6 H5 F mixture at −27°C for 7 days [26].

**C46** was formed by mixing **L33** with ZnCl<sup>2</sup> in THF (**Scheme 29**). The reaction mixture was stirred for 4 h at ambient temperature. All volatiles were removed using rotary evaporator. Yellow solid product was washed with toluene and was dried in vacuum. Single crystals of **C46** were grown from its hot acetonitrile solution for X-ray diffraction studies. The end product was obtained as yellow solid in 94% isolated yield. Melting point of the end product was 152°C [32]. **C47** was synthesized when a solution of **L34** was transferred into GeCl<sup>2</sup> solution in THF at room temperature, and the reaction mixture was stirred for 4 h. All volatiles were removed using rotary evaporator. The yellow solid was washed with n-hexane and was

**Scheme 28.** Synthesis of germanium alkoxide complex.

**Scheme 29.** Synthesis of germanone from a germanium-μ-oxo dimer.

dried in vacuum to obtain pure sample of **C47** as yellow solid. Single crystals of complex were grown from its solution in THF and hexane at −40°C, which remained suitable for X-ray diffraction studies. The end product was obtained as yellow solid in 94% isolated yield. Melting point of the end product was 110°C [32].

by evaporation method. According to this method, a slow evaporation of solvent from its saturated solution in chloroform was managed to obtain crystals suitable for X-ray diffraction study. The end product was obtained as yellow solid in 98% isolated yield. Melting point of

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in toluene (**Scheme 32**). The reaction mixture was stirred at room temperature overnight. All volatiles were removed from reaction mixture under vacuum. The product was obtained as yellow solid. The pure product was synthesized by recrystallization of yellow solid from an

**C51** was synthesized by adding **L37** solution in THF slowly into phenyl lithium at −80°C (**Scheme 33**). The reaction mixture was warmed slowly at room temperature and stirred continuously for 2 h. All volatiles were removed in vacuum. The product was extracted twice with n-pentane. The major diastereomer as **C51** was obtained in pure form from a concentrated

solution

**C50** was obtained when selenium powder was added slowly into a Ge(dmampS)<sup>2</sup>

ether solution. At the end, yellow crystals were obtained in 89% isolated yield [28].

**9.3. Germanium complexes involving bonding through nitrogen, phosphorus,** 

the end product was 178°C [29].

**Scheme 31.** Synthesis of sulfur-bonded germaester complex.

**Scheme 30.** Synthesis of aromatic [28]hexaphyrin germanium(IV) complex.

**carbon (N, P, C)**

**L34** in CH3 CN was placed in a round bottom flask under an inert atmosphere using argon gas (**Scheme 30**). Triethyleneamine (NEt3 ) and GeCl<sup>4</sup> were added in the reaction medium. The reaction mixture was then stirred at room temperature for 15 min and passed through a short pad of silica gel column (C-200, CH<sup>2</sup> Cl<sup>2</sup> ). Separation through silica gel column (C-300, n-hexane: CH<sup>2</sup> Cl<sup>2</sup> = 2:1) gave **C48** as a second fraction. All volatiles were removed. The end product was obtained as dark brown solid in 76% isolated yield [33].

### **9.2. Germanium complexes involving bonding through nitrogen, oxygen, and sulfur/selenium (N, O, S/Se)**

**C49** was formed when elemental sulfur was added into a solution of **L35** in THF at room temperature (**Scheme 31**). The reaction mixture was stirred at room temperature for 2 h. All volatiles were removed using rotary evaporator. The residue was washed with n-hexane and dried to obtain product as yellow solid. Single crystals of complex were obtained Modern Techniques in Synthesis of Organometallic Compounds of Germanium http://dx.doi.org/10.5772/intechopen.79985 27

**Scheme 30.** Synthesis of aromatic [28]hexaphyrin germanium(IV) complex.

**Scheme 31.** Synthesis of sulfur-bonded germaester complex.

dried in vacuum to obtain pure sample of **C47** as yellow solid. Single crystals of complex were grown from its solution in THF and hexane at −40°C, which remained suitable for X-ray diffraction studies. The end product was obtained as yellow solid in 94% isolated yield. Melting

CN was placed in a round bottom flask under an inert atmosphere using argon

Cl<sup>2</sup> = 2:1) gave **C48** as a second fraction. All volatiles were removed. The end

were added in the reaction medium.

). Separation through silica gel column (C-300,

) and GeCl<sup>4</sup>

The reaction mixture was then stirred at room temperature for 15 min and passed through a

**C49** was formed when elemental sulfur was added into a solution of **L35** in THF at room temperature (**Scheme 31**). The reaction mixture was stirred at room temperature for 2 h. All volatiles were removed using rotary evaporator. The residue was washed with n-hexane and dried to obtain product as yellow solid. Single crystals of complex were obtained

Cl<sup>2</sup>

**9.2. Germanium complexes involving bonding through nitrogen, oxygen, and** 

product was obtained as dark brown solid in 76% isolated yield [33].

point of the end product was 110°C [32].

**Scheme 29.** Synthesis of germanone from a germanium-μ-oxo dimer.

**Scheme 28.** Synthesis of germanium alkoxide complex.

26 Basic Concepts Viewed from Frontier in Inorganic Coordination Chemistry

gas (**Scheme 30**). Triethyleneamine (NEt3

short pad of silica gel column (C-200, CH<sup>2</sup>

**L34** in CH3

n-hexane: CH<sup>2</sup>

**sulfur/selenium (N, O, S/Se)**

by evaporation method. According to this method, a slow evaporation of solvent from its saturated solution in chloroform was managed to obtain crystals suitable for X-ray diffraction study. The end product was obtained as yellow solid in 98% isolated yield. Melting point of the end product was 178°C [29].

**C50** was obtained when selenium powder was added slowly into a Ge(dmampS)<sup>2</sup> solution in toluene (**Scheme 32**). The reaction mixture was stirred at room temperature overnight. All volatiles were removed from reaction mixture under vacuum. The product was obtained as yellow solid. The pure product was synthesized by recrystallization of yellow solid from an ether solution. At the end, yellow crystals were obtained in 89% isolated yield [28].

### **9.3. Germanium complexes involving bonding through nitrogen, phosphorus, carbon (N, P, C)**

**C51** was synthesized by adding **L37** solution in THF slowly into phenyl lithium at −80°C (**Scheme 33**). The reaction mixture was warmed slowly at room temperature and stirred continuously for 2 h. All volatiles were removed in vacuum. The product was extracted twice with n-pentane. The major diastereomer as **C51** was obtained in pure form from a concentrated

**10. Miscellaneous**

in 33% isolated yield [3]**.**

perature. GeCl<sup>2</sup>

**10.1. Germanium complexes involving bonding through oxygen**

**10.2. Germanium complexes involving bonding through phosphorus (P)**

tals in 6% isolated yield. Melting point of the end product was 110–112°C [34].

**10.3. Germanium complexes involving bonding through carbon and sulfur (C, S)**

(**Scheme 37**). The reaction mixture was stirred continuously for 30 min. (CH3

**10.4. Germanium complexes involving bonding through nitrogen and boron (N, B)**

yield. Melting point of the end product was 79–80°C [35].

**C56** was formed by adding **L42** solution into a solution of B(C6

**Scheme 35.** Synthesis of *N*-alkoxy carboxylamide-stabilized germanium(II) complexes.

**C53** was formed when N-methoxypropanamide was added dropwise to a stirring diethyl ether solution of **L39** (**Scheme 35**). After reaction mixture was placed overnight at room temperature, volatiles were removed in vacuum and crude product was distilled at 10−<sup>1</sup> torr to afford pure complex. The resulting pure complex was obtained as a colorless liquid at 120°C

**L40** was dissolved in THF and n-butyl lithium was added into reaction mixture through a syringe (**Scheme 36**). The resulting white suspension was stirred for 30 min at room tem-

solution was stirred for 3 h at room temperature. All volatiles were removed under vacuum. n-Pentane was added in residue, which was then filtered to remove LiCl. n-Pentane solution was concentrated and cooled at 25°C. The end product was obtained as yellow rod-like crys-

**C55** was synthesized when superhydride was added into the solution of naphthol in THF

added and the reaction mixture was stirred overnight. All volatiles were removed under vacuum. The product was dissolved in DCM and filtered through celite. The product was washed with hexane. The end product was obtained as cream crystalline solid in 25% isolated

The resultant yellow reaction mixture was warmed at room temperature and stirred for 24 h. All volatiles were removed under vacuum and were extracted with toluene. The end product was obtained as yellow crystals in 60% isolated yield. Melting point of the end product was 157°C [16]**.**

was added as a solid, and dark yellow solution was formed. The dark yellow

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F5 ) 3 in Et2 )2 GeCl<sup>2</sup>

O at 0°C (**Scheme 38**).

was

29

**Scheme 32.** Synthesis of selenium-bonded germaester complex.

**Scheme 33.** Synthesis of phosphine-stabilized germylene complex.

solution of n-pentane at −30°C. At the end, pale yellow crystals were obtained in 45% isolated yield. Melting point of the end product was 25°C [6].

### **9.4. Germanium complexes involving bonding through nitrogen, carbon, manganese (N, C, Mn)**

**C52** was formed when a solution of **L38** was added dropwise to a stirred suspension of Mn<sup>2</sup> (CO)10 in toluene at room temperature (**Scheme 34**). The reaction mixture was refluxed overnight. After filtration, the filtrate was concentrated. The end product was obtained as dark red crystals in 46.3% isolated yield. Melting point of the end product was 261°C [17].

**Scheme 34.** Synthesis of germanium(I) dimer stabilized by dimanganese decacarbonyl.

### **10. Miscellaneous**

solution of n-pentane at −30°C. At the end, pale yellow crystals were obtained in 45% isolated

**C52** was formed when a solution of **L38** was added dropwise to a stirred suspension of

(CO)10 in toluene at room temperature (**Scheme 34**). The reaction mixture was refluxed overnight. After filtration, the filtrate was concentrated. The end product was obtained as dark red crystals in 46.3% isolated yield. Melting point of the end product was 261°C [17].

**9.4. Germanium complexes involving bonding through nitrogen, carbon,** 

**Scheme 34.** Synthesis of germanium(I) dimer stabilized by dimanganese decacarbonyl.

yield. Melting point of the end product was 25°C [6].

**Scheme 33.** Synthesis of phosphine-stabilized germylene complex.

**Scheme 32.** Synthesis of selenium-bonded germaester complex.

28 Basic Concepts Viewed from Frontier in Inorganic Coordination Chemistry

**manganese (N, C, Mn)**

Mn<sup>2</sup>

### **10.1. Germanium complexes involving bonding through oxygen**

**C53** was formed when N-methoxypropanamide was added dropwise to a stirring diethyl ether solution of **L39** (**Scheme 35**). After reaction mixture was placed overnight at room temperature, volatiles were removed in vacuum and crude product was distilled at 10−<sup>1</sup> torr to afford pure complex. The resulting pure complex was obtained as a colorless liquid at 120°C in 33% isolated yield [3]**.**

### **10.2. Germanium complexes involving bonding through phosphorus (P)**

**L40** was dissolved in THF and n-butyl lithium was added into reaction mixture through a syringe (**Scheme 36**). The resulting white suspension was stirred for 30 min at room temperature. GeCl<sup>2</sup> was added as a solid, and dark yellow solution was formed. The dark yellow solution was stirred for 3 h at room temperature. All volatiles were removed under vacuum. n-Pentane was added in residue, which was then filtered to remove LiCl. n-Pentane solution was concentrated and cooled at 25°C. The end product was obtained as yellow rod-like crystals in 6% isolated yield. Melting point of the end product was 110–112°C [34].

### **10.3. Germanium complexes involving bonding through carbon and sulfur (C, S)**

**C55** was synthesized when superhydride was added into the solution of naphthol in THF (**Scheme 37**). The reaction mixture was stirred continuously for 30 min. (CH3 )2 GeCl<sup>2</sup> was added and the reaction mixture was stirred overnight. All volatiles were removed under vacuum. The product was dissolved in DCM and filtered through celite. The product was washed with hexane. The end product was obtained as cream crystalline solid in 25% isolated yield. Melting point of the end product was 79–80°C [35].

### **10.4. Germanium complexes involving bonding through nitrogen and boron (N, B)**

**C56** was formed by adding **L42** solution into a solution of B(C6 F5 ) 3 in Et2 O at 0°C (**Scheme 38**). The resultant yellow reaction mixture was warmed at room temperature and stirred for 24 h. All volatiles were removed under vacuum and were extracted with toluene. The end product was obtained as yellow crystals in 60% isolated yield. Melting point of the end product was 157°C [16]**.**

**Scheme 35.** Synthesis of *N*-alkoxy carboxylamide-stabilized germanium(II) complexes.

**Scheme 36.** Synthesis of bicyclic low-valent germanium complex bridged by bis(diisopropylphosphino)amine.

**Scheme 37.** Complexation of aromatic dichalcogen ligands to germanium.

volatiles were removed under vacuum. Pure pale yellow crystals of **C58** were obtained in 93% isolated yield by recrystallization of compound using diethyl ether. Melting point of the

Modern Techniques in Synthesis of Organometallic Compounds of Germanium

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31

**C59** was synthesized by mixing **L45** and NaOCP·dioxane in toluene at room temperature (**Scheme 41**). The solution was stirred for 2 h. At that time, the reaction flask was wrapped

**10.7. Germanium complexes involving bonding through phosphorus and carbon (P, C)**

end product was 146–150°C [37].

**Scheme 39.** Synthesis of β-diketiminate germanium(II) complex.

**Scheme 40.** Synthesis of digermyne with a Ge-Ge single-bonded compounds.

**Scheme 41.** Synthesis of the bis-NHC chlorogermyliumylidene borate.

**Scheme 38.** Synthesis of boron-substituted metallogermylenes.

### **10.5. Germanium complexes involving bonding through nitrogen and phosphorous (N, P)**

**C57** was formed when a suspension of TPH was added to a mixture of LGeCl (**L43**) in presence of free NHC in Et<sup>2</sup> O at −18°C (**Scheme 39**). After stirring for 12 h, all volatiles were removed using rotary evaporator to get an oily paste. n-hexane was layered on this paste. The n-hexane-layered oily paste was stored at room temperature for 1 week. The end product was obtained as dark red crystals in 38% isolated yield. Melting point of the end product was 198°C [36].

#### **10.6. Germanium complexes involving bonding through nitrogen and sulfur (N, S)**

**C58** was formed when CS<sup>2</sup> was added in **L44** solution in toluene at −70°C (**Scheme 40**). The reaction mixture was warmed at room temperature and was further stirred for 18 h. All Modern Techniques in Synthesis of Organometallic Compounds of Germanium http://dx.doi.org/10.5772/intechopen.79985 31

**Scheme 40.** Synthesis of digermyne with a Ge-Ge single-bonded compounds.

volatiles were removed under vacuum. Pure pale yellow crystals of **C58** were obtained in 93% isolated yield by recrystallization of compound using diethyl ether. Melting point of the end product was 146–150°C [37].

### **10.7. Germanium complexes involving bonding through phosphorus and carbon (P, C)**

**C59** was synthesized by mixing **L45** and NaOCP·dioxane in toluene at room temperature (**Scheme 41**). The solution was stirred for 2 h. At that time, the reaction flask was wrapped

**Scheme 41.** Synthesis of the bis-NHC chlorogermyliumylidene borate.

**10.5. Germanium complexes involving bonding through nitrogen and phosphorous** 

**Scheme 36.** Synthesis of bicyclic low-valent germanium complex bridged by bis(diisopropylphosphino)amine.

crystals in 38% isolated yield. Melting point of the end product was 198°C [36].

**10.6. Germanium complexes involving bonding through nitrogen and sulfur (N, S)**

**C57** was formed when a suspension of TPH was added to a mixture of LGeCl (**L43**) in presence of

rotary evaporator to get an oily paste. n-hexane was layered on this paste. The n-hexane-layered oily paste was stored at room temperature for 1 week. The end product was obtained as dark red

reaction mixture was warmed at room temperature and was further stirred for 18 h. All

O at −18°C (**Scheme 39**). After stirring for 12 h, all volatiles were removed using

was added in **L44** solution in toluene at −70°C (**Scheme 40**). The

**(N, P)**

free NHC in Et<sup>2</sup>

**C58** was formed when CS<sup>2</sup>

**Scheme 38.** Synthesis of boron-substituted metallogermylenes.

**Scheme 37.** Complexation of aromatic dichalcogen ligands to germanium.

30 Basic Concepts Viewed from Frontier in Inorganic Coordination Chemistry

[2] Svarnas P, Botzakaki M, Skoulatakis G, Kennou S, Ladas S, Tsamis C, et al. Controllable growth of stable germanium dioxide ultra-thin layer by means of capacitively driven

Modern Techniques in Synthesis of Organometallic Compounds of Germanium

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33

[3] George SM, Nam JH, Lee GY, Han JH, Park BK, Kim CG, et al. N-alkoxy carboxamide stabilized tin (II) and germanium (II) complexes for thin-film applications. European

[4] Harris LM, Tam EC, Cummins SJ, Coles MP, Fulton JR. The reactivity of germanium

[5] Katir N, Matioszek D, Ladeira S, Escudié J, Castel A. Stable N-heterocyclic carbene complexes of hypermetallyl germanium (II) and tin (II) compounds. Angewandte Chemie

[6] García JM, Ocando-Mavárez E, Kato T, Coll DS, Briceño A, Saffon-Merceron N, et al. Synthesis and characterization of rhodium complexes with phosphine-stabilized germyl-

[7] Ochiai T, Szilvási T, Franz D, Irran E, Inoue S. Isolation and structure of germylenegermyliumylidenes stabilized by N-heterocyclic imines. Angewandte Chemie. 2016;

[8] Yao S, Xiong Y, Driess M. A new area in main-group chemistry: Zerovalent monoatomic silicon compounds and their analogues. Accounts of Chemical Research. 2017;

[9] Filippou AC, Stumpf KW, Chernov O, Schnakenburg G. Metal activation of a germylenoid, a new approach to metal–germanium triple bonds: Synthesis and reactions of the germylidyne complexes [Cp (CO) 2M Ge–C (SiMe3) 3](M= Mo, W). Organometallics.

[10] Xiong Y, Yao S, Inoue S, Berkefeld A, Driess M. Taming the germyliumylidene [CIGe:]+ and germathionium [CIGe=S]+ ions by donor-acceptor stabilization using 1,8-bis (tributylphosphazenyl)naphthalene. Chemical Communications. 2012;**48**(100):12198-12200.

[11] Woodul WD, Carter E, Müller R, Richards AF, Stasch A, Kaupp M, et al. A neutral, monomeric germanium (I) radical. Journal of the American Chemical Society. 2011;**133**(26):

[12] Matioszek D, Saffon N, Sotiropoulos J-M, Miqueu K, Castel A, Escudié J. Bis (amidinato) germylenerhodium complexes: Synthesis, structure, and density functional theory cal-

[13] Leung W-P, Chan Y-C, So C-W, Mak TC. Reactivity study of a pyridyl-1-azaallylgermanium (I) dimer: Synthesis of heavier ether and Ester analogues of germanium. Inorganic

culations. Inorganic Chemistry. 2012;**51**(21):11716-11721

phosphanides with chalcogens. Inorganic Chemistry. 2017;**56**(5):3087-3094

radio frequency discharge. Thin Solid Films. 2016;**599**:49-53

Journal of Inorganic Chemistry. 2016;**2016**(36):5539-5546

International Edition. 2011;**50**(23):5352-5355

enes. Inorganic Chemistry. 2012;**51**(15):8187-8193

**128**(38):11791-11796

**50**(8):2026-2037

2012;**31**(2):748-755

10074-10077

DOI: 10.1039/C2CC36926E

Chemistry. 2016;**55**(7):3553-3557

**Scheme 42.** Synthesis of functionalized germanium complex.

with aluminum foil to protect day light. The precipitate of NaCl was separated from reaction mixture through centrifugation. All volatiles were removed under reduced pressure. Then, the residue was washed with n-hexane and extracted with diethyl ether. The end product was crystallized as yellow rods in 67% isolated yield. Melting point of the end product was 190°C [38].

### **10.8. Germanium complexes involving bonding through oxygen and hydrogen (O, H)**

**C60** was formed when HSO3 CF3 was added to a stirred solution of **L46** in toluene at 0°C (**Scheme 42**). The color of reaction mixture changed immediately into pale yellow. The reaction mixture was further stirred for 2 h, and volume of solution is reduced under vacuum. After addition of n-hexane in flask, the reaction mixture was cooled slowly. The reaction mixture was placed unattended at −20°C overnight. The end product was obtained as colorless blocks in 83% isolated yield [19].

### **Author details**

Hina Hayat1 and Muhammad Adnan Iqbal1,2\*

\*Address all correspondence to: adnan.iqbal@uaf.edu.pk

1 Department of Chemistry, University of Agriculture, Faisalabad, Pakistan

2 Organometallic & Coordination Chemistry Laboratory, Department of Chemistry, University of Agriculture, Faisalabad, Pakistan

### **References**

[1] Haller E. Germanium: From its discovery to SiGe devices. Materials Science in Semiconductor Processing. 2006;**9**(4-5):408-422


with aluminum foil to protect day light. The precipitate of NaCl was separated from reaction mixture through centrifugation. All volatiles were removed under reduced pressure. Then, the residue was washed with n-hexane and extracted with diethyl ether. The end product was crystallized as yellow rods in 67% isolated yield. Melting point of the end product was 190°C [38].

was added to a stirred solution of **L46** in toluene at 0°C

**10.8. Germanium complexes involving bonding through oxygen and hydrogen (O, H)**

(**Scheme 42**). The color of reaction mixture changed immediately into pale yellow. The reaction mixture was further stirred for 2 h, and volume of solution is reduced under vacuum. After addition of n-hexane in flask, the reaction mixture was cooled slowly. The reaction mixture was placed unattended at −20°C overnight. The end product was obtained as colorless

CF3

**Scheme 42.** Synthesis of functionalized germanium complex.

32 Basic Concepts Viewed from Frontier in Inorganic Coordination Chemistry

 and Muhammad Adnan Iqbal1,2\* \*Address all correspondence to: adnan.iqbal@uaf.edu.pk

University of Agriculture, Faisalabad, Pakistan

conductor Processing. 2006;**9**(4-5):408-422

1 Department of Chemistry, University of Agriculture, Faisalabad, Pakistan

2 Organometallic & Coordination Chemistry Laboratory, Department of Chemistry,

[1] Haller E. Germanium: From its discovery to SiGe devices. Materials Science in Semi-

**C60** was formed when HSO3

blocks in 83% isolated yield [19].

**Author details**

Hina Hayat1

**References**


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): Synthesis and structural characterization. Inorganic Chemistry. 2012;**51**(16):

](AgC6 F5 )2 F5

}2 (L = HC[C(Me)N-2,6-*i*

)*n*]2 (*n* = 1, 2),

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Pr<sup>2</sup> C6 H3 ]2 )N<sup>2</sup>

]AgC6 F5

34 Basic Concepts Viewed from Frontier in Inorganic Coordination Chemistry

Inorganic Chemistry. 2017;**56**(9):5402-5410


**Chapter 3**

**Provisional chapter**

], by Robert Koch, at

**Inorganic Coordination Chemistry: Where We Stand in**

**Inorganic Coordination Chemistry: Where We Stand in** 

Metals have unique characteristics such as variable coordination modes, redox activity, and reactivity being indispensable for several biochemical processes in cells. Due to their reactivity, their concentration is tightly regulated inside the cells, and abnormal concentrations are associated with many disorders, such as cancer. As such metal complexes turned out to be very attractive as potential anticancer agents. The discovery of cisplatin was a crucial moment, which prompted the interest in Pt(II) and other metal complexes as potential anticancer agents. This chapter highlights the state of the art on metal complexes in cancer therapy, highlighting their uptake mechanisms, biological targets, toxicity, and drug resistance. Finally, based on the importance of selective target of cancer

**Keywords:** cancer therapy, metal complexes, mechanism of action, clinical trials,

Metal compounds are of undeniable importance to medicine, either for their toxicity or for their effectiveness in disease treatment. In ancient Egypt, copper was used to reduce inflammation and iron to treat anemia [1]. In modern medicine, noticeable discoveries of

around 1890, to treat tuberculosis; arsphenamine developed in the 1910s to cure syphilis; and Cisplatin discovered by Barnett Rosenberg in the late 1960s as an anticancer agent [2]. The latter marked a milestone in drug discovery for inorganic complexes, revolutionizing cancer

metal-based compounds marked the last centuries such as K[Au(CN)<sup>2</sup>

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

DOI: 10.5772/intechopen.80233

**Cancer Treatment?**

**Cancer Treatment?**

Pedro Pedrosa, Andreia Carvalho,

and Alexandra R. Fernandes

**Abstract**

**1. Introduction**

http://dx.doi.org/10.5772/intechopen.80233

platinum, ruthenium, copper

Pedro V. Baptista and Alexandra R. Fernandes

Pedro Pedrosa, Andreia Carvalho, Pedro V. Baptista

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

cells, drug delivery systems will also be discussed.

#### **Inorganic Coordination Chemistry: Where We Stand in Cancer Treatment? Inorganic Coordination Chemistry: Where We Stand in Cancer Treatment?**

DOI: 10.5772/intechopen.80233

Pedro Pedrosa, Andreia Carvalho, Pedro V. Baptista and Alexandra R. Fernandes Pedro Pedrosa, Andreia Carvalho, Pedro V. Baptista and Alexandra R. Fernandes

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.80233

#### **Abstract**

Metals have unique characteristics such as variable coordination modes, redox activity, and reactivity being indispensable for several biochemical processes in cells. Due to their reactivity, their concentration is tightly regulated inside the cells, and abnormal concentrations are associated with many disorders, such as cancer. As such metal complexes turned out to be very attractive as potential anticancer agents. The discovery of cisplatin was a crucial moment, which prompted the interest in Pt(II) and other metal complexes as potential anticancer agents. This chapter highlights the state of the art on metal complexes in cancer therapy, highlighting their uptake mechanisms, biological targets, toxicity, and drug resistance. Finally, based on the importance of selective target of cancer cells, drug delivery systems will also be discussed.

**Keywords:** cancer therapy, metal complexes, mechanism of action, clinical trials, platinum, ruthenium, copper

### **1. Introduction**

Metal compounds are of undeniable importance to medicine, either for their toxicity or for their effectiveness in disease treatment. In ancient Egypt, copper was used to reduce inflammation and iron to treat anemia [1]. In modern medicine, noticeable discoveries of metal-based compounds marked the last centuries such as K[Au(CN)<sup>2</sup> ], by Robert Koch, at around 1890, to treat tuberculosis; arsphenamine developed in the 1910s to cure syphilis; and Cisplatin discovered by Barnett Rosenberg in the late 1960s as an anticancer agent [2]. The latter marked a milestone in drug discovery for inorganic complexes, revolutionizing cancer

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

treatment and shifting focus to rational design to improve metal-based drugs, where other coordination compounds (e.g., gold, ruthenium, titanium, and copper) were also explored with some reports of (pre)clinical and clinical candidates [3, 4].

In the following sections, we will summarize the current knowledge on Pt, Au, Ru, Ti, Pd, Ir Cu, V, Co, Ga, and Os complexes, highlighting their uptake mechanisms, biological targets, toxicity, and drug resistance mechanisms and elucidating how far they are from translation to the clinics

Inorganic Coordination Chemistry: Where We Stand in Cancer Treatment?

http://dx.doi.org/10.5772/intechopen.80233

39

Platinum-containing complexes revolutionized cancer treatment since the introduction of cisplatin. Synthesized in 1844, it was used for the first time, more than 100 years later to treat patients with testicular cancer with survival rates over 90% [9]. Since then, more than 3000 platinum derivatives were synthesized and tested for antiproliferative potential against cancer cells. Today, there are six platinum drugs approved in cancer treatment, three of them—cisplatin, carboplatin, and oxaliplatin—by Food and Drug Administration (FDA) and used worldwide and the other three approved in specific countries—nedaplatin in Japan, lobaplatin in Korea, and heptaplatin in China [10]. Platins are the first-line therapeutics in several cancers either alone, in combination with radiotherapy, or with other antitumor or antiangiogenic drugs [9, 11, 12]. Their cellular effects result from four main steps: (i) internalization, (ii) aquation, (iii) formation of DNA adducts, and (iv) cell response (either survival or apoptosis) [13]. Once inside the cells, the ligands (chloride in cisplatin, dicarboxylate in carboplatin, and oxalate in oxaliplatin) are substituted by water molecules that interact with nucleophilic centers on purine bases of DNA, promoting not only cross-linking of the N7 sites of adjacent guanine nucleobases, but also interstrand crosslinks, inducing severe structural distortion of the double helix. This stalls DNA transcription and arrests the cell cycle at the G2/M transition. DNA repair machinery is recruited, and if unable to repair, cells trigger apoptotic cell death [13]. However, some cells enhance their DNA repair activity becoming resistant to cisplatin that have been associated with patient's relapse [14, 15]. Other DNA damage-independent processes have been proposed such as destabilization of redox homeostasis by increasing the intracellular levels of ROS. Cisplatin metabolism is in part performed by glutathione leading to its decrease, affecting NADPH pools, resulting in dysfunctional mitochondrial redox status, and causing ROS [16]. For all FDA approved platins, the mechanism of action is believed to be very similar, with incremental variations [17, 18]. Carboplatin has less toxicity than cisplatin because 1,1-cyclobutanedicarboxylate is a poorer leaving group than chloride lowering its potency being primarily used for ovarian cancer treatment [19]. Oxaliplatin was the latest approved platinum drug and is a part of the first-line treatment for colorectal cancer. In contrast to cisplatin and carboplatin, oxaliplatin features a quelating nonleaving group, 1,2-diaminocyclohexane (DACH) in place of the two monodentate amine ligands. It also features a bidentate chelating oxalate leaving group ligand [19]. Oxaliplatin does not form adducts as efficient as cisplatin, but the hydrophobicity and size of the DACH group make it more efficient in inhibiting DNA polymerization and repair [3]. Oxaliplatin cellular uptake is active and through copper transporters 1 and 2 and organic cation transporters (OCTs) 1 and 2; the latter explains its efficacy against colorectal cancer (with OCTs overexpression) [9]. Nedaplatin features *cis* ammine nonleaving group ligand (glycolate), associated with its greater water solubility. It has less toxicity than cisplatin and less nephrotoxic and is mainly used in combination therapy to manage urological tumors [20]. Heptaplatin features malonate as a chelating leaving group ligand and a chelating 2-(1-methylethyl)-1,3-dioxolane-4,5-dimethanamine nonleaving group ligand, which forms a seven-membered chelate ring. It is used for gastric cancer, but its advantage over cisplatin

in cancer therapy.

**1.1. Platinum**

Transition metals, such as zinc, iron, and copper, are involved in several biological processes, from electron transfer to enzyme cofactors meaning that their intracellular concentration is tightly regulated, otherwise it can lead to the development of various pathological disorders such as Menkes and Wilson diseases associated with copper impairment and accumulation, respectively [4]. A common characteristic of these metals is their ability to form reactive oxygen species (ROS), which are a part of cellular redox balance and fundamental in cell metabolism, signal transduction for proliferation, differentiation, and cell death, among others [3]. Redox homeostasis is controlled by compartmentalizing reactions in the cell in subcellular units such as mitochondria and peroxisomes [3]. It is therefore understandable the great impact that metal complexes can have on such redox balance. Disturbing the oxidant-antioxidant balance promotes an oxidizing environment leading to oxidative stress. When ROS are formed inside the cells, they can induce the lipid peroxidation of cell membranes, disrupt the mitochondrial membrane potential promoting membrane depolarization, induce DNA single-strand breaks, and oxidize the cysteine residues resulting in protein structural changes [3]. Cancer cells are known to have a different redox metabolism from normal cells, with augmented levels of intracellular ROS, mostly due to increased metabolic activity and hypoxia, especially in the core of solid tumors [4]. Metal complexes, due to their redox properties, have been shown to disturb cellular redox homeostasis resulting in enhanced levels of oxidative stress prompting cancer cell death [4–8].

DNA is the main intracellular target for a high number of anticancer metal complexes (e.g., cisplatin, carboplatin, and oxaliplatin); however, several other targets are known (**Figure 1**) [4].

**Figure 1.** Schematics of metal complex mechanisms of action that promotes cell death.

In the following sections, we will summarize the current knowledge on Pt, Au, Ru, Ti, Pd, Ir Cu, V, Co, Ga, and Os complexes, highlighting their uptake mechanisms, biological targets, toxicity, and drug resistance mechanisms and elucidating how far they are from translation to the clinics in cancer therapy.

### **1.1. Platinum**

**Figure 1.** Schematics of metal complex mechanisms of action that promotes cell death.

treatment and shifting focus to rational design to improve metal-based drugs, where other coordination compounds (e.g., gold, ruthenium, titanium, and copper) were also explored

Transition metals, such as zinc, iron, and copper, are involved in several biological processes, from electron transfer to enzyme cofactors meaning that their intracellular concentration is tightly regulated, otherwise it can lead to the development of various pathological disorders such as Menkes and Wilson diseases associated with copper impairment and accumulation, respectively [4]. A common characteristic of these metals is their ability to form reactive oxygen species (ROS), which are a part of cellular redox balance and fundamental in cell metabolism, signal transduction for proliferation, differentiation, and cell death, among others [3]. Redox homeostasis is controlled by compartmentalizing reactions in the cell in subcellular units such as mitochondria and peroxisomes [3]. It is therefore understandable the great impact that metal complexes can have on such redox balance. Disturbing the oxidant-antioxidant balance promotes an oxidizing environment leading to oxidative stress. When ROS are formed inside the cells, they can induce the lipid peroxidation of cell membranes, disrupt the mitochondrial membrane potential promoting membrane depolarization, induce DNA single-strand breaks, and oxidize the cysteine residues resulting in protein structural changes [3]. Cancer cells are known to have a different redox metabolism from normal cells, with augmented levels of intracellular ROS, mostly due to increased metabolic activity and hypoxia, especially in the core of solid tumors [4]. Metal complexes, due to their redox properties, have been shown to disturb cellular redox homeostasis

resulting in enhanced levels of oxidative stress prompting cancer cell death [4–8].

DNA is the main intracellular target for a high number of anticancer metal complexes (e.g., cisplatin, carboplatin, and oxaliplatin); however, several other targets are known (**Figure 1**) [4].

with some reports of (pre)clinical and clinical candidates [3, 4].

38 Basic Concepts Viewed from Frontier in Inorganic Coordination Chemistry

Platinum-containing complexes revolutionized cancer treatment since the introduction of cisplatin. Synthesized in 1844, it was used for the first time, more than 100 years later to treat patients with testicular cancer with survival rates over 90% [9]. Since then, more than 3000 platinum derivatives were synthesized and tested for antiproliferative potential against cancer cells. Today, there are six platinum drugs approved in cancer treatment, three of them—cisplatin, carboplatin, and oxaliplatin—by Food and Drug Administration (FDA) and used worldwide and the other three approved in specific countries—nedaplatin in Japan, lobaplatin in Korea, and heptaplatin in China [10]. Platins are the first-line therapeutics in several cancers either alone, in combination with radiotherapy, or with other antitumor or antiangiogenic drugs [9, 11, 12]. Their cellular effects result from four main steps: (i) internalization, (ii) aquation, (iii) formation of DNA adducts, and (iv) cell response (either survival or apoptosis) [13]. Once inside the cells, the ligands (chloride in cisplatin, dicarboxylate in carboplatin, and oxalate in oxaliplatin) are substituted by water molecules that interact with nucleophilic centers on purine bases of DNA, promoting not only cross-linking of the N7 sites of adjacent guanine nucleobases, but also interstrand crosslinks, inducing severe structural distortion of the double helix. This stalls DNA transcription and arrests the cell cycle at the G2/M transition. DNA repair machinery is recruited, and if unable to repair, cells trigger apoptotic cell death [13]. However, some cells enhance their DNA repair activity becoming resistant to cisplatin that have been associated with patient's relapse [14, 15]. Other DNA damage-independent processes have been proposed such as destabilization of redox homeostasis by increasing the intracellular levels of ROS. Cisplatin metabolism is in part performed by glutathione leading to its decrease, affecting NADPH pools, resulting in dysfunctional mitochondrial redox status, and causing ROS [16]. For all FDA approved platins, the mechanism of action is believed to be very similar, with incremental variations [17, 18]. Carboplatin has less toxicity than cisplatin because 1,1-cyclobutanedicarboxylate is a poorer leaving group than chloride lowering its potency being primarily used for ovarian cancer treatment [19]. Oxaliplatin was the latest approved platinum drug and is a part of the first-line treatment for colorectal cancer. In contrast to cisplatin and carboplatin, oxaliplatin features a quelating nonleaving group, 1,2-diaminocyclohexane (DACH) in place of the two monodentate amine ligands. It also features a bidentate chelating oxalate leaving group ligand [19]. Oxaliplatin does not form adducts as efficient as cisplatin, but the hydrophobicity and size of the DACH group make it more efficient in inhibiting DNA polymerization and repair [3]. Oxaliplatin cellular uptake is active and through copper transporters 1 and 2 and organic cation transporters (OCTs) 1 and 2; the latter explains its efficacy against colorectal cancer (with OCTs overexpression) [9]. Nedaplatin features *cis* ammine nonleaving group ligand (glycolate), associated with its greater water solubility. It has less toxicity than cisplatin and less nephrotoxic and is mainly used in combination therapy to manage urological tumors [20].

Heptaplatin features malonate as a chelating leaving group ligand and a chelating 2-(1-methylethyl)-1,3-dioxolane-4,5-dimethanamine nonleaving group ligand, which forms a seven-membered chelate ring. It is used for gastric cancer, but its advantage over cisplatin has controversial results in clinical trials [11]. Lobaplatin, a derivative of heptaplatin, fuses a cyclobutene ring to the seven-membered chelate ring instead of a dioxolane with an S-lactate as a leaving group ligand. It was originally approved to manage patients with chronic myelogenous leukemia, small-cell lung cancer, and metastatic cancer showing noncross-resistance to cisplatin [21]. Phase I clinical trial is undergoing to expand its use in combination therapy in solid tumors [22].

Despite all advances, platinum complexes still suffer from severe side effects as well as intrinsic or acquired multidrug drug resistance (MDR), limiting its applications. To surpass this, novel strategies are being explored. Some examples include the "rule-breaking" platinum compounds: complexes with glucose ligands, complexes that display trans geometries [28], positively charged molecules, Pt(IV) prodrugs that become reduced to Pt(II) inside the cells, and photoactive molecules, among others [6, 29]. Of those we will highlight three approaches, first the tentative to vectorize Pt(II) to cancer cells through glucose as a ligand. Cancer cells overexpress glucose transporters making them an ideal target for active therapy [29]. Patra and coworkers showed that this is a viable conjugation with increased accumulation of platinum in tumor cells and comparable efficacy *in vivo* with oxaliplatin [29]. Later, Lippard et al. described a Pt(IV)- (D)-1methyltryptophan conjugate coupled with an indoleamine-2,3-dioxygenase (IDO) ligand. IDO is an inhibitory immune checkpoint target that enhances antitumor immune response, thus increasing the efficacy of common chemotherapeutics and radiotherapy. This prodrug killed hormone-dependent, cisplatin resistant, and human ovarian cancer cells, by deregulating the autocrine-signaling loop IDO-AHR-IL6 and paving the way to new platinum immune-

Inorganic Coordination Chemistry: Where We Stand in Cancer Treatment?

http://dx.doi.org/10.5772/intechopen.80233

chemotherapy [30]. A photoactive platinum(IV) anticancer complex trans-[Pt(N<sup>3</sup>

tive uptake by the tumor compared with healthy tissues [36].

ity/antiproliferative activities [8, 39–44]. KP1019, trans-[Ru(In)<sup>2</sup>

ing the formation of ROS [45]. [Ru(bpy)(phpy)(dppz)]<sup>+</sup>

esophageal [10, 31].

**1.2. Ruthenium**

was used in photodynamic therapy. Upon irradiation with blue light, it binds to amino acid residues of thioredoxin, a multifunctional enzyme that regulates gene transcription, redox signaling, and cell growth, inhibiting cell apoptosis, overexpressed in several cancers, leading to an increase oxidative stress persistent for more than 48 h *in vitro*, with a potent antiproliferative activity. The complex might be suitable for treatment of peripheral cancers such as bladder and

Ruthenium complexes are already recognized as an effective alternative to platinum complexes, providing different mechanisms of action, different spectrum of activities, and potential to overcome platinum associated MDR [32]. Ruthenium has numerous properties: (i) they can exist in multiple oxidation states (II, III, and IV), all accessible under physiologic conditions, an advantage in the reducing environment of cancer tissues; (ii) they have the ability to coordinate ligands that can modulate their activity and have the same kinetics of ligand substitution in aqueous medium as that of Pt(II) complexes [33]; (iii) they have the possibility of occupying a large number of spatial positions due to its octahedral coordination geometry allowing to explore more and different ligands compared to platinum complexes; (iv) they reduced toxicity compared to platinum compounds and attributed to their ability to mimic iron binding to serum transferrin [34, 35] with higher selectivity for their targets due to selec-

In the last year, several ruthenium compounds have been synthetized, and their antiproliferative activities and mechanism of action against several tumors characterized [8, 37–39], where cell membrane changes, cell death due to intrinsic apoptosis pathway and/or autophagic pathway, ROS induction, inhibition of topoisomerase I and II might be the cause of their cytotoxic-

known to bind transferrin and causes apoptosis through the mitochondrial pathway promot-

cancer cell line, the high affinity that presents for DNA leads to damages in the transcription

Cl<sup>4</sup>

] [InH] (In = indazole), is

has found to be very cytotoxic against

) 2 (OH)2

(Py)2 ] 41

Currently, there are other platinum drugs in clinical trials: satraplatin, picoplatin, and two polymer/liposomal-based platinum drugs—ProLindac and Lipoplatin. Satraplatin, bis-(acetato) -ammine-dichloro-(cyclohexylamine) platinum(IV), was enrolled in several Phase I, II and III clinical trials mainly in conjunction with other drugs (e.g., docetaxel, paclitaxel, and capecitabine), but all have been recently terminated or concluded. Satraplatin was administered orally, absorbed by the gastrointestinal mucosa, and reduced in the bloodstream into more than six different Pt(II) complexes of which cis ammine dichloride(cyclohexylamine)-platinum(II) is the most important and showed anticancer activity against platinum sensitive and resistant cell lines. One of the most relevant Phase III trials evaluated a combination of satraplatin and prednisone against hormone refractory prostate cancer who had progressed after initial chemotherapy. In this study, 40% of patients had reduced risk of prostate cancer progression [23].

Picoplatin, cis-ammine-dichloride(2-methylpyridine) platinum(II), has a pyridine ring nearly perpendicular to the platinum plane, thus positioning the ligand's methylpyridine in a position that protects the metal center from nucleophilic attacks, specially by thiols. It has shown ability to overcome platinum drug resistance [23]. In Phase I clinical trials, picoplatin showed some side effects such as neutropenia, thrombocytopenia, nausea, and vomiting; however, no neuro- or nephrotoxicity was observed, and in three different Phase II clinical trials, it showed reduced efficacy as first- and second-line therapy. It is currently undergoing Phase I and Phase II studies as a combination therapy for colorectal cancer [24, 25].

Lipoplatin is a liposomal nanoparticle formulation of cisplatin with dipalmitoyl phosphatidyl glycerol (DPPG), soy phosphatidyl choline (SPC-3), cholesterol, and methoxy polyethylene glycol (mPEG2000)-distearoyl phosphatidylethanolamine (DSPE). The PEG allows cisplatin to evade the immune system increasing the circulation time. Lipoplatin fuses with cancer cells through DPPG, a fusogenic lipid embedded in the lipid bilayer allowing the release of cisplatin inside the cytoplasm of tumor cells [26]. It has successfully finished Phase III clinical trials showing superior effects when in combination with paclitaxel compared to cisplatin. Due to enhanced permeability and retention (EPR) effect, the nanoparticles are concentrated inside the tumor with 40- to 200-fold higher platinum concentration than healthy tissues [26].

ProLindac is a nanopolymer composed of [Pt(R,R-dach)], the active group of oxaliplatin, bound to an hydrophilic biocompatible polymer [hydroxypropylmethacrylamide (HPMA)] to better increase tumor targeting by EPR. The polymer segments are connected by amidomalonate chelating group and a triglycine spacer. The amidomalonate-platinum chelate bond breaks at low pH for releasing platinum complex in the hypoxic tumor microenvironment. ProLindac showed activity against cisplatin resistant cell lines [27]. Clinical trials showed no acute significant adverse effects. ProLindac has currently finished Phase II in combination with paclitaxel in the second-line treatment of pretreated advanced ovarian cancer with 66% of all patients achieving disease stabilization [27].

Despite all advances, platinum complexes still suffer from severe side effects as well as intrinsic or acquired multidrug drug resistance (MDR), limiting its applications. To surpass this, novel strategies are being explored. Some examples include the "rule-breaking" platinum compounds: complexes with glucose ligands, complexes that display trans geometries [28], positively charged molecules, Pt(IV) prodrugs that become reduced to Pt(II) inside the cells, and photoactive molecules, among others [6, 29]. Of those we will highlight three approaches, first the tentative to vectorize Pt(II) to cancer cells through glucose as a ligand. Cancer cells overexpress glucose transporters making them an ideal target for active therapy [29]. Patra and coworkers showed that this is a viable conjugation with increased accumulation of platinum in tumor cells and comparable efficacy *in vivo* with oxaliplatin [29]. Later, Lippard et al. described a Pt(IV)- (D)-1methyltryptophan conjugate coupled with an indoleamine-2,3-dioxygenase (IDO) ligand. IDO is an inhibitory immune checkpoint target that enhances antitumor immune response, thus increasing the efficacy of common chemotherapeutics and radiotherapy. This prodrug killed hormone-dependent, cisplatin resistant, and human ovarian cancer cells, by deregulating the autocrine-signaling loop IDO-AHR-IL6 and paving the way to new platinum immunechemotherapy [30]. A photoactive platinum(IV) anticancer complex trans-[Pt(N<sup>3</sup> ) 2 (OH)2 (Py)2 ] was used in photodynamic therapy. Upon irradiation with blue light, it binds to amino acid residues of thioredoxin, a multifunctional enzyme that regulates gene transcription, redox signaling, and cell growth, inhibiting cell apoptosis, overexpressed in several cancers, leading to an increase oxidative stress persistent for more than 48 h *in vitro*, with a potent antiproliferative activity. The complex might be suitable for treatment of peripheral cancers such as bladder and esophageal [10, 31].

### **1.2. Ruthenium**

has controversial results in clinical trials [11]. Lobaplatin, a derivative of heptaplatin, fuses a cyclobutene ring to the seven-membered chelate ring instead of a dioxolane with an S-lactate as a leaving group ligand. It was originally approved to manage patients with chronic myelogenous leukemia, small-cell lung cancer, and metastatic cancer showing noncross-resistance to cisplatin [21]. Phase I clinical trial is undergoing to expand its use in combination therapy in

40 Basic Concepts Viewed from Frontier in Inorganic Coordination Chemistry

Currently, there are other platinum drugs in clinical trials: satraplatin, picoplatin, and two polymer/liposomal-based platinum drugs—ProLindac and Lipoplatin. Satraplatin, bis-(acetato) -ammine-dichloro-(cyclohexylamine) platinum(IV), was enrolled in several Phase I, II and III clinical trials mainly in conjunction with other drugs (e.g., docetaxel, paclitaxel, and capecitabine), but all have been recently terminated or concluded. Satraplatin was administered orally, absorbed by the gastrointestinal mucosa, and reduced in the bloodstream into more than six different Pt(II) complexes of which cis ammine dichloride(cyclohexylamine)-platinum(II) is the most important and showed anticancer activity against platinum sensitive and resistant cell lines. One of the most relevant Phase III trials evaluated a combination of satraplatin and prednisone against hormone refractory prostate cancer who had progressed after initial chemotherapy. In this study, 40% of patients had reduced risk of prostate cancer progression [23].

Picoplatin, cis-ammine-dichloride(2-methylpyridine) platinum(II), has a pyridine ring nearly perpendicular to the platinum plane, thus positioning the ligand's methylpyridine in a position that protects the metal center from nucleophilic attacks, specially by thiols. It has shown ability to overcome platinum drug resistance [23]. In Phase I clinical trials, picoplatin showed some side effects such as neutropenia, thrombocytopenia, nausea, and vomiting; however, no neuro- or nephrotoxicity was observed, and in three different Phase II clinical trials, it showed reduced efficacy as first- and second-line therapy. It is currently undergoing Phase I

Lipoplatin is a liposomal nanoparticle formulation of cisplatin with dipalmitoyl phosphatidyl glycerol (DPPG), soy phosphatidyl choline (SPC-3), cholesterol, and methoxy polyethylene glycol (mPEG2000)-distearoyl phosphatidylethanolamine (DSPE). The PEG allows cisplatin to evade the immune system increasing the circulation time. Lipoplatin fuses with cancer cells through DPPG, a fusogenic lipid embedded in the lipid bilayer allowing the release of cisplatin inside the cytoplasm of tumor cells [26]. It has successfully finished Phase III clinical trials showing superior effects when in combination with paclitaxel compared to cisplatin. Due to enhanced permeability and retention (EPR) effect, the nanoparticles are concentrated inside the tumor with 40- to 200-fold higher platinum concentration than healthy tissues [26].

ProLindac is a nanopolymer composed of [Pt(R,R-dach)], the active group of oxaliplatin, bound to an hydrophilic biocompatible polymer [hydroxypropylmethacrylamide (HPMA)] to better increase tumor targeting by EPR. The polymer segments are connected by amidomalonate chelating group and a triglycine spacer. The amidomalonate-platinum chelate bond breaks at low pH for releasing platinum complex in the hypoxic tumor microenvironment. ProLindac showed activity against cisplatin resistant cell lines [27]. Clinical trials showed no acute significant adverse effects. ProLindac has currently finished Phase II in combination with paclitaxel in the second-line treatment of pretreated advanced ovarian cancer with 66%

and Phase II studies as a combination therapy for colorectal cancer [24, 25].

of all patients achieving disease stabilization [27].

solid tumors [22].

Ruthenium complexes are already recognized as an effective alternative to platinum complexes, providing different mechanisms of action, different spectrum of activities, and potential to overcome platinum associated MDR [32]. Ruthenium has numerous properties: (i) they can exist in multiple oxidation states (II, III, and IV), all accessible under physiologic conditions, an advantage in the reducing environment of cancer tissues; (ii) they have the ability to coordinate ligands that can modulate their activity and have the same kinetics of ligand substitution in aqueous medium as that of Pt(II) complexes [33]; (iii) they have the possibility of occupying a large number of spatial positions due to its octahedral coordination geometry allowing to explore more and different ligands compared to platinum complexes; (iv) they reduced toxicity compared to platinum compounds and attributed to their ability to mimic iron binding to serum transferrin [34, 35] with higher selectivity for their targets due to selective uptake by the tumor compared with healthy tissues [36].

In the last year, several ruthenium compounds have been synthetized, and their antiproliferative activities and mechanism of action against several tumors characterized [8, 37–39], where cell membrane changes, cell death due to intrinsic apoptosis pathway and/or autophagic pathway, ROS induction, inhibition of topoisomerase I and II might be the cause of their cytotoxicity/antiproliferative activities [8, 39–44]. KP1019, trans-[Ru(In)<sup>2</sup> Cl<sup>4</sup> ] [InH] (In = indazole), is known to bind transferrin and causes apoptosis through the mitochondrial pathway promoting the formation of ROS [45]. [Ru(bpy)(phpy)(dppz)]<sup>+</sup> has found to be very cytotoxic against cancer cell line, the high affinity that presents for DNA leads to damages in the transcription factor NF-κB [46]. DW1/2 inhibits PI3K and GSK3-β, which leads to apoptosis mediated by the mitochondrial and p53 pathways [34]. Several Ru(II) complexes demonstrate high-binding affinity to DNA [47–49]. Some of these complexes appear to act by intercalation in the tumor cells, although in some cases it has been demonstrated that they can operate by DNA photocleavage [50–52]. Ruthenium complexes with polypyridine ligands such as 2,2-bipyridine (bpy), 1,10-phenanthroline (phen), and 2,2′:6,2″-terpyridine (terpy) ligands have been largely explored as molecular DNA probes due to their photophysical properties and the ability of polypyridyl ligands to intercalate with DNA [35, 38, 53–55]. This type of ligands stabilizes the ruthenium metal ion in the oxidation state (II), resulting in solution-stable complexes of aqueous solution. Polypyridine ligands can confer photoluminescent properties to Ru(II) complexes, through a charge transfer between the metal and the ligand [56].

Of the numerous ruthenium complexes with antitumor action studied, only five Ru(III) com-

ole), KP1019, NKP-1339 (KP1019 sodium salt), KP1339, and Ru(II)-based therapeutic TLD1433 [35, 69]. NAMI-A is an antimetastatic compound that reduces the metastases and prevents the spread of secondary tumors [70, 71], whereas KP1019 is a cytotoxic compound effective against primary tumors [72]. NAMI-A and KP1019 are prodrugs that are activated *in vivo* by reduction to Ru(II) and well tolerated in clinical applications. The exact mode of action of both complexes is not clear, but it is known that they interact with DNA. NAMI-A and KP1019 successfully completed Phase I clinical trials; however, NAMI-A was recently withdrawn after Phase II due to its poor efficacy [69, 73]. In addition, the combination of gemcitabine with NAMI-A allows entry into a new Phase II [70], but the combination was not well tolerated by patients and did not continue to Phase III [73]. KP1019 demonstrated low solubility that limited further development. NKP-1339 is a GRP78-targeted ruthenium-based anticancer compound and administered intravenously with promising results in solid tumors, such as colorectal carcinoma and neuroendocrine tumors [74]. The results obtained so far in clinical trials with some of these Ru(III) drug candidates fostered the increased interest in Ru(II) candidates for cancer therapy [40]. Recently, TLD1433, a mixed ligand Ru(II)-polypyridyl compound, entered Phase I of clinical trials for nonmuscle invasive bladder cancer treatment

The interaction between the compounds and the plasma proteins is recognized as a crucial step in the access to bioavailability of metal complexes [32, 76, 77]. Serum albumin is the major protein in blood plasma acting as the carrier and distributor of many drugs because of its ability to bind reversibly to a variety of exogenous compounds [78, 79]. Their binding may increase solubility and prolong the *in vivo* half-life of the compounds, with a specific drug release at the target [77, 79, 80]. The interaction between compounds and proteins is usually analyzed by electronic absorption and fluorescence quenching. As various drugs bind to proteins in plasma, there has been an increasing investigation in the field of plasma protein binding (PPB). Ru(II) compounds bind preferentially to human serum albumin (HSA) and serum transferrin (Tf). These binding affinities showed that HSA appears to be the better partner [81]. KP1019 is known to strongly bind to serum proteins and hamper P-glycoprotein-mediated efflux, making this ruthenium therapeutic attractive for multidrugresistant tumor therapy [82]. RAPTA-C has shown a binding affinity to thioredoxin reductase

More recently, nanotechnology has provided numerous nanoplatforms that may act as vehicles for the active and more specific deliver of ruthenium(II) complexes toward cancer cells, namely Ru(II)—selenium nanoparticles, Ru(II)—gold nanomaterials, and Ru(II)—silica composite [39, 78–80]. Recently, Ru(II)-polypyridyl/thiol-selenium nanoparticles were found to be a powerful theranostic system, acting simultaneously as an imaging agent while fostering cancer cell death [84]. Chen and collaborators described a nanoparticle/Ru(II) polypyridyl

[85]. In this sight, this nanosystem might improve ruthenium complex stability, distribution, and delivery specifically toward cancer cells providing a new avenue as a future therapeutic

(H2O)2 ]

2+ upon laser irradiation

system that is able to release a DNA-binding agent [Ru(bpy)<sup>2</sup>

(DMSO) (Im)] [ImH] (NAMI-A, Im = imidaz-

http://dx.doi.org/10.5772/intechopen.80233

43

Inorganic Coordination Chemistry: Where We Stand in Cancer Treatment?

plexes have entered clinical trials: trans-[RuCl<sup>4</sup>

with photodynamic therapy (PDT) [75].

and cathepsin B [83].

strategy [86].

Cellular uptake of ruthenium complexes may occur through two mechanisms, energy dependent (endocytosis and active transport) and energy independent (facilitated diffusion and passive diffusion) [40]. For example, the complex [Ru(phen)<sup>2</sup> (mitatp)]2+ exhibited significant antitumor activity against several tumor cells, and flow cytometry experiments showed that the ruthenium compounds penetrate the cell membrane and accumulate in the nucleus, leading to cell cycle arrest and apoptosis [57]. The ruthenium compound [Ru(DIP)<sup>2</sup> (dppz)]2+ showed cellular uptake through an energy-independent process [58]. Transferrin is used to transport iron centers into the cell, where the cancer cells have a high number of transferrin receptors compared to healthy cells [59]. Ruthenium complexes are transported by transferrin into cells by binding to two ruthenium centers. Upon entry into cells, the complex is released at acidic pH. For example, KP1019 can use iron transport systems to locate itself inside the cell, binding to the DNA with a preference shown for G and A residues [36].

Several other ruthenium(II) metal complexes have been described in the literature that offers the possibility of designing molecules suitable for binding to specific biological targets, due to the fact that they exhibit a wide range of coordination numbers and possible geometries that allow the spatial organization of the different anions and organic ligands (for a review, See [60–64]). Examples with *in vitro* and *in vivo* antitumor activities are ruthenium(II) (η6 arene) complexes, such as [Ru (η6 -C6 H6 ) (dien)] Cl (dien = ethylenediamine), and RAPTA, ruthenium(II)-arene complexes with the monodent ligand PTA (PTA = 1,3,5-triaza-7-phosphoadamantene) [46–48]. Stable bidentate chelating ligands (e.g., dien), more hydrophobic arene ligand (tetrahydroanthracene), and chloride ligand were associated with complexes with increased activity [65]. The RAPTA family comprises a monodent ligand PTA and the η6-arene ligand. Recently, the RAPTA-C complex has been shown to reduce the growth of primary tumors in preclinical models in ovarian and colorectal carcinomas through an antiangiogenic mechanism [66]. RAPTA-C binds selectively to the nucleus of the histone protein in the chromatin, resulting in the chloride binding of the ligands, and the inhibition of moderate growth in primary tumors *in vivo* is translated [67]. Sadler and coworkers studied ruthenium complexes (II)-arene with dien ligands ([Ru (n-6-arene) Cl (dien)] and demonstrated to be stable and soluble in water, exhibiting anticancer activity both *in vitro* and *in vivo*, including activity against cisplatin-resistant cancer cells. The dien ligand was used because of the similarities presented with the ammonium ligands in cisplatin, which are thought to contribute for cytotoxicity, forming a hydrogen bond with the DNA [68].

Of the numerous ruthenium complexes with antitumor action studied, only five Ru(III) complexes have entered clinical trials: trans-[RuCl<sup>4</sup> (DMSO) (Im)] [ImH] (NAMI-A, Im = imidazole), KP1019, NKP-1339 (KP1019 sodium salt), KP1339, and Ru(II)-based therapeutic TLD1433 [35, 69]. NAMI-A is an antimetastatic compound that reduces the metastases and prevents the spread of secondary tumors [70, 71], whereas KP1019 is a cytotoxic compound effective against primary tumors [72]. NAMI-A and KP1019 are prodrugs that are activated *in vivo* by reduction to Ru(II) and well tolerated in clinical applications. The exact mode of action of both complexes is not clear, but it is known that they interact with DNA. NAMI-A and KP1019 successfully completed Phase I clinical trials; however, NAMI-A was recently withdrawn after Phase II due to its poor efficacy [69, 73]. In addition, the combination of gemcitabine with NAMI-A allows entry into a new Phase II [70], but the combination was not well tolerated by patients and did not continue to Phase III [73]. KP1019 demonstrated low solubility that limited further development. NKP-1339 is a GRP78-targeted ruthenium-based anticancer compound and administered intravenously with promising results in solid tumors, such as colorectal carcinoma and neuroendocrine tumors [74]. The results obtained so far in clinical trials with some of these Ru(III) drug candidates fostered the increased interest in Ru(II) candidates for cancer therapy [40]. Recently, TLD1433, a mixed ligand Ru(II)-polypyridyl compound, entered Phase I of clinical trials for nonmuscle invasive bladder cancer treatment with photodynamic therapy (PDT) [75].

factor NF-κB [46]. DW1/2 inhibits PI3K and GSK3-β, which leads to apoptosis mediated by the mitochondrial and p53 pathways [34]. Several Ru(II) complexes demonstrate high-binding affinity to DNA [47–49]. Some of these complexes appear to act by intercalation in the tumor cells, although in some cases it has been demonstrated that they can operate by DNA photocleavage [50–52]. Ruthenium complexes with polypyridine ligands such as 2,2-bipyridine (bpy), 1,10-phenanthroline (phen), and 2,2′:6,2″-terpyridine (terpy) ligands have been largely explored as molecular DNA probes due to their photophysical properties and the ability of polypyridyl ligands to intercalate with DNA [35, 38, 53–55]. This type of ligands stabilizes the ruthenium metal ion in the oxidation state (II), resulting in solution-stable complexes of aqueous solution. Polypyridine ligands can confer photoluminescent properties to Ru(II) com-

Cellular uptake of ruthenium complexes may occur through two mechanisms, energy dependent (endocytosis and active transport) and energy independent (facilitated diffusion and

antitumor activity against several tumor cells, and flow cytometry experiments showed that the ruthenium compounds penetrate the cell membrane and accumulate in the nucleus,

showed cellular uptake through an energy-independent process [58]. Transferrin is used to transport iron centers into the cell, where the cancer cells have a high number of transferrin receptors compared to healthy cells [59]. Ruthenium complexes are transported by transferrin into cells by binding to two ruthenium centers. Upon entry into cells, the complex is released at acidic pH. For example, KP1019 can use iron transport systems to locate itself inside the

Several other ruthenium(II) metal complexes have been described in the literature that offers the possibility of designing molecules suitable for binding to specific biological targets, due to the fact that they exhibit a wide range of coordination numbers and possible geometries that allow the spatial organization of the different anions and organic ligands (for a review, See [60–64]). Examples with *in vitro* and *in vivo* antitumor activities are ruthenium(II) (η6

ruthenium(II)-arene complexes with the monodent ligand PTA (PTA = 1,3,5-triaza-7-phosphoadamantene) [46–48]. Stable bidentate chelating ligands (e.g., dien), more hydrophobic arene ligand (tetrahydroanthracene), and chloride ligand were associated with complexes with increased activity [65]. The RAPTA family comprises a monodent ligand PTA and the η6-arene ligand. Recently, the RAPTA-C complex has been shown to reduce the growth of primary tumors in preclinical models in ovarian and colorectal carcinomas through an antiangiogenic mechanism [66]. RAPTA-C binds selectively to the nucleus of the histone protein in the chromatin, resulting in the chloride binding of the ligands, and the inhibition of moderate growth in primary tumors *in vivo* is translated [67]. Sadler and coworkers studied ruthenium complexes (II)-arene with dien ligands ([Ru (n-6-arene) Cl (dien)] and demonstrated to be stable and soluble in water, exhibiting anticancer activity both *in vitro* and *in vivo*, including activity against cisplatin-resistant cancer cells. The dien ligand was used because of the similarities presented with the ammonium ligands in cisplatin, which are thought to contribute

leading to cell cycle arrest and apoptosis [57]. The ruthenium compound [Ru(DIP)<sup>2</sup>

cell, binding to the DNA with a preference shown for G and A residues [36].


for cytotoxicity, forming a hydrogen bond with the DNA [68].

(mitatp)]2+ exhibited significant

) (dien)] Cl (dien = ethylenediamine), and RAPTA,

(dppz)]2+


plexes, through a charge transfer between the metal and the ligand [56].

passive diffusion) [40]. For example, the complex [Ru(phen)<sup>2</sup>

42 Basic Concepts Viewed from Frontier in Inorganic Coordination Chemistry

arene) complexes, such as [Ru (η6

The interaction between the compounds and the plasma proteins is recognized as a crucial step in the access to bioavailability of metal complexes [32, 76, 77]. Serum albumin is the major protein in blood plasma acting as the carrier and distributor of many drugs because of its ability to bind reversibly to a variety of exogenous compounds [78, 79]. Their binding may increase solubility and prolong the *in vivo* half-life of the compounds, with a specific drug release at the target [77, 79, 80]. The interaction between compounds and proteins is usually analyzed by electronic absorption and fluorescence quenching. As various drugs bind to proteins in plasma, there has been an increasing investigation in the field of plasma protein binding (PPB). Ru(II) compounds bind preferentially to human serum albumin (HSA) and serum transferrin (Tf). These binding affinities showed that HSA appears to be the better partner [81]. KP1019 is known to strongly bind to serum proteins and hamper P-glycoprotein-mediated efflux, making this ruthenium therapeutic attractive for multidrugresistant tumor therapy [82]. RAPTA-C has shown a binding affinity to thioredoxin reductase and cathepsin B [83].

More recently, nanotechnology has provided numerous nanoplatforms that may act as vehicles for the active and more specific deliver of ruthenium(II) complexes toward cancer cells, namely Ru(II)—selenium nanoparticles, Ru(II)—gold nanomaterials, and Ru(II)—silica composite [39, 78–80]. Recently, Ru(II)-polypyridyl/thiol-selenium nanoparticles were found to be a powerful theranostic system, acting simultaneously as an imaging agent while fostering cancer cell death [84]. Chen and collaborators described a nanoparticle/Ru(II) polypyridyl system that is able to release a DNA-binding agent [Ru(bpy)<sup>2</sup> (H2O)2 ]2+ upon laser irradiation [85]. In this sight, this nanosystem might improve ruthenium complex stability, distribution, and delivery specifically toward cancer cells providing a new avenue as a future therapeutic strategy [86].

### **1.3. Copper**

Copper is an essential element in the organism, important for the function of enzymes and proteins involved in energy metabolism, respiration, and DNA synthesis [87]. This metal acts as a catalytic cofactor in several enzymes and is involved in hemoglobin formation, xenobiotics, catecholamines biosynthesis, collagen crosslinking, and oxidation-reduction reactions in which it reacts with molecular oxygen for the production of free radicals [87]. Copper-dependent enzymes, such as cytochrome C oxidase, superoxide dismutase, ferroxidases, monoamine oxidase, and dopamine b-monooxygenase, are involved in ROS neutralization. In addition, efflux of anticancer drugs such as cisplatin employs specific copper efflux transporters ATP7A and ATP7B, together with multidrug efflux pumps belonging to the ABC superfamily [e.g., P-glycoprotein (Pgp, ABCB1) and multidrug resistance protein 2 (MRP2, ABCC2)] [88, 89].

dithiocarbamate, or (pyridine-2-ylmethylamino)-methylphenolate have been shown to induce

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45

Copper complexes with thiosemicarbazone ligands have antitumor activity by inhibiting enzymatic activity and inducing cell apoptosis [106]. A Cu pro-drug derived from thiosemicarbazone based on the His146 residue in the IB subdomain of palmitic acid (PA)-modified human serum albumin (HSA-PA) was able to kill cancer cell by targeting DNA and proteins. Also, the efficient delivery of the Cu pro-drug was improved when the leaving group was replaced with His146 and coordinated with Cu2+ to form the HSA − PA complex. The HSA-PA complex showed better tolerance and a higher drug accumulation in the tumor, a stronger

Casiopeína IIgly, one of the most promising drugs, shows a strong inhibition of cell proliferation against a glioma C6 cell line, *in vivo* as well as *in vitro*. This drug promotes cell death by an increase of ROS, with the consequence mitochondria damage followed by apoptosis caused through, caspase dependent and caspase independent pathways. Cas IIgly prevents malignant cells to continue with their life cycle, by inhibiting estrogen-mediated G1/S cell cycle progression [108, 109]. Currently, Cas IIIia is in Phase I clinical trials in Mexico, and experimental evidences demonstrated that the main mechanism of action is related to genera-

Copper complexes are normally water insoluble. Therefore, the use of polymers/nanoparticles with suitable size can increase cellular internalization, distribution, and targeting of tumor cells with reduced toxicity in healthy cells. Intramolecular copper containing amphiphilic hyperbranched polytriazoles (mPEGhb-S-S-PTAs) was synthesized via Cu(I)-catalyzed azidealkyne cycloaddition (CuAAC) reaction, forming copper-triazole coordination polyprodrugs that were used to delivery copper and for label-free cellular bioimaging, a novel theranostic

The major molecular targets for anticancer effects of vanadium compounds are the breakdown of cellular metabolism through the generation of ROS, GSH depletion, changes in cellular organelles, some pathways of signal transduction, and caspases, which can lead to cell cycle arrest and cell death. Pombeiro et al. synthesized two water-soluble heterometallic potassiumdioxidovanadium(V) complexes, with an antiproliferative potential toward human colorectal carcinoma, lung, and breast adenocarcinoma cell lines. They demonstrate that the complex has a very high cytotoxic potential in the HCT116 cell line, a positive trait for future *in vivo*

Vanadocene is a metallocene with a metal ion sandwiched between two cyclopentadienyl

results in preclinical studies [113]. This complex showed a strong activity *in vitro* against several tumor cells. In addition, *in vivo* studies demonstrated antitumor properties with vanadocene dichloride [114]. Some vanadocene derivatives present cytotoxic effect against T-lymphocytic leukemia cells, where the mechanism used evolves the DNA damage and p53 activation [115]. On the other hand, vanadocenes are effective agents against human testicular

], was the first vanadocene that showed interesting

Cl<sup>2</sup>

(diagnostic and therapy simultaneously) application toward cancer therapy [111].

capacity for inhibiting tumor growth, and a lower toxicity in other tissues [107].

tion of ROS and DNA damage, through intercalation process [110].

apoptosis by proteasome inhibition [105].

**1.4. Vanadium**

studies [112].

rings. Vanadocene dichloride, [VCp<sup>2</sup>

Copper complexes are the most studied transition metal complexes for their antitumor properties because endogenous metal ions may lead to less systemic toxicity. The properties of the copper complexes are determined by the nature of their ligands, which themselves may exhibit antiproliferative activity [87]. Several Cu(II) complexes with a variety of ligands containing N, S, or O have been developed, demonstrating different mechanisms for their antitumor activity [6, 90, 91]. The ligands neutralize the electrical charge of the copper ion and facilitate the transport of the complex through the cell membrane, interacting noncovalently with proteins or intercalating into the DNA molecule [92]. Copper complexes are capable of inducing DNA breaks through hydrolytic or oxidative cleavages [93–97]. Recently, a copper(II) complex [Cu(C20H22NO<sup>3</sup> ) 2 ]·H2 O was synthesized, and its mechanism of action evaluated by spectroscopic methods, showing that the complex binds to calf-thymus DNA through a partial intercalation and presents a static quenching process as binding mechanism. The cytotoxicity evaluation in cancer cell lines showed an enhanced cytotoxicity compared with the Schiff base ligand; thus, a positive synergetic effect may be occurring [98]. Horman et al. developed functionalized Cu(II) cyclen complexes with three (2-anthraquinonyl)methyl substituents that efficiently inhibited DNA and RNA syntheses resulting in high cytotoxicity accompanied by DNA condensation/aggregation phenomena [99]. Sigman et al. reported the first set of copper complexes with phen ligand with good cytotoxic activities [100]. The complex with two phen ligands is capable of cleaving the DNA by binding to the deoxyribose units, acting as a chemical nuclease [101]. Trejo-Solis et al. synthesized a class of Cu(II) complexes having the general formula [Cu (NN) (AA)] NO<sup>3</sup> , wherein NN is phen or bipy, and AA is a nitrogen-oxygen donor or oxygen-oxygen donor ligand that is capable of inducing autophagy and programmed cell death cells by activation of ROS and JNK in glioma cells [102]. Another study demonstrated the antitumor properties of phen Cu(II) complexes with different alkyl chains. One of them showed a promising anticancer activity as well as antimetastatic and antiangiogenic potential, evidencing the versatility of Cu(II) complexes for cancer therapy [103].

A complex of Topo-I inhibitors, [Cu (N) L] Cl (N = phen, bipy or 5,50-dimethyl-2,20-bipyridine; L = doubly 5-triphenylphosphonium-methyl)-salicylaldehyde deprotonated hyde-benzoyl hydrazone, exhibits good cytotoxic activity against human lung and prostate adenocarcinoma cell lines [104], with the most active compound of this family being the one containing the fen motif.

Proteasome inhibition is another mechanism by which copper complexes exercise their antitumor activity. For example, Cu(II) complexes containing phen, 8-hydroxyquinolinate, pyrrolidine dithiocarbamate, or (pyridine-2-ylmethylamino)-methylphenolate have been shown to induce apoptosis by proteasome inhibition [105].

Copper complexes with thiosemicarbazone ligands have antitumor activity by inhibiting enzymatic activity and inducing cell apoptosis [106]. A Cu pro-drug derived from thiosemicarbazone based on the His146 residue in the IB subdomain of palmitic acid (PA)-modified human serum albumin (HSA-PA) was able to kill cancer cell by targeting DNA and proteins. Also, the efficient delivery of the Cu pro-drug was improved when the leaving group was replaced with His146 and coordinated with Cu2+ to form the HSA − PA complex. The HSA-PA complex showed better tolerance and a higher drug accumulation in the tumor, a stronger capacity for inhibiting tumor growth, and a lower toxicity in other tissues [107].

Casiopeína IIgly, one of the most promising drugs, shows a strong inhibition of cell proliferation against a glioma C6 cell line, *in vivo* as well as *in vitro*. This drug promotes cell death by an increase of ROS, with the consequence mitochondria damage followed by apoptosis caused through, caspase dependent and caspase independent pathways. Cas IIgly prevents malignant cells to continue with their life cycle, by inhibiting estrogen-mediated G1/S cell cycle progression [108, 109]. Currently, Cas IIIia is in Phase I clinical trials in Mexico, and experimental evidences demonstrated that the main mechanism of action is related to generation of ROS and DNA damage, through intercalation process [110].

Copper complexes are normally water insoluble. Therefore, the use of polymers/nanoparticles with suitable size can increase cellular internalization, distribution, and targeting of tumor cells with reduced toxicity in healthy cells. Intramolecular copper containing amphiphilic hyperbranched polytriazoles (mPEGhb-S-S-PTAs) was synthesized via Cu(I)-catalyzed azidealkyne cycloaddition (CuAAC) reaction, forming copper-triazole coordination polyprodrugs that were used to delivery copper and for label-free cellular bioimaging, a novel theranostic (diagnostic and therapy simultaneously) application toward cancer therapy [111].

### **1.4. Vanadium**

**1.3. Copper**

the fen motif.

Copper is an essential element in the organism, important for the function of enzymes and proteins involved in energy metabolism, respiration, and DNA synthesis [87]. This metal acts as a catalytic cofactor in several enzymes and is involved in hemoglobin formation, xenobiotics, catecholamines biosynthesis, collagen crosslinking, and oxidation-reduction reactions in which it reacts with molecular oxygen for the production of free radicals [87]. Copper-dependent enzymes, such as cytochrome C oxidase, superoxide dismutase, ferroxidases, monoamine oxidase, and dopamine b-monooxygenase, are involved in ROS neutralization. In addition, efflux of anticancer drugs such as cisplatin employs specific copper efflux transporters ATP7A and ATP7B, together with multidrug efflux pumps belonging to the ABC superfamily [e.g., P-glycoprotein (Pgp, ABCB1) and multidrug resistance protein 2 (MRP2, ABCC2)] [88, 89].

44 Basic Concepts Viewed from Frontier in Inorganic Coordination Chemistry

Copper complexes are the most studied transition metal complexes for their antitumor properties because endogenous metal ions may lead to less systemic toxicity. The properties of the copper complexes are determined by the nature of their ligands, which themselves may exhibit antiproliferative activity [87]. Several Cu(II) complexes with a variety of ligands containing N, S, or O have been developed, demonstrating different mechanisms for their antitumor activity [6, 90, 91]. The ligands neutralize the electrical charge of the copper ion and facilitate the transport of the complex through the cell membrane, interacting noncovalently with proteins or intercalating into the DNA molecule [92]. Copper complexes are capable of inducing DNA breaks through

hydrolytic or oxidative cleavages [93–97]. Recently, a copper(II) complex [Cu(C20H22NO<sup>3</sup>

Cu(II) complexes having the general formula [Cu (NN) (AA)] NO<sup>3</sup>

was synthesized, and its mechanism of action evaluated by spectroscopic methods, showing that the complex binds to calf-thymus DNA through a partial intercalation and presents a static quenching process as binding mechanism. The cytotoxicity evaluation in cancer cell lines showed an enhanced cytotoxicity compared with the Schiff base ligand; thus, a positive synergetic effect may be occurring [98]. Horman et al. developed functionalized Cu(II) cyclen complexes with three (2-anthraquinonyl)methyl substituents that efficiently inhibited DNA and RNA syntheses resulting in high cytotoxicity accompanied by DNA condensation/aggregation phenomena [99]. Sigman et al. reported the first set of copper complexes with phen ligand with good cytotoxic activities [100]. The complex with two phen ligands is capable of cleaving the DNA by binding to the deoxyribose units, acting as a chemical nuclease [101]. Trejo-Solis et al. synthesized a class of

and AA is a nitrogen-oxygen donor or oxygen-oxygen donor ligand that is capable of inducing autophagy and programmed cell death cells by activation of ROS and JNK in glioma cells [102]. Another study demonstrated the antitumor properties of phen Cu(II) complexes with different alkyl chains. One of them showed a promising anticancer activity as well as antimetastatic and antiangiogenic potential, evidencing the versatility of Cu(II) complexes for cancer therapy [103]. A complex of Topo-I inhibitors, [Cu (N) L] Cl (N = phen, bipy or 5,50-dimethyl-2,20-bipyridine; L = doubly 5-triphenylphosphonium-methyl)-salicylaldehyde deprotonated hyde-benzoyl hydrazone, exhibits good cytotoxic activity against human lung and prostate adenocarcinoma cell lines [104], with the most active compound of this family being the one containing

Proteasome inhibition is another mechanism by which copper complexes exercise their antitumor activity. For example, Cu(II) complexes containing phen, 8-hydroxyquinolinate, pyrrolidine

) 2 ]·H2 O

, wherein NN is phen or bipy,

The major molecular targets for anticancer effects of vanadium compounds are the breakdown of cellular metabolism through the generation of ROS, GSH depletion, changes in cellular organelles, some pathways of signal transduction, and caspases, which can lead to cell cycle arrest and cell death. Pombeiro et al. synthesized two water-soluble heterometallic potassiumdioxidovanadium(V) complexes, with an antiproliferative potential toward human colorectal carcinoma, lung, and breast adenocarcinoma cell lines. They demonstrate that the complex has a very high cytotoxic potential in the HCT116 cell line, a positive trait for future *in vivo* studies [112].

Vanadocene is a metallocene with a metal ion sandwiched between two cyclopentadienyl rings. Vanadocene dichloride, [VCp<sup>2</sup> Cl<sup>2</sup> ], was the first vanadocene that showed interesting results in preclinical studies [113]. This complex showed a strong activity *in vitro* against several tumor cells. In addition, *in vivo* studies demonstrated antitumor properties with vanadocene dichloride [114]. Some vanadocene derivatives present cytotoxic effect against T-lymphocytic leukemia cells, where the mechanism used evolves the DNA damage and p53 activation [115]. On the other hand, vanadocenes are effective agents against human testicular cell lines [36]. Vanadocenes containing fen ligands are promising anticancer agents, due to their high anticancer activity, solubility, and stability [37]. Currently, there are two complexes under preclinical trial [VCp<sup>2</sup> Cl<sup>2</sup> ] and Metvan, bis(4,7-dimethyl-1,10-phenanthroline) sulfatooxovanadium(IV). Metvan induces cell damage through apoptosis in several cell lines, with a special cytotoxic in ovarian and testicular cancer cell resistant to cisplatin. *In vivo* models, Metvan shows a promising anticancer activity on glioblastoma and breast cancer [116]. Cortizo et al. developed a delivery system of vanadium(IV) with aspirin (VOAspi) functionalized with poly(beta-propiolactone) (PbetaPL) films. VOAspi-PbetaPL film inhibited cell proliferation of UMR106 osteosarcoma cells in a dose-response manner [117].

condition and low solubility in aqueous media were the reasons of low activity in Phase II trials [124]. On the other hand, it was found that titanocene dichloride binds to DNA through the phosphate backbone, inhibiting DNA synthesis and leading to cell death [125]. The binding studies allowed to conclude that the cellular uptake of titanocene dichloride can be medi-

The biological activity of gallium(III) arises from chemical similarity with iron(III). They have similar ionic radius, ionization potential, and electronic affinity [127]. However, the principal difference is that Ga(III) is nonreducible, whereas Fe(III) is reduced to Fe(II) under physiological

Clinical Phase I and Phase II studies were performed on gallium nitrate, gallium chloride, and gallium maltolate. The first-generation gallium nitrate demonstrated, in several clinical trials, efficacy against bladder cancer and urothelium carcinoma, but these studies were discontinued due to ocular toxicity. The most promising results, come from the combination with vinblastine and ifosfamide, in a Phase II trial GA were effective in metastatic urothelial

responses was short at 20 weeks. This was associated with a high toxicity, and 11 of 27 patients had anemia and renal function alteration [128]. Oral gallium chloride seems to potentiate the action of cisplatin and etoposide. Oral gallium maltolate demonstrated higher bioavailability than gallium chloride. Preclinical studies have demonstrated synergy between Ga and paclitaxel [129]/gemcitabine [130]. Currently, two compounds are in clinical trials, gallium tris-8-quinolinolate (KP46) and gallium tris-maltolate. KP46 contains the metal chelating agent 8-hydroxyquinoline and has an inhibitory effect in cell growth proliferation *in vitro* and *in vivo* superior to gallium salt. An oral formulation of KP46 demonstrates a pattern of cytotoxicity with synergism across a broad range of antitumor agents targeting the endoplasmic reticulum in multiple tumor types [131, 132]. Gallium maltolate, (3-hydroxy-2-methyl-4H-pyran-4-onato) gallium, is an oral formulation for therapeutic use. This compound entry in Phase I demonstrated an oral bioavailability of about 27–47%. At doses as high as 3500 mg/day for 28-day cycles, no dose-limiting toxicity or drug-related adverse effects were observed [133]. However, this study was discontinued, and no new results were published. The mechanism of action of gallium(III) has been studied, and Ga3+ ions normally compete with Fe3+ for binding transferrin. Analyzing the biological pathways of gallium(III), it seems that its mechanism of action is associated with the inhibition of ribonucleotide reductase (RR). The enzyme RR produces during the transition from G1 to S phase of the cell cycle and catalyzes the conver-

Osmium(II) complexes are the heavier congeners of ruthenium, exhibit slower kinetic than ruthenium, and are substitution-inert (Os(II) and Os(III) complexes). In addition, they offer a more complex interaction with double-helical DNA. However, the reactivity of the Os(II)-arene complexes can be adjusted by the chemistry of the aqueous solution. Sadler et al. synthesized

/24 h for 5 consecutive days. However, the duration of the

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47

ated by the iron transferrin transporter protein [126].

sion of ribonucleotides to deoxyribonucleotides [63].

**1.7. Gallium**

condition [63].

**1.8. Osmium**

carcinomas at a dose of 300 mg/m<sup>2</sup>

### **1.5. Iridium**

Iridium complexes are emerging as a class of anticancer agents. Novohradsky et al. studied the mechanisms of new cytotoxic iridium(III) complex in cancer cells. A half-sandwich cyclometallated Ir(III) complex [(η<sup>5</sup> -Cp\*)(Ir)(7,8-benzoquinoline)Cl] bearing a C^N chelating ligand was designed and studied its uptake in ovarian cancer cells [118]. The temperature dependence and the coincubation with different substrates (such as ouabain, 2-deoxy-Dglucose and oligomycin, verapamil, reversan, and buthionine sulfoximine) indicate that an energy-independent passive diffusion and an energy-dependent transport play a partial role in the complex accumulation. Moreover, the competition experiments with CuCl<sup>2</sup> suggested an involvement of Ctr1 pathway in the compound's uptake. The authors highlighted the importance of ATP-dependent processes and transport proteins, such as Na/K-ATPase for accumulation of Ir complexes. The iridium complexes may exert anticancer efficacy through various mechanisms including modulation of cellular redox reactions and inhibition of protein kinases. Recently, the cyclometalated iridium(III) complexes have gained increasing attention in bioimaging and biosensing applications due to their luminescence properties, for example, large Stokes shifts, long-lived luminescence, high quantum yields, and cell permeability [119].

### **1.6. Titanium**

Since the 1970s, when the first titanium complex arises, a series of complexes containing titanium, Ti, as a metal center have been synthesized and characterized, and some of them were shown to possess a wide spectrum of antitumor properties. Indeed, titanium complexes such as titanocene dichloride and octahedral species budotitane are promising anticancer results being translated to (pre)- and clinical trials. Preclinical trials had shown efficacy in a broad of tumors [113, 120]. Budotitane was investigated in Phase I trial, and pharmacokinetic study administered as i.v. infusion twice weekly with a starting dose of 100 mg/m<sup>2</sup> . However, no response was observed, but 17 of 18 patients have been resistant as they had received prior chemotherapy [121]. Titanocene dichloride showed promising results in Phase I trials with patients suffering from various cancer types. In one study, 40 patients with refractory solid malignancies the titanocene dichloride revealed a two minor responses (in bladder carcinoma and in nonsmall cell lung cancer), with dose-limiting toxicity side effect was nephrotoxicity [122]. Phase II trials were conducted at 270 mg/m<sup>2</sup> every 3 weeks with 14 patients suffering from metastatic renal-cell carcinoma [123]. However, no significant response was noted, and the effectiveness of the treatment was limited in both cases. The instability under physiological condition and low solubility in aqueous media were the reasons of low activity in Phase II trials [124]. On the other hand, it was found that titanocene dichloride binds to DNA through the phosphate backbone, inhibiting DNA synthesis and leading to cell death [125]. The binding studies allowed to conclude that the cellular uptake of titanocene dichloride can be mediated by the iron transferrin transporter protein [126].

### **1.7. Gallium**

cell lines [36]. Vanadocenes containing fen ligands are promising anticancer agents, due to their high anticancer activity, solubility, and stability [37]. Currently, there are two com-

sulfatooxovanadium(IV). Metvan induces cell damage through apoptosis in several cell lines, with a special cytotoxic in ovarian and testicular cancer cell resistant to cisplatin. *In vivo* models, Metvan shows a promising anticancer activity on glioblastoma and breast cancer [116]. Cortizo et al. developed a delivery system of vanadium(IV) with aspirin (VOAspi) functionalized with poly(beta-propiolactone) (PbetaPL) films. VOAspi-PbetaPL film inhibited cell pro-

Iridium complexes are emerging as a class of anticancer agents. Novohradsky et al. studied the mechanisms of new cytotoxic iridium(III) complex in cancer cells. A half-sandwich

ligand was designed and studied its uptake in ovarian cancer cells [118]. The temperature dependence and the coincubation with different substrates (such as ouabain, 2-deoxy-Dglucose and oligomycin, verapamil, reversan, and buthionine sulfoximine) indicate that an energy-independent passive diffusion and an energy-dependent transport play a partial role

an involvement of Ctr1 pathway in the compound's uptake. The authors highlighted the importance of ATP-dependent processes and transport proteins, such as Na/K-ATPase for accumulation of Ir complexes. The iridium complexes may exert anticancer efficacy through various mechanisms including modulation of cellular redox reactions and inhibition of protein kinases. Recently, the cyclometalated iridium(III) complexes have gained increasing attention in bioimaging and biosensing applications due to their luminescence properties, for example, large Stokes shifts, long-lived luminescence, high quantum yields, and cell permeability [119].

Since the 1970s, when the first titanium complex arises, a series of complexes containing titanium, Ti, as a metal center have been synthesized and characterized, and some of them were shown to possess a wide spectrum of antitumor properties. Indeed, titanium complexes such as titanocene dichloride and octahedral species budotitane are promising anticancer results being translated to (pre)- and clinical trials. Preclinical trials had shown efficacy in a broad of tumors [113, 120]. Budotitane was investigated in Phase I trial, and pharmacokinetic study

response was observed, but 17 of 18 patients have been resistant as they had received prior chemotherapy [121]. Titanocene dichloride showed promising results in Phase I trials with patients suffering from various cancer types. In one study, 40 patients with refractory solid malignancies the titanocene dichloride revealed a two minor responses (in bladder carcinoma and in nonsmall cell lung cancer), with dose-limiting toxicity side effect was nephrotoxicity

from metastatic renal-cell carcinoma [123]. However, no significant response was noted, and the effectiveness of the treatment was limited in both cases. The instability under physiological

administered as i.v. infusion twice weekly with a starting dose of 100 mg/m<sup>2</sup>

[122]. Phase II trials were conducted at 270 mg/m<sup>2</sup>

in the complex accumulation. Moreover, the competition experiments with CuCl<sup>2</sup>

] and Metvan, bis(4,7-dimethyl-1,10-phenanthroline)


suggested

. However, no

every 3 weeks with 14 patients suffering

Cl<sup>2</sup>

liferation of UMR106 osteosarcoma cells in a dose-response manner [117].

plexes under preclinical trial [VCp<sup>2</sup>

46 Basic Concepts Viewed from Frontier in Inorganic Coordination Chemistry

cyclometallated Ir(III) complex [(η<sup>5</sup>

**1.5. Iridium**

**1.6. Titanium**

The biological activity of gallium(III) arises from chemical similarity with iron(III). They have similar ionic radius, ionization potential, and electronic affinity [127]. However, the principal difference is that Ga(III) is nonreducible, whereas Fe(III) is reduced to Fe(II) under physiological condition [63].

Clinical Phase I and Phase II studies were performed on gallium nitrate, gallium chloride, and gallium maltolate. The first-generation gallium nitrate demonstrated, in several clinical trials, efficacy against bladder cancer and urothelium carcinoma, but these studies were discontinued due to ocular toxicity. The most promising results, come from the combination with vinblastine and ifosfamide, in a Phase II trial GA were effective in metastatic urothelial carcinomas at a dose of 300 mg/m<sup>2</sup> /24 h for 5 consecutive days. However, the duration of the responses was short at 20 weeks. This was associated with a high toxicity, and 11 of 27 patients had anemia and renal function alteration [128]. Oral gallium chloride seems to potentiate the action of cisplatin and etoposide. Oral gallium maltolate demonstrated higher bioavailability than gallium chloride. Preclinical studies have demonstrated synergy between Ga and paclitaxel [129]/gemcitabine [130]. Currently, two compounds are in clinical trials, gallium tris-8-quinolinolate (KP46) and gallium tris-maltolate. KP46 contains the metal chelating agent 8-hydroxyquinoline and has an inhibitory effect in cell growth proliferation *in vitro* and *in vivo* superior to gallium salt. An oral formulation of KP46 demonstrates a pattern of cytotoxicity with synergism across a broad range of antitumor agents targeting the endoplasmic reticulum in multiple tumor types [131, 132]. Gallium maltolate, (3-hydroxy-2-methyl-4H-pyran-4-onato) gallium, is an oral formulation for therapeutic use. This compound entry in Phase I demonstrated an oral bioavailability of about 27–47%. At doses as high as 3500 mg/day for 28-day cycles, no dose-limiting toxicity or drug-related adverse effects were observed [133]. However, this study was discontinued, and no new results were published. The mechanism of action of gallium(III) has been studied, and Ga3+ ions normally compete with Fe3+ for binding transferrin. Analyzing the biological pathways of gallium(III), it seems that its mechanism of action is associated with the inhibition of ribonucleotide reductase (RR). The enzyme RR produces during the transition from G1 to S phase of the cell cycle and catalyzes the conversion of ribonucleotides to deoxyribonucleotides [63].

### **1.8. Osmium**

Osmium(II) complexes are the heavier congeners of ruthenium, exhibit slower kinetic than ruthenium, and are substitution-inert (Os(II) and Os(III) complexes). In addition, they offer a more complex interaction with double-helical DNA. However, the reactivity of the Os(II)-arene complexes can be adjusted by the chemistry of the aqueous solution. Sadler et al. synthesized and developed osmium(II) arene complexes and proved their anticancer properties by systematically varying the chelating ligand in kinetics and thermodynamic reaction of the complexes [134, 135]. These series of N,O-chelates ligands are important choices in the stability and cancer toxicity [134, 136]. DNA-binding studies on a series of complexes of the type osmium(II)-arene have shown that these complexes bind to polymeric DNA, where some coordinate with guanine and others undergo quantitative reaction with DNA [137].

nonsmall cell lung cancer, ovarian, and pancreatic cancers, playing a critical role in oncogenesis. Aurothiomalate has been shown to inhibit PKCiota signaling having potent antitumor activity in preclinical studies [142, 143]. Using the same mechanism, aurothioglucose also showed antitumor efficacy *in vitro* against nonsmall cell lung cancer cells [144]. For the cellular uptake, it was proposed that Au(I) enters the cell through albumin bond or through other thiol metabolites [144]. A recent study by Mármol proposes an alkynyl gold(I) com-

cells, gold complex enters the mitochondria and disrupts its normal function, triggering the necroptosis. Necrose-inducing compounds are mainly interesting as they are an alternative

Cobalt complexes have normally two accessible oxidation states. Co(III) is kinetically inert, whereas Co(II) is labile. Some studies demonstrated that Co(III) complexes can act as carriers for selective delivery of drugs [69]. However, when Co(III) is reduced to Co(II), the molecule is released in its active form and can kill cancer cells [146]. Hexacarbonyl dicobalt and alkynes exhibit a promising activity of antitumor activity [147]. The activity is most pronounced when the alkyne is the propargyl ester of aspirin (CoASS), which inhibits the cyclooxygenase enzymes COX-1 and COX-2 [147, 148]. It was shown that CoASS itself inhibits COX-1 and COX-2 more strongly than ASA alone and enhanced the cytotoxicity against breast cancer cell line [148]. The development of new complexes bearing different types of pyrazole-based ligands demonstrated the potential use of these complexes as anti-

][BF<sup>4</sup>

(TS265) was demonstrated to induce cell cycle arrest in S phase with a subsequent cell death by apoptosis and high cytotoxicity against colorectal carcinoma cell [76]. Fernandes et al.

anthroline-5,6-dione) and TS265 and the application of AuNPs as a drug delivery system to improve the anticancer efficacy of these compounds in a new canine mammary tumor (FR37- CMT) [150]. The same group formulated a multifunctional nanovectorization system using gold nanoparticles to enhance cytotoxic of TS265. This nanoformulation efficient delivered the cytotoxic cargo in a controlled selective manner [151]. Two mononuclear NiII and MnII compounds with a "scorpionate" type precursor demonstrated to induce damage in ovarian cancer cells through ROS accumulation. In addition, the mononuclear NiII compound induced

Although the intensive study of transition metals is focused on a specific biomolecular target, some complexes are developed for other purposes. For example, palladium-porphyrin complex (TOOKAD-soluble) acts as a photosensitizer and has progressed to Phase III clinical trial for the photodynamic treatment of prostate cancer (NCT01875393). Phase II clinical trials were evaluated the efficacy and safety of a single dose of the drug and light dosage combination of TOOKAD® Soluble in the focal treatment of patients with localized prostate cancer, 6 months after treatment. Positive results obtained at 6-month negative biopsies were acquire. This complex has a dual role; that is, it provides the ideal photophysical properties to the

porphyrin and is inert enough not to be displaced during therapy (**Table 1**) [152].

)(PTA)] to treat colorectal carcinoma. In their study, using Caco-2

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49

] (phendione = 1,10-phenanthroline-5,6-dione)

]Cl (TS262, DION = 1,10-phen-

plex [Au(C ≡ C-2-NC<sup>5</sup>

**1.10. Other complexes**

proliferative agents [149].

A new compound CoCl(H<sup>2</sup>

H4

chemotherapy for apoptosis resistance tumors [145].

O)(phendione)2

evaluated the efficiency of two metal compounds [Zn(DION)<sup>2</sup>

mitochondria dysfunction and autophagy cell death [5].

Recent work from Sadler and coworkers showed the distribution of osmium in cancer cells treated with relevant doses of OsII arene azopyridine complex by using X-ray fluorescence nanoprobe. This analysis shows localization of Os in mitochondria and not in nucleus and mobilization of calcium from endoplasmic reticulum [138]. Osmium compounds have been extensively exploited because they are capable to induce the formation of ROS, targeting mitochondria, and oxidize NADH to NAD<sup>+</sup> that lead to interference in the redox signaling pathways in cancer cells and are capable to interfere with cell cycle [69, 139]. In the last year, osmium analogs of the ruthenium anticancer agents, such as RAPTA-C, NAMI-A, and KP1019, have been developed. Therefore, osmium complexes demonstrated a good stability and inertness toward hydrolysis or ligand substitution. These are promising results for a future understanding of the mechanism of action of osmium compounds [134].

### **1.9. Gold**

Gold in its elemental form is stable in an extensive range of conditions. Gold oxidation states range from −1 to +5, but I and III are the most relevant. The coordination geometry of gold(I) complexes is not only generally linear accepting two ligands, but it can also coordinate three (trigonal) or four (tetragonal) ligands. Au(I) prefers to bind with thiolates, cyanides, phosphines, and soft halides [140]. Mainly due to the success of platinum compounds, and that gold(III) is isoelectronic with platinum(II) and forms similar square-planar complexes, a large number of gold(I) and gold(III) compounds have been studied for their anticancer activity [6]. Till now, auranofin [tetra-O-acetyl-b-D-(glucopyranosyl)thio](triethylphosphine) is the only gold compound ever approved. Used since 1985 as oral drug for the treatment of rheumatoid arthritis, its side effects, and restricted efficacy, it is only used for severe cases [141]. Some studies proposed its use as anticancer drug, and it is currently under several Phase I and II clinical trials to treat chronic lymphocytic leukemia (NCT01419691), lung cancer (NCT01737502), and glioblastoma (Glioblastoma).

The mode of action of auranofin is still not clear, and it is thought to be related with inhibition of thioredoxin reductase (TrxR). As gold has a high affinity for thiol and selenol groups, it tends to bind to amino acid residues, forming stable, irreversible adducts. TrxR is an essential enzyme in many cellular processes, mainly in balancing the redox homeostasis, controlling the level of ROS, and preventing DNA damage. As cancer cells tend to overexpress redox enzymes, they are mostly affected by auranofin. Selenoproteins, such as TrxR, when inhibited by auranofin compromise the mitochondria, leading to production of ROS that cause cellular oxidative stress and ultimately intrinsic apoptosis [141]. Several reports show the effect of auranofin against several tumors *in vitro*, including cisplatin resistant tumors [141]. Aurothiomalate is another gold compound, which is currently investigated in Phase I clinical trials to treat patients with advanced nonsmall cell lung cancer (NCT00575393). Its mechanism of action seems to be linked with protein kinase Ciota, which is overexpressed in nonsmall cell lung cancer, ovarian, and pancreatic cancers, playing a critical role in oncogenesis. Aurothiomalate has been shown to inhibit PKCiota signaling having potent antitumor activity in preclinical studies [142, 143]. Using the same mechanism, aurothioglucose also showed antitumor efficacy *in vitro* against nonsmall cell lung cancer cells [144]. For the cellular uptake, it was proposed that Au(I) enters the cell through albumin bond or through other thiol metabolites [144]. A recent study by Mármol proposes an alkynyl gold(I) complex [Au(C ≡ C-2-NC<sup>5</sup> H4 )(PTA)] to treat colorectal carcinoma. In their study, using Caco-2 cells, gold complex enters the mitochondria and disrupts its normal function, triggering the necroptosis. Necrose-inducing compounds are mainly interesting as they are an alternative chemotherapy for apoptosis resistance tumors [145].

### **1.10. Other complexes**

and developed osmium(II) arene complexes and proved their anticancer properties by systematically varying the chelating ligand in kinetics and thermodynamic reaction of the complexes [134, 135]. These series of N,O-chelates ligands are important choices in the stability and cancer toxicity [134, 136]. DNA-binding studies on a series of complexes of the type osmium(II)-arene have shown that these complexes bind to polymeric DNA, where some coordinate with gua-

Recent work from Sadler and coworkers showed the distribution of osmium in cancer cells treated with relevant doses of OsII arene azopyridine complex by using X-ray fluorescence nanoprobe. This analysis shows localization of Os in mitochondria and not in nucleus and mobilization of calcium from endoplasmic reticulum [138]. Osmium compounds have been extensively exploited because they are capable to induce the formation of ROS, targeting

ing pathways in cancer cells and are capable to interfere with cell cycle [69, 139]. In the last year, osmium analogs of the ruthenium anticancer agents, such as RAPTA-C, NAMI-A, and KP1019, have been developed. Therefore, osmium complexes demonstrated a good stability and inertness toward hydrolysis or ligand substitution. These are promising results for a

Gold in its elemental form is stable in an extensive range of conditions. Gold oxidation states range from −1 to +5, but I and III are the most relevant. The coordination geometry of gold(I) complexes is not only generally linear accepting two ligands, but it can also coordinate three (trigonal) or four (tetragonal) ligands. Au(I) prefers to bind with thiolates, cyanides, phosphines, and soft halides [140]. Mainly due to the success of platinum compounds, and that gold(III) is isoelectronic with platinum(II) and forms similar square-planar complexes, a large number of gold(I) and gold(III) compounds have been studied for their anticancer activity [6]. Till now, auranofin [tetra-O-acetyl-b-D-(glucopyranosyl)thio](triethylphosphine) is the only gold compound ever approved. Used since 1985 as oral drug for the treatment of rheumatoid arthritis, its side effects, and restricted efficacy, it is only used for severe cases [141]. Some studies proposed its use as anticancer drug, and it is currently under several Phase I and II clinical trials to treat chronic lymphocytic leukemia (NCT01419691), lung cancer (NCT01737502), and

The mode of action of auranofin is still not clear, and it is thought to be related with inhibition of thioredoxin reductase (TrxR). As gold has a high affinity for thiol and selenol groups, it tends to bind to amino acid residues, forming stable, irreversible adducts. TrxR is an essential enzyme in many cellular processes, mainly in balancing the redox homeostasis, controlling the level of ROS, and preventing DNA damage. As cancer cells tend to overexpress redox enzymes, they are mostly affected by auranofin. Selenoproteins, such as TrxR, when inhibited by auranofin compromise the mitochondria, leading to production of ROS that cause cellular oxidative stress and ultimately intrinsic apoptosis [141]. Several reports show the effect of auranofin against several tumors *in vitro*, including cisplatin resistant tumors [141]. Aurothiomalate is another gold compound, which is currently investigated in Phase I clinical trials to treat patients with advanced nonsmall cell lung cancer (NCT00575393). Its mechanism of action seems to be linked with protein kinase Ciota, which is overexpressed in

future understanding of the mechanism of action of osmium compounds [134].

that lead to interference in the redox signal-

nine and others undergo quantitative reaction with DNA [137].

48 Basic Concepts Viewed from Frontier in Inorganic Coordination Chemistry

mitochondria, and oxidize NADH to NAD<sup>+</sup>

**1.9. Gold**

glioblastoma (Glioblastoma).

Cobalt complexes have normally two accessible oxidation states. Co(III) is kinetically inert, whereas Co(II) is labile. Some studies demonstrated that Co(III) complexes can act as carriers for selective delivery of drugs [69]. However, when Co(III) is reduced to Co(II), the molecule is released in its active form and can kill cancer cells [146]. Hexacarbonyl dicobalt and alkynes exhibit a promising activity of antitumor activity [147]. The activity is most pronounced when the alkyne is the propargyl ester of aspirin (CoASS), which inhibits the cyclooxygenase enzymes COX-1 and COX-2 [147, 148]. It was shown that CoASS itself inhibits COX-1 and COX-2 more strongly than ASA alone and enhanced the cytotoxicity against breast cancer cell line [148]. The development of new complexes bearing different types of pyrazole-based ligands demonstrated the potential use of these complexes as antiproliferative agents [149].

A new compound CoCl(H<sup>2</sup> O)(phendione)2 ][BF<sup>4</sup> ] (phendione = 1,10-phenanthroline-5,6-dione) (TS265) was demonstrated to induce cell cycle arrest in S phase with a subsequent cell death by apoptosis and high cytotoxicity against colorectal carcinoma cell [76]. Fernandes et al. evaluated the efficiency of two metal compounds [Zn(DION)<sup>2</sup> ]Cl (TS262, DION = 1,10-phenanthroline-5,6-dione) and TS265 and the application of AuNPs as a drug delivery system to improve the anticancer efficacy of these compounds in a new canine mammary tumor (FR37- CMT) [150]. The same group formulated a multifunctional nanovectorization system using gold nanoparticles to enhance cytotoxic of TS265. This nanoformulation efficient delivered the cytotoxic cargo in a controlled selective manner [151]. Two mononuclear NiII and MnII compounds with a "scorpionate" type precursor demonstrated to induce damage in ovarian cancer cells through ROS accumulation. In addition, the mononuclear NiII compound induced mitochondria dysfunction and autophagy cell death [5].

Although the intensive study of transition metals is focused on a specific biomolecular target, some complexes are developed for other purposes. For example, palladium-porphyrin complex (TOOKAD-soluble) acts as a photosensitizer and has progressed to Phase III clinical trial for the photodynamic treatment of prostate cancer (NCT01875393). Phase II clinical trials were evaluated the efficacy and safety of a single dose of the drug and light dosage combination of TOOKAD® Soluble in the focal treatment of patients with localized prostate cancer, 6 months after treatment. Positive results obtained at 6-month negative biopsies were acquire. This complex has a dual role; that is, it provides the ideal photophysical properties to the porphyrin and is inert enough not to be displaced during therapy (**Table 1**) [152].


**2. Conclusion**

TOOKAD® Soluble

Gallium tris-maltolate

new avenue and the future for cancer therapy.

also acknowledges FCT-MCTES grant PD/BD/105734/2014.

**Acknowledgements**

Since the discovery of cisplatin, coordination complexes have been widely used in cancer therapy. Thirty years after its approval as a chemotherapeutic agent by the FDA, cisplatin remains to be one of the best-selling anticancer agents. Thousands of metal compounds have been described since then with only a few passing for clinical trials and even less getting approval. Both the high costs translating a promising drug to the clinic and the focus of pharma to go for new targeted therapies with minimum side effects instead of new cytotoxic agents can explain the current stall in the discovery of novel metal anticancer drugs. Despite the significant efforts in cancer treatment to increase efficacy without promoting side effects and/or resistance by cancer cells, cancer remains one of the major causes of death worldwide. To overcome this fatality, the identification of unique cellular and biochemical features of each tumor and the knowledge of the molecular mechanisms and biological targets of anticancer agents have, together, brought up the necessity for both synthesis and evaluation of new compounds with more promising antiproliferative potential with specific intracellular targets in cancer cells. The success of clinical treatment sparked interest in platinum compounds and other complexes (Ru, Cu, Au, and Co) containing metal ions to be used as anticancer agents. Well-established *in vitro* and *in vivo* studies, such as those shown in this chapter, are extremely important because the interest of a better quality of treatment is increasingly demanded. In addition to the development of more effective drugs, novel nanoscale drug delivery systems showing improved pharmacokinetic and pharmacodynamic properties, such as increased bioavailability, have emerged in the last decade as promising solutions for the required therapeutic efficacy. Combination of new metal complexes with known chemotherapeutic agents already in the market targeting different cellular pathways in a nanostructure may provide a

palladium-porphyrin

**trial**

Inorganic Coordination Chemistry: Where We Stand in Cancer Treatment?

Hepatocellular carcinoma Phase I [160]

Phase III [152]

http://dx.doi.org/10.5772/intechopen.80233

**Refs.**

51

**Name Description Target cancer Approved/clinical** 

complex

**Table 1.** Clinical approved/undergoing clinical trials and metal compounds for anticancer therapeutic application.

Palladium-porphyrin

(3-Hydroxy-2-methyl-4Hpyran-4-onato) gallium

complex

This work was supported by the Unidade de Ciências Biomoleculares Aplicadas-UCIBIO, which is financed by national funds from FCT/MEC (UID/Multi/04378/2013) and cofinanced by the ERDF under the PT2020 Partnership Agreement (POCI-01-0145-FEDER-007728). PP


**Table 1.** Clinical approved/undergoing clinical trials and metal compounds for anticancer therapeutic application.

### **2. Conclusion**

**Name Description Target cancer Approved/clinical** 

Paraplatin Carboplatin Advanced ovarian cancer FDA approval [153]

Aqupla Nedaplatin Urological tumors Approved in Japan [153]

Heptaplatin Cisplatin analogs Gastric cancer Approved in Korea [154]

leucovorin

docetaxel

neck cancer

(DMSO) (Im) Metastatic tumor (lung,

Colorectal cancer in combination with 5-FU and

Colorectal cancer in combination with 5-FU and leucovorin/prostate cancer in combination with

cancer/squamous cell carcinoma of head and neck

Ovarian cancer/head and

colorectal, melanoma, ovarian, and pancreatic) in combination with gemcitabine

neuroendocrine tumors

Nonmuscle invasive bladder cancer treatment with photodynamic therapy

Chronic lymphocytic leukemia, lung cancer, and

(PDT)

lung cancer

glioblastoma

CasII-gly Casiopeína Cervical cancer cell Phase I in Mexico [159] KP46 Gallium tris-8-quinolinolate Solid tumors Phase I [132]

] [InH] Advanced colorectal cancer Phase I [157]

and leucovorin

ovarian and bladder cancers

in combination with 5-FU

Inoperable metastatic breast and small cell lung cancer

Platinol Cisplatin Metastatic testicular,

50 Basic Concepts Viewed from Frontier in Inorganic Coordination Chemistry

Lobaplatin 1,2-Diammino-l-

methylcyclobutaneplatinum(II)-lactate

dichloro-(cyclohexylamine)

Lipoplatin Liposomal form of cisplatin Locally advanced gastric

Cl<sup>4</sup>

NKP-1339 KP1019 sodium salt Colorectal carcinoma and

Aurothiomalate Gold compound Advanced nonsmall cell

(glucopyranosyl)thio] (triethylphosphine)

Picoplatin 2-Methylpyridine analog of cisplatin

platinum(IV)

ProLindac Oxaliplatin with hydrophilic polymer

NAMIA-A RuCl<sup>4</sup>

KP1019 Trans-[Ru(In)<sup>2</sup>

TLD1433 Ru(II)-polypyridyl

Auranofin TetraO-acetyl-b-D-

compound

Satraplatin Bis-(acetate)-ammine

Eloxatin Oxaliplatin Advanced colorectal cancer

**trial**

FDA approval [153]

FDA approval [153]

Approved in China [153]

Phase II [11]

Phase II/III [153]

Phase II/III [155]

Phase II/III [153]

Phase II [156]

Phase I [74]

Phase I [75]

Phase I [158]

Phase I/II [141]

**Refs.**

Since the discovery of cisplatin, coordination complexes have been widely used in cancer therapy. Thirty years after its approval as a chemotherapeutic agent by the FDA, cisplatin remains to be one of the best-selling anticancer agents. Thousands of metal compounds have been described since then with only a few passing for clinical trials and even less getting approval. Both the high costs translating a promising drug to the clinic and the focus of pharma to go for new targeted therapies with minimum side effects instead of new cytotoxic agents can explain the current stall in the discovery of novel metal anticancer drugs. Despite the significant efforts in cancer treatment to increase efficacy without promoting side effects and/or resistance by cancer cells, cancer remains one of the major causes of death worldwide. To overcome this fatality, the identification of unique cellular and biochemical features of each tumor and the knowledge of the molecular mechanisms and biological targets of anticancer agents have, together, brought up the necessity for both synthesis and evaluation of new compounds with more promising antiproliferative potential with specific intracellular targets in cancer cells. The success of clinical treatment sparked interest in platinum compounds and other complexes (Ru, Cu, Au, and Co) containing metal ions to be used as anticancer agents. Well-established *in vitro* and *in vivo* studies, such as those shown in this chapter, are extremely important because the interest of a better quality of treatment is increasingly demanded. In addition to the development of more effective drugs, novel nanoscale drug delivery systems showing improved pharmacokinetic and pharmacodynamic properties, such as increased bioavailability, have emerged in the last decade as promising solutions for the required therapeutic efficacy. Combination of new metal complexes with known chemotherapeutic agents already in the market targeting different cellular pathways in a nanostructure may provide a new avenue and the future for cancer therapy.

### **Acknowledgements**

This work was supported by the Unidade de Ciências Biomoleculares Aplicadas-UCIBIO, which is financed by national funds from FCT/MEC (UID/Multi/04378/2013) and cofinanced by the ERDF under the PT2020 Partnership Agreement (POCI-01-0145-FEDER-007728). PP also acknowledges FCT-MCTES grant PD/BD/105734/2014.

## **Conflict of interest**

Authors declare no conflict of interests.

## **Author details**

Pedro Pedrosa† , Andreia Carvalho† , Pedro V. Baptista and Alexandra R. Fernandes\*

\*Address all correspondence to: ma.fernandes@fct.unl.pt

UCIBIO, Department of Life Sciences, Faculty of Science and Technology, NOVA University of Lisbon, Caparica, Portugal

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**Chapter 4**

**Provisional chapter**

**Coordination Chemistry of Networking Materials**

**Coordination Chemistry of Networking Materials**

DOI: 10.5772/intechopen.80864

The coordination chemistry explains the chemistry, physical properties, structure, bonding, and other properties of the compounds of d-block elements. In the current chapter, we have discussed the coordination chemistry of networking complexes of d-block elements. The networking complexes of d-block elements comprise of metal organic frameworks (MOF) also known as coordination polymers. In this context, the geometry around central metal atom of MOFs has been discussed to explain their different properties. Different theoretical approaches (like hybridization, valance bond theory, molecular orbital theory, and crystal field theory) have been utilized to explain the properties of some selected exem-

SO3

**Keywords:** coordination chemistry, networking materials, metal organic frameworks,

The coordination chemistry mention to a versatile branch of which flourishes depends upon inorganic chemistry. The foundation of coordination chemistry breaks down the boundaries of physical, organic, and inorganic chemistry and it alters to joint part of various chemical fields. Coordination chemistry forms an assured achievement in research and practical applications due to its different properties. Theories that explain bonds in coordination compounds are valence bond theory (VBT), crystal field theory (CFT), and ligand field theory (LFT). Properties of coordination chemistry enter into microscale from macrolevel. It accentuates the study on microlevel such as study of the internal structure of molecule. Latest coordination chemistry follows different mathematical models to turn the qualitative description of compounds into quantitative way [1].

], [[Cu(3,4-Hpdc)2

 (H2 O)2

]·2dmso]n, and

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Ataf Ali Altaf, Sumbal Naz and Amin Badshah

Ataf Ali Altaf, Sumbal Naz and Amin Badshah

Additional information is available at the end of the chapter

plary compounds, e.g., [Ag(1,4-pyrazine)1.5CF3

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.80864

**Abstract**

[Zn(II)(SEPCPU)]n.

**1. Introduction**

geometries, properties of MOF

#### **Coordination Chemistry of Networking Materials Coordination Chemistry of Networking Materials**

DOI: 10.5772/intechopen.80864

Ataf Ali Altaf, Sumbal Naz and Amin Badshah Ataf Ali Altaf, Sumbal Naz and Amin Badshah

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.80864

#### **Abstract**

The coordination chemistry explains the chemistry, physical properties, structure, bonding, and other properties of the compounds of d-block elements. In the current chapter, we have discussed the coordination chemistry of networking complexes of d-block elements. The networking complexes of d-block elements comprise of metal organic frameworks (MOF) also known as coordination polymers. In this context, the geometry around central metal atom of MOFs has been discussed to explain their different properties. Different theoretical approaches (like hybridization, valance bond theory, molecular orbital theory, and crystal field theory) have been utilized to explain the properties of some selected exemplary compounds, e.g., [Ag(1,4-pyrazine)1.5CF3 SO3 ], [[Cu(3,4-Hpdc)2 (H2 O)2 ]·2dmso]n, and [Zn(II)(SEPCPU)]n.

**Keywords:** coordination chemistry, networking materials, metal organic frameworks, geometries, properties of MOF

### **1. Introduction**

The coordination chemistry mention to a versatile branch of which flourishes depends upon inorganic chemistry. The foundation of coordination chemistry breaks down the boundaries of physical, organic, and inorganic chemistry and it alters to joint part of various chemical fields. Coordination chemistry forms an assured achievement in research and practical applications due to its different properties. Theories that explain bonds in coordination compounds are valence bond theory (VBT), crystal field theory (CFT), and ligand field theory (LFT). Properties of coordination chemistry enter into microscale from macrolevel. It accentuates the study on microlevel such as study of the internal structure of molecule. Latest coordination chemistry follows different mathematical models to turn the qualitative description of compounds into quantitative way [1].

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Due to higher valency of transition metals, the solution of bonding was expected by Alfred Werner.Werner's analysis provided the basis for field of transition metal complexes in coordination chemistry [2]. Werner, the beginner of coordination chemistry, granted his concepts of metal ligand complexes in his book in 1905 and his book was translated into another language like English in 1911 [3]. According to Webster, coordinate means to convey into proper order of molecules. Coordination chemistry provides important conceptual basics and chemical content of chemistry. In this chemical branch, some important concepts of chemistry were developed like stereochemistry of compounds of higher coordination numbers, bonding in d orbital systems, and mechanism of reactions [4]. The control of molecular conformation in solid materials is the significant motif of modern chemistry. For proper molecular organization, there is preference to use directional bonds (coordinate covalent bond and hydrogen bond) [5]. Coordination compounds are formed by dual aggregation of metal and multidentate ligands. In these coordination compounds, molecules and atoms may be considered as specific points. In these, network is connected, and metal and ligand are connected with each other to form a coordination compound. If inferred impulsions are applied to coordination number of metal through beating its coordination sphere by its counterions, then prediction of formation of final network should increase. The chorography of coordination network is expected to follow from geometry of its constituent parts [6]. The connection of ligand toward metal atom is controlled by covalent synthesis. The prophecy of network structure depends upon coordination properties of metal atom. The coordination of metal is effected by counter ion, duplicity of ligand, and solvent [7].

turbid. The resulting mixture was heated in oven at 70°C and homogeneous mixture was cooled at

Coordination Chemistry of Networking Materials http://dx.doi.org/10.5772/intechopen.80864 69

Stoichiometry of complex of silver as a central metal atom and 1,4-pyrazine as a ligand is ML1.5. The structure of complex contains endless chains of cyclical 1,4-pyrazine molecules and metal ions to form ladder-like structure. This ladder-like structure was formed by alternation of 1,4-pyrazine and metal ions. The pyrazine subunits on chain are at a distance of about 3.55. The plane of pyrazine units is 77.8° toward plane of poles of ladder structure. The crystallization solvent of this complex is acetone. Silver is four-coordinated metal bonding to one oxygen atom of triflate and three nitrogen atoms of 1,4-pyrazine. Silver adopts sawhorse geometry. The N-Ag(1) bond distances are 2.246 (N1), 2.312 (N2), and 2.460 Å (N3) and the N-Ag(1)-N

room temperature; colorless long needle-like structures were formed for XRD analysis.

bond angles are 173.2 and 87.3°. The Ag(1)-O bond distance is 2.590 Å [7] (**Figure 1**).

**Figure 1.** In the [Ag(1,4-pyrazine)1.5CF3

SO3

geometry with specified bond lengths and bond angles (at the bottom of figure).

the coordination sphere of silver(I) in the [Ag(1,4-pyrazine)1.5CF3

] complex, chains that run along an axis (at top of figure). This figure indicating

] complex in which geometry of silver(I) is sawhorse

SO3

Hybridization of given complex can be explained on the basis of VBT. In this complex, charge on Ag is +1, its magnetic moment indicates that paired electrons are present per atom and one electron is lost from 5s orbital, no electron loss from d orbital, one of d orbital electrons may participate in bonding by acting as lone pair to cause lone pair-bond pair repulsion.

### **2. Coordination polymers**

Polymers can be described as molecules of high molecular weight which are formed by repetition of their monomeric subunits connected by covalent bonds [8]. However, coordination polymers are formed by central metal atom connected with organic ligands via coordination bonds and weak chemical bonds. These compounds are also named as metal organic frameworks [9]. The organization of different factors in coordination polymers exists in solid form most of the time [10]. Coordination polymers are completely regular in shape, having high porosity and designable frameworks. Synthesis of these networks is done under mild conditions by using discrete subunits and this method is commonly known as bottom-up method. Components of these polymers are blocking ligands, counteranions, and template molecules. Transition metal ions are often used as functional connectors in the formation of coordination polymers. Variable geometries of a polymer can be formed by varying reaction conditions like solvents, ligands, and counteranions, etc. [11].

### **3. Examples of coordination polymers**

#### **3.1. [Ag(1,4-pyrazine)1.5CF3 SO3 ] complex**

In a clean glass vial, a solution of silver triflate in acetone was added to a solution of 1,4-pyrazine in acetone covered by Teflon cap. Precipitates of white color are formed. For production of clear solution, heat this vial on hot water bath at 85°C. The resultant mixture was filtered at the same time to remove water by using Whatman No. 50 filter paper. On cooling, the clear solution becomes turbid. The resulting mixture was heated in oven at 70°C and homogeneous mixture was cooled at room temperature; colorless long needle-like structures were formed for XRD analysis.

Due to higher valency of transition metals, the solution of bonding was expected by Alfred Werner.Werner's analysis provided the basis for field of transition metal complexes in coordination chemistry [2]. Werner, the beginner of coordination chemistry, granted his concepts of metal ligand complexes in his book in 1905 and his book was translated into another language like English in 1911 [3]. According to Webster, coordinate means to convey into proper order of molecules. Coordination chemistry provides important conceptual basics and chemical content of chemistry. In this chemical branch, some important concepts of chemistry were developed like stereochemistry of compounds of higher coordination numbers, bonding in d orbital systems, and mechanism of reactions [4]. The control of molecular conformation in solid materials is the significant motif of modern chemistry. For proper molecular organization, there is preference to use directional bonds (coordinate covalent bond and hydrogen bond) [5]. Coordination compounds are formed by dual aggregation of metal and multidentate ligands. In these coordination compounds, molecules and atoms may be considered as specific points. In these, network is connected, and metal and ligand are connected with each other to form a coordination compound. If inferred impulsions are applied to coordination number of metal through beating its coordination sphere by its counterions, then prediction of formation of final network should increase. The chorography of coordination network is expected to follow from geometry of its constituent parts [6]. The connection of ligand toward metal atom is controlled by covalent synthesis. The prophecy of network structure depends upon coordination properties of metal atom. The coordination

Polymers can be described as molecules of high molecular weight which are formed by repetition of their monomeric subunits connected by covalent bonds [8]. However, coordination polymers are formed by central metal atom connected with organic ligands via coordination bonds and weak chemical bonds. These compounds are also named as metal organic frameworks [9]. The organization of different factors in coordination polymers exists in solid form most of the time [10]. Coordination polymers are completely regular in shape, having high porosity and designable frameworks. Synthesis of these networks is done under mild conditions by using discrete subunits and this method is commonly known as bottom-up method. Components of these polymers are blocking ligands, counteranions, and template molecules. Transition metal ions are often used as functional connectors in the formation of coordination polymers. Variable geometries of a polymer can be formed by varying reaction conditions like solvents, ligands, and counteranions, etc. [11].

In a clean glass vial, a solution of silver triflate in acetone was added to a solution of 1,4-pyrazine in acetone covered by Teflon cap. Precipitates of white color are formed. For production of clear solution, heat this vial on hot water bath at 85°C. The resultant mixture was filtered at the same time to remove water by using Whatman No. 50 filter paper. On cooling, the clear solution becomes

of metal is effected by counter ion, duplicity of ligand, and solvent [7].

68 Basic Concepts Viewed from Frontier in Inorganic Coordination Chemistry

**2. Coordination polymers**

**3. Examples of coordination polymers**

**SO3**

**] complex**

**3.1. [Ag(1,4-pyrazine)1.5CF3**

Stoichiometry of complex of silver as a central metal atom and 1,4-pyrazine as a ligand is ML1.5. The structure of complex contains endless chains of cyclical 1,4-pyrazine molecules and metal ions to form ladder-like structure. This ladder-like structure was formed by alternation of 1,4-pyrazine and metal ions. The pyrazine subunits on chain are at a distance of about 3.55. The plane of pyrazine units is 77.8° toward plane of poles of ladder structure. The crystallization solvent of this complex is acetone. Silver is four-coordinated metal bonding to one oxygen atom of triflate and three nitrogen atoms of 1,4-pyrazine. Silver adopts sawhorse geometry. The N-Ag(1) bond distances are 2.246 (N1), 2.312 (N2), and 2.460 Å (N3) and the N-Ag(1)-N bond angles are 173.2 and 87.3°. The Ag(1)-O bond distance is 2.590 Å [7] (**Figure 1**).

Hybridization of given complex can be explained on the basis of VBT. In this complex, charge on Ag is +1, its magnetic moment indicates that paired electrons are present per atom and one electron is lost from 5s orbital, no electron loss from d orbital, one of d orbital electrons may participate in bonding by acting as lone pair to cause lone pair-bond pair repulsion.

**Figure 1.** In the [Ag(1,4-pyrazine)1.5CF3 SO3 ] complex, chains that run along an axis (at top of figure). This figure indicating the coordination sphere of silver(I) in the [Ag(1,4-pyrazine)1.5CF3 SO3 ] complex in which geometry of silver(I) is sawhorse geometry with specified bond lengths and bond angles (at the bottom of figure).

Due to presence of repulsion, this complex showed sawhorse geometry instead of tetrahedral geometry having dsp3 hybridization in which one d orbital, one s orbital, and three p orbitals of almost same energy of same shell are involved, such type of complexes are known as spin paired complexes. Magnetic moment indicates that this complex is diamagnetic in nature because all electrons present in d orbital are paired. After intermixing of these orbitals, this complex gives five dsp<sup>3</sup> hybrid orbitals.

coordinated water molecules—one with DMSO molecule and another with carboxylate ion—

Hybridization of this complex polymer molecule can be explained on the basis of VBT. The charge on central metal atom is Cu2+. Its magnetic moment indicates that complex is paramag-

These polymer metal complexes were prepared by using template method. A solution of polyvinyl alcohol is dissolved in water and the given solution was stirred magnetically and was heated at specific temperature on hot plate. One mole of metal chloride was diffused in water; this mixture was added dropwise into solution of polymer, again stirred and heated on hot plate approximately for 1 h. Complexes were precipitated by using acetone and filtered, then washed with acetone and then dried in oven. Complexes of polyvinyl alcohol are not soluble in water. Elemental analysis showed polymer and metal ratio of about 126:1. These complexes are not prepared in the form of tablets and pellets due to its springy nature [18, 19]. These complex polymers are diamagnetic and show square planar geometry [20]. No electronic bands were formed due to insolubility of these polymers in water; these metal complex polymers show rubber-like structure. This polymer exhibited about 17% of rubber naturally. Due to its rubber-like structure, stress-strain experiments of these complex materials were performed. This complex polymer molecule has breaking strain value of about 83%. These

d2

hybrids [17].


hybrid orbitals. All water

Coordination Chemistry of Networking Materials http://dx.doi.org/10.5772/intechopen.80864

d2

and 4dz2

71

netic because one unpaired electron was left in one of 3d orbitals. The vacant 4dx2

orbitals are hybridized with vacant 4s and 4p orbitals to give six sp3

and 3,4-Hpdc− can donate two electrons to one of sp3

stress-strain values are due to hydroxyl group (**Figure 3**).

**Figure 3.** Structure of PVA-metal complex polymer.

are observed [16] (**Figure 2**).

**3.3. [PVA-Ni(II)]n complex**

#### **3.2. [[Cu(3,4-Hpdc)2 (H2 O)2 ]·2dmso]n**

Formula weight of this compound is 588.05 g M−<sup>1</sup> and density is 1.607 g cm−<sup>3</sup> . Its crystal system is monoclinic. To synthesize this complex, 3,4-pyridinedicorboxlic acid was dissolved in DMSO, and this mixture was added in ethanol solution of CuCl2 .6H2 O by diffusion method. Elemental analysis shows that ratio of metal and ligand is 1:2 in this complex [12]. The resultant mixture becomes green; after 3 weeks, the color of the solution has changed to blue. Blue crystals were suitable for XRD analysis; these crystals were collected by filtration and washed by using DMSO.

XRD analysis indicates that crystals which are formed are monoclinic in nature with space group P21/n. In given complex, central metal atom is coordinated to two nitrogen and two oxygen atoms of 3,4-Hpdc− ligands and two molecules of water leads to six coordination with octahedral geometry. Each 3,4-Hpdc− molecule is deprotonated partially, with only one carboxylate ion involving in coordination toward metal center due to the presence of vibrational frequency of CO and (COO−). No any basic material was added into reaction mixture and the reaction was carried out under optimum conditions to obtain partially protonated material. The bond distance of Cu-O5 (2.467(3) Å) is much larger than that of Cu-O4 and Cu-N1ii are (1.977(2) Å) and (2.006(2) Å) [13, 14]. In two-dimensional sheet of polymer, Cu…Cu distance is about 8.781 Å [15].

Thermal analysis indicates that this complex polymer molecule has coordinated molecules of water and DMSO molecule in the resulting network. Two hydrogen bonds involved in

**Figure 2.** Three-dimensional diagram of complex {[Cu(3,4-Hpdc)2 (H2 O)2 ]·2dmso}n with only one lattice molecule of DMSO with different symmetry codes showing distorted octahedral geometry.

coordinated water molecules—one with DMSO molecule and another with carboxylate ion are observed [16] (**Figure 2**).

Hybridization of this complex polymer molecule can be explained on the basis of VBT. The charge on central metal atom is Cu2+. Its magnetic moment indicates that complex is paramagnetic because one unpaired electron was left in one of 3d orbitals. The vacant 4dx2 -y2 and 4dz2 orbitals are hybridized with vacant 4s and 4p orbitals to give six sp3 d2 hybrid orbitals. All water and 3,4-Hpdc− can donate two electrons to one of sp3 d2 hybrids [17].
