**Stoichiometry of Polymer Complexes**

A.Z. El-Sonbati, M.A. Diab and A.A. El-Bindary

*Chemistry Department, Faculty of Science, Mansoura University, Demiatta, Egypt* 

### **1. Introduction**

146 Stoichiometry and Research – The Importance of Quantity in Biomedicine

[4] Crawford M.A., Leigh, Broadhurst C., Galli, C., Ghebremeskel, K., Holmsen, H.,

[5] Grahl-Nielson O. and O. Mjaavatten. 1991. Dietary influence on fatty acid composition of

[6] Gawrisch, K., Naddukkudy, V.E, Holte, L.L. 2003. The structure of DHA in Phospholipid

[7] Huber, T, Rajamoorthi, K, Kurze V.F, Beyer, K, Brown M.F. 2002. Structure of

[8] Koch, D. E., Pearson, A. M., Magee, W. T., Hoefer J. A., Schweigert, B. S. 2008. Effect of Diet on the Fatty Acid Composition of Pork Fat. J. Anim. Sci. 27, 360-365. [9] Maw, S.J, Fowler, V.R, Hamilton, M and Petchey, A.M. 2003. Physical characteristics of pig fat and their relation to fatty acid composition. Meat Science. 63, 185-190. [10] Mozaffarian D., Katan, M..B., Ascherio, A. Stampfer, M.J. Willett W.C. 2006. Trans Fatty Acids and Cardiovascular Disease. N. Engl. J. Med. 354(15) 1601-13. [11] Pitman, M.C, Suits, F., MacKerell, A.D., Feller, S.E. 2004. Molecular Level Organization

[12] Rabel, S.R, Jona, J.A, Maurin, M.B. 1999. Applications of modulated differential

[13] Schmidt, W.F, Barone, J.R, Francis, B, Reeves III, J.B. 2006. Stearic acid solubility and

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[15] Schubring, R. Crystallization and melting behaviour of fish oil measured by DSC. 2009.

[16] Seale, R., Bjork, B.,Yang, W., Kajimura, S., Chin, S., Kuang, S., Scime, A., Devarakonda,

[17] Seelig J and W Niederberger. 1974. Deuterium-labeled lipids as structural probes in liquid crystalline bilayers. Journal of American Chemical Society. 96(7), 2069-2072 [18] Uauy R., Hoffman D.R., Peirano P., Birch D.G., Birch E.E. 2001. Essential fatty acids in

[19] Yavin E., Himovichi E., Eilam R. 2009. Delayed cell migration in the developing rat

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cubic phase volume. Chem.and Phys.of Lipids.142, 23-32.

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Saugstad, L.F., Schmidt, W.F., Sinclair, A.J., Cunnane, S.C. 2008. The Role of Docosahexaenoic and Arachidonic Acids as Determinants of Evolution and Hominid Brain Development. In Fisheries for Global Welfare and Environment: K. Tsukamoto, T. Kawamura, T. Takeuchi, T. D. Beard, Jr. and M. J. Kaiser, eds., 5th

blubber fat of seals as determined by biopsy: a multivariate approach. Marine

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brain following maternal Omega 3 alpha linolenic acid dietary deficiency.

Polymer complexes have been attracting interest in many scientific and technological fields in recent years. Polymer complexes have found wide applications in bioinorganic industry (Fenger & Le Drian, 1998), wastewater treatment (Mizuta et al., 2000), pollution control (Orazzhanova et al., 2003), hydrometallurgy (Varvara et al., 2004), preconcentration (Ro et al., 2003), anionic polyelectrolyte hydrogels (Varghesa et al., 2001), cation-exchange resins (Ahmed et al., 2004) etc. Moreover, they recently showed potential applications in material science as catalytic, conductive, luminescent, magnetic, porous, chiral or non-linear optical materials (Janiak, 2003; James, 2003; Maspoch et al., 2004; Batten & Murray, 2003).

Although various extensive investigations on polymer complexes have been reported, most of these complexes are too complicated to be discussed quantitatively due to the nonuniformity of their structure. These compounds include not only "complexes of macromolecules" but also the structurally labile "metal complex". Before detailed information can be obtained about the properties of polymer complexes, in particular about the reactivity and the catalytic activity, their structure must be elucidated. A polymer complex possessing a uniform structure may be defined as follows:


Hence, it is possible to prepare polymer complexes having different use and applications by varying the polymer chain, the nature of the ligand and the metal ion.

Stoichiometry of Polymer Complexes 149

**CH2**

**CH2**

**H**

The new electrophilic acceptor monomer has an increased rate constant and an unchanged termination rate constant resulting in a more rapid rate of propagation and in the formation of a higher molecular weight polymer (Banford et al., 1966b). The kinetics of polymerization were extended to methyl acrylate (MA) with transition metal bromides (El-Sonbati et al., 1992). The presence of Cu(II), Ni(II) and Zn(II) bromides retards the rate of polymerization. This retardation effect of the polymerization of MA is attributable to the formation of addition products, which must be inactive in initiating the polymerization of MA and

decrease the rate of polymerization in the order MA-ZnBr2 < MA-CuBr2 < MA-NiBr2.

The enhanced reactivity of the complex monomer extends to copolymerization with olefinic or allylic monomer, which is poorly responsive to free radical initiated polymerization (Imoto et al., 1965; Serniuk & Thomas, 1965; Serniuk & Thomas, 1966). The free radical initiated copolymerization of such monomers which a metal halide complexed polar monomer results in an increased concentration of olefinic monomer in the polymer as compared with that obtained in the absence of the complexing agent, as well as an increase

The reaction of polymer ligands with metal ions usually results in various coordination structures, which are divided into pendant and inter- and/or intra-molecular bridged

The metal ion in a pendant metal complex is attached to the polymer ligand function, which is appended on the polymer chain. Based on the chelating abilities of the ligands, pendant

A metal ion or a metal complex has only one labile ligand, which is easily substituted by a polymeric ligand, and when other coordination sites are substitution inactive, the complex

complexes are classified as monodentate or polydentate polymer metal complexes.

formed has a simple structure of monodentate type as shown in Fig. 2.

δ+

δ+

**C C O**

**C C N**

**CH3 OCH3**

δ−

**ZnCl2**

δ−

**ZnCl2**

**C C O**

**OCH3**

in the polymer molecular weight.

**2.1.1 Pendant polymer complexes** 

**a. Monodentate pendant polymer complexes** 

complexes.

+

**ZnCl2**

**ZnCl2**

**N** +

**CH3**

**CH2**

**CH2**

**C C**

**H**

Fig. 1.

A polymer complex is composed of synthetic polymer and metal ions, with the metal ions bound to the polymer ligand by a coordinate bond. A polymer ligand contains anchoring sites like nitrogen, oxygen or sulphur obtained either by polymerization of monomer possessing the coordinating site or by a chemical reaction between a polymer and a low molecular weight compound with coordinating ability. The synthesis results in an organic polymer with inorganic functions. The metal atoms attached to the polymer backbone are bound to exhibit a characteristic catalytic behavior, distinctly different from their low molecular weight analogues. Indeed, many synthetic polymer complexes have been found to possess high catalytic activity, in addition to semiconductivity, heat resistance and biomedical potentials.

This review will focus mainly on the stoichiometry and the characterization of polymer complexes structure by using elemental analyses, electronic spectra, magnetic susceptibilities, FT-IR, IR, 1H-NMR, ESR and thermogravimetric analyses.

### **2. Classification of polymer metal complexes**

The polymer complexes may be classified into three different groups according to the position occupied by the metal, which is decided by the methods of preparation:

	- a. Pendant metal polymer complexes.
	- b. Inter/intra-molecular bridged polymer complexes.

### **2.1 Complexation of polymeric ligand with metal ion**

Only decades ago polychelats derived from polymeric ligands and transition metal ions attracted the attention of many investigators. Bamford, Jenkins and Johnson (Bamford et al., 1958) were the first who noticed and described that radical polymerization of vinyl monomers is accelerated by addition of an inorganic salt not participating in redox reactions. They showed that the rate of polymerization of acrylonitrile (AN) initiated by azobisisobutyronitrile (AIBN) in dimethyl formamide (DMF), increases when lithium chloride is dissolved in the reaction mixture. According to the kinetic measurements, the effect was ascribed to an increased propagation of the rate constant and explained by the complexation of the nitrile groups at the radicals with lithium chloride.

A number of authors (Tazuke & Okamura, 1966; Tazuke et al. 1966; Tazuke & Okamura, 1967) have studied radical polymerization of this type. From a kinetic point of view methyl methacrylate (MMA) and AN-metal salt (AlCl3, AlBr3, ZnCl2, GaCl2, etc) systems were most intensively investigated (Imoto et al., 1963; Bamford et al., 1966a & Zubov et al., 1968). The increased reactivity of the complexed monomer has been attributed to the delocalization of the electrons in the double and triple bonds of the acceptor monomer as a result of the complexation with the electron accepting metal halide (Fig. 1) (Lazuke et al., 1967).

### Fig. 1.

148 Stoichiometry and Research – The Importance of Quantity in Biomedicine

A polymer complex is composed of synthetic polymer and metal ions, with the metal ions bound to the polymer ligand by a coordinate bond. A polymer ligand contains anchoring sites like nitrogen, oxygen or sulphur obtained either by polymerization of monomer possessing the coordinating site or by a chemical reaction between a polymer and a low molecular weight compound with coordinating ability. The synthesis results in an organic polymer with inorganic functions. The metal atoms attached to the polymer backbone are bound to exhibit a characteristic catalytic behavior, distinctly different from their low molecular weight analogues. Indeed, many synthetic polymer complexes have been found to possess high catalytic activity, in addition to semiconductivity, heat resistance and

This review will focus mainly on the stoichiometry and the characterization of polymer complexes structure by using elemental analyses, electronic spectra, magnetic

The polymer complexes may be classified into three different groups according to the

1. Complexation of polymeric ligand with metal ions which could be divided into two

Only decades ago polychelats derived from polymeric ligands and transition metal ions attracted the attention of many investigators. Bamford, Jenkins and Johnson (Bamford et al., 1958) were the first who noticed and described that radical polymerization of vinyl monomers is accelerated by addition of an inorganic salt not participating in redox reactions. They showed that the rate of polymerization of acrylonitrile (AN) initiated by azobisisobutyronitrile (AIBN) in dimethyl formamide (DMF), increases when lithium chloride is dissolved in the reaction mixture. According to the kinetic measurements, the effect was ascribed to an increased propagation of the rate constant and explained by the

A number of authors (Tazuke & Okamura, 1966; Tazuke et al. 1966; Tazuke & Okamura, 1967) have studied radical polymerization of this type. From a kinetic point of view methyl methacrylate (MMA) and AN-metal salt (AlCl3, AlBr3, ZnCl2, GaCl2, etc) systems were most intensively investigated (Imoto et al., 1963; Bamford et al., 1966a & Zubov et al., 1968). The increased reactivity of the complexed monomer has been attributed to the delocalization of the electrons in the double and triple bonds of the acceptor monomer as a result of the complexation with the electron accepting metal halide (Fig. 1) (Lazuke et

susceptibilities, FT-IR, IR, 1H-NMR, ESR and thermogravimetric analyses.

position occupied by the metal, which is decided by the methods of preparation:

**2. Classification of polymer metal complexes** 

a. Pendant metal polymer complexes.

3. Polymerization of metal containing monomers.

**2.1 Complexation of polymeric ligand with metal ion** 

b. Inter/intra-molecular bridged polymer complexes. 2. Complexation of multifunctional ligands with a metal.

complexation of the nitrile groups at the radicals with lithium chloride.

biomedical potentials.

categories:

al., 1967).

The new electrophilic acceptor monomer has an increased rate constant and an unchanged termination rate constant resulting in a more rapid rate of propagation and in the formation of a higher molecular weight polymer (Banford et al., 1966b). The kinetics of polymerization were extended to methyl acrylate (MA) with transition metal bromides (El-Sonbati et al., 1992). The presence of Cu(II), Ni(II) and Zn(II) bromides retards the rate of polymerization. This retardation effect of the polymerization of MA is attributable to the formation of addition products, which must be inactive in initiating the polymerization of MA and decrease the rate of polymerization in the order MA-ZnBr2 < MA-CuBr2 < MA-NiBr2.

The enhanced reactivity of the complex monomer extends to copolymerization with olefinic or allylic monomer, which is poorly responsive to free radical initiated polymerization (Imoto et al., 1965; Serniuk & Thomas, 1965; Serniuk & Thomas, 1966). The free radical initiated copolymerization of such monomers which a metal halide complexed polar monomer results in an increased concentration of olefinic monomer in the polymer as compared with that obtained in the absence of the complexing agent, as well as an increase in the polymer molecular weight.

The reaction of polymer ligands with metal ions usually results in various coordination structures, which are divided into pendant and inter- and/or intra-molecular bridged complexes.

### **2.1.1 Pendant polymer complexes**

The metal ion in a pendant metal complex is attached to the polymer ligand function, which is appended on the polymer chain. Based on the chelating abilities of the ligands, pendant complexes are classified as monodentate or polydentate polymer metal complexes.

### **a. Monodentate pendant polymer complexes**

A metal ion or a metal complex has only one labile ligand, which is easily substituted by a polymeric ligand, and when other coordination sites are substitution inactive, the complex formed has a simple structure of monodentate type as shown in Fig. 2.

Stoichiometry of Polymer Complexes 151

system due to the sterically hindered environment of the ligand, allowing only one pyridine moiety to complex each copper cation. Partial reduction of the cupric cation occurred during sample preparation, as observed by X-ray photoelectron spectroscopy (XPS) and magnetic

When the polymer pendant coordination group has a polydentate structure, the coordination structure of the polymer metal complex is very clear, and high stability can be

**L L L L L L L L**

The reaction of polymer ligands with metal ions very often results in inter-and/or

(a)

(b)

**+ M**

L : Coordinate atom (or) group, M = Metal ion, a : intra-polydentate, b : inter-polydentate

**+ <sup>M</sup>**

**M**

**2.1.2 Inter-and/or intra-molecular bridging polymer complexes** 

**M M**

**L L L**

**M L L**

**L L L L**

**L L L L**

**M**

susceptibility measurements.

expected as shown in Fig. 4.

interamolecular bridging (Fig. 5).

**L L L L L**

**L L L L**

**L L L L**

Fig. 4.

Fig. 5.

**b. Polydentate pendant polymer complexes** 

Fig. 2.

If the metal ion or metal complex has more than two labile ligands, it is often possible to realize a monodentate complex structure by selecting an appropriate reaction condition (Kaneko & Tsuchide, 1981). Important characteristics of this type of polymer complexes are:


The reaction of poly(4-vinylpyridine)(PVP) with various metal chelates such as cis[Co(en)2Cl2]Cl.H2O (en = ethylendiamine), cis-α-[Co(trien)Cl2]Cl.H2O, (trien = triethylenetetramine) and cis-[Co(en)2PyCl]Cl2 (Py = pyridine) gives simple structures of monodentate type (Fig. 3) (Kurimura et al., 1971; Tsuchide et al., 1974).

Fig. 3.

Soluble copper chloride complexes of poly(2-vinylpyridine) (P2VPy) were prepared (Lyons et al., 1988) in a methanol-water solution. Solubility was achieved with the proper solvent system due to the sterically hindered environment of the ligand, allowing only one pyridine moiety to complex each copper cation. Partial reduction of the cupric cation occurred during sample preparation, as observed by X-ray photoelectron spectroscopy (XPS) and magnetic susceptibility measurements.

### **b. Polydentate pendant polymer complexes**

When the polymer pendant coordination group has a polydentate structure, the coordination structure of the polymer metal complex is very clear, and high stability can be expected as shown in Fig. 4.

Fig. 4.

150 Stoichiometry and Research – The Importance of Quantity in Biomedicine

**L L L L L L L L L L M**

If the metal ion or metal complex has more than two labile ligands, it is often possible to realize a monodentate complex structure by selecting an appropriate reaction condition (Kaneko & Tsuchide, 1981). Important characteristics of this type of polymer complexes are:

The reaction of poly(4-vinylpyridine)(PVP) with various metal chelates such as cis[Co(en)2Cl2]Cl.H2O (en = ethylendiamine), cis-α-[Co(trien)Cl2]Cl.H2O, (trien = triethylenetetramine) and cis-[Co(en)2PyCl]Cl2 (Py = pyridine) gives simple structures of

iii. The polymer complex is very often soluble in water or in organic solvents.

monodentate type (Fig. 3) (Kurimura et al., 1971; Tsuchide et al., 1974).

**N**

**N H2**

**H2C**

**H2 N**

**H C** **H2 C**

**Cl**

**H2C Cl2.nH2O**

cis-[Co(en)2 PVPCl] Cl2.nH2O

**N H2 CH2**

**HN H2C**

**N**

**NH NH**

**HN**

**H2C CH2**

**H2 N**

**H2C**

**Cl**

**H2C Cl2.nH2O**

**CH2**

**CH H2 C**

Fig. 2.

Fig. 3.

i. The coordination is very clear.

ii. The effect of the polymer chain is clearly exhibited.

**M M M**

**N**

**Co X**

**X Co**

**CH2 X**

cis-[Co(trien)2PVPCl]Cl2.nH2O

Soluble copper chloride complexes of poly(2-vinylpyridine) (P2VPy) were prepared (Lyons et al., 1988) in a methanol-water solution. Solubility was achieved with the proper solvent

**HC CH2**

**<sup>X</sup>**

**HC CH2**

**N**

### **2.1.2 Inter-and/or intra-molecular bridging polymer complexes**

The reaction of polymer ligands with metal ions very often results in inter-and/or interamolecular bridging (Fig. 5).

(b)

L : Coordinate atom (or) group, M = Metal ion, a : intra-polydentate, b : inter-polydentate

Stoichiometry of Polymer Complexes 153

able to form polymer metal complexes of this type are classified as follows : (i) compounds having more than two coordinating groups, and (ii) simple compounds having more than two coordinating atoms, or simple ions which are able to function as bridged ligands. When the complex formation of ligands having four coordinating groups induces chemical reaction between the ligands, the resulting polymer complex sometimes has a network

**L**

**M**

**L**

**L**

**L**

**M**

**L**

**L**

Dithiooxamide (rubeanic acid) is a typical bifunctional ligand which forms a linear-type

**NH**

**S**

A simple ion or compound can work as a bridging ligand giving a polymeric structure. A metal salt such as cupric chloride forms an associated structure (Fig. 10) in a very concentrated aqueous solution of hydrogen chloride (Wertz & Tyvoll, 1974) with the chloride ions

occupying as bridging ligands both the axial and equatorial coordination sites of Cu2+.

**O Cl**

**Cl O Cu**

**M**

**O Cl**

**(V)**

**Cl**

**Cl O Cu**

**S**

**NH**

**C**

**C**

**NH**

**S**

**M**

**n**

**L**

**L**

polymer metal complex with metal ions (Fig. 9) (Amon & Kane, 1950).

**M 2+**

structure.

Fig. 8.

**S**

Fig. 9.

Fig. 10.

**H2N**

**L L**

**+ M**

**a. Linear coordinated polymer i. Linked by a bifunctional ligand**

**C C**

**ii- Linked by simple compound or ion** 

**NH2**

**S**

**L L**

The coordination structure of the resulting polymer metal complex is not clear in this case, and the polymer complex is sometimes insoluble in water or in organic solvent. It is usually difficult to distinguish between the inter and intra-molecular bridging. The fact that it is not often easy to elucidate the polymer effect in studying the characteristics of the polymer complex. The simplest example of this type of polymer complex is the poly(vinyl alcohol)(PVA)-Cu(II) complex (Fig. 6) (Hojo & Shiria, 1972).

### Fig. 6.

The coordination reaction is generally affected by the polymer ligand tacticity. The different coordination behavior of atactic poly (4-vinylpyridine)(PVP) and isotactic (2 vinylpyridine)(P2VP) with M(II)Cl2, where M=Co, Ni, Cu or Zn, is reported (Agnew, 1976). Atactic PVP and NiCl2 precipitated a mixture of a tetrahedral structure having stoichiometry Ni(PVP)2Cl2. Isotactic P2VP gave no precipitation with NiCl2 in ethanol, showing no coordination in UV and visible spectra as shown in Fig. 7.

Fig. 7.

### **2.1.3 The chain linked through complexation of bifunctional ligands with metal ions**

When bifunctional ligands form a complex with metal ions having more than two labile ligands, i.e. easily replaceable a polymer complex (Fig. 8) is formed through metal ion bridging.

This type of polymer metal complex has been synthesized as semiconducting organic materials (Katon, 1970), heat resistant organic polymer or polymer catalysts. Bridged ligands able to form polymer metal complexes of this type are classified as follows : (i) compounds having more than two coordinating groups, and (ii) simple compounds having more than two coordinating atoms, or simple ions which are able to function as bridged ligands. When the complex formation of ligands having four coordinating groups induces chemical reaction between the ligands, the resulting polymer complex sometimes has a network structure.

Fig. 8.

152 Stoichiometry and Research – The Importance of Quantity in Biomedicine

The coordination structure of the resulting polymer metal complex is not clear in this case, and the polymer complex is sometimes insoluble in water or in organic solvent. It is usually difficult to distinguish between the inter and intra-molecular bridging. The fact that it is not often easy to elucidate the polymer effect in studying the characteristics of the polymer complex. The simplest example of this type of polymer complex is the poly(vinyl

The coordination reaction is generally affected by the polymer ligand tacticity. The different coordination behavior of atactic poly (4-vinylpyridine)(PVP) and isotactic (2 vinylpyridine)(P2VP) with M(II)Cl2, where M=Co, Ni, Cu or Zn, is reported (Agnew, 1976). Atactic PVP and NiCl2 precipitated a mixture of a tetrahedral structure having stoichiometry Ni(PVP)2Cl2. Isotactic P2VP gave no precipitation with NiCl2 in ethanol, showing no

**N N**

Ni(PVP)2Cl2(IV)

**2.1.3 The chain linked through complexation of bifunctional ligands with metal ions**  When bifunctional ligands form a complex with metal ions having more than two labile ligands, i.e. easily replaceable a polymer complex (Fig. 8) is formed through metal ion

This type of polymer metal complex has been synthesized as semiconducting organic materials (Katon, 1970), heat resistant organic polymer or polymer catalysts. Bridged ligands

**Cl**

**Cl**

**Ni Cl**

**Cl**

**N**

**Cl Cl Ni**

**Ni N**

**CH CH2 CH CH2**

**CH CH2 CH CH2**

**O OH Cu HO O**

alcohol)(PVA)-Cu(II) complex (Fig. 6) (Hojo & Shiria, 1972).

coordination in UV and visible spectra as shown in Fig. 7.

**+ Cu2+**

**CH CH2**

**OH**

Fig. 6.

Fig. 7.

bridging.

### **a. Linear coordinated polymer**

### **i. Linked by a bifunctional ligand**

Dithiooxamide (rubeanic acid) is a typical bifunctional ligand which forms a linear-type polymer metal complex with metal ions (Fig. 9) (Amon & Kane, 1950).

Fig. 9.

### **ii- Linked by simple compound or ion**

A simple ion or compound can work as a bridging ligand giving a polymeric structure. A metal salt such as cupric chloride forms an associated structure (Fig. 10) in a very concentrated aqueous solution of hydrogen chloride (Wertz & Tyvoll, 1974) with the chloride ions occupying as bridging ligands both the axial and equatorial coordination sites of Cu2+.

Fig. 10.

Stoichiometry of Polymer Complexes 155

Methacrylate monomer coordinated to Co(III) complex, e.g. methacrylato-pentaamine cobalt (III) perchlorate, was radically polymerized giving the polymer (VI) (Fig. 14) (Osada, 1975;

**CH3**

**O H3N NH3**

**Co3+**

**NH3 (VI)**

The free radical initiated polymerization of polar monomers containing pendant nitrile and carbonyl groups, e.g. acrylonitrile and methyl methacrylate, in the presence of metal halides such as ZnCl2 and AlCl3 is characterized by an increased rate of polymerization. On the contrary, the formation of polymers with considerably higher molecular weight is likely in the absence of the metal halide (Bamford et al, 1957; Bovey, 1960; Arthur & Blouin, 1964).

The reaction of methyl methacrylate (MMA) with transition metal bromides gives examples

**or C**

**H3CO**

This behavior is similar to the one suggested (Kabanov, 1969) for the polymerization of

The polymerization of acrylonitrile (AN) in presence of Cu(I), Cu(II), Co(II), Ni(II) and Cd(II) bromides was studied (El-Sonbati & Diab, 1988b & 1988c). The IR spectrum of the formed AN-Cu(II) bromide polymer complex shows the absence of the C≡N band and the presence of two new bands corresponding to NH2 and OH groups. These bands are not

**C C H2**

**Br**

**CH3**

**O**

**M**

**Br**

of bidentated polymer complexes (El-Sonbati & Diab, 1988a) as shown in Fig. 15.

**2+**

**2ClO4**

**n**

**C O**

**Br Br**

**C**

**CH3**

**H3CO**

**H2 C**

**M**

**\_ C O**

**CH2 C**

**NH3 H3N**

Osada, 1976a; Osada, 1976b; Osada & Ishida, 1976).

**C O**

**CH3**

**C C H2**

**M**

**Br Br**

M = Cu(II), Co(II) and Ni(II)

Fig. 15.

**OCH3**

MMA in presence of inorganic salts such as ZnCl2 and AlBr3.

Fig. 14.

### **b. Network-coordinated polymers**

The most usual method to prepare this type of complexes is use a "template reaction". This is a reaction between two functional groups of the ligand induced by their coordination to the metal ion, resulting in a chelated-type metal complex (Fig. 11).

Fig. 11.

A typical example is poly(metal phthalocyanine) formed during the reaction of tetracyanobenzene with metal halides catalyzed by urea as shown in Fig. 12 (Epstein & Wildi, 1960).

Fig. 12.

### **2.1.4 Formation through polymerization of metal complexes**

Polymer containing the metal as part of a pendent or substituent group may be formed when complex possessing functionalized ligands undergo polymerization. The most widely studied are vinyl complexes and their derivatives, formed through radical polymerization of vinyl monomer containing transition metal ions. Vinyl compounds of metal complex are polymerized giving polymer metal complexes as shown in Fig. 13.

Fig. 13.

This type of polymer complex is characterized by its clear coordination structure. Nevertheless, the limitations of the vinyl compounds, and the metal complex tendency to hinder the vinyl polymerization, may constitute an obstacle in this type of polymerization.

Methacrylate monomer coordinated to Co(III) complex, e.g. methacrylato-pentaamine cobalt (III) perchlorate, was radically polymerized giving the polymer (VI) (Fig. 14) (Osada, 1975; Osada, 1976a; Osada, 1976b; Osada & Ishida, 1976).

Fig. 14.

154 Stoichiometry and Research – The Importance of Quantity in Biomedicine

The most usual method to prepare this type of complexes is use a "template reaction". This is a reaction between two functional groups of the ligand induced by their coordination to the

A typical example is poly(metal phthalocyanine) formed during the reaction of tetracyanobenzene with metal halides catalyzed by urea as shown in Fig. 12 (Epstein &

Polymer containing the metal as part of a pendent or substituent group may be formed when complex possessing functionalized ligands undergo polymerization. The most widely studied are vinyl complexes and their derivatives, formed through radical polymerization of vinyl monomer containing transition metal ions. Vinyl compounds of metal complex are

This type of polymer complex is characterized by its clear coordination structure. Nevertheless, the limitations of the vinyl compounds, and the metal complex tendency to hinder the vinyl polymerization, may constitute an obstacle in this type of polymerization.

**MX2**

**+**

**2.1.4 Formation through polymerization of metal complexes** 

polymerized giving polymer metal complexes as shown in Fig. 13.

**L**

**M**

**urea 300-350°C** **L L L**

**L L L M M**

**N N**

**N**

**LLL L**

**M M M M**

**M**

**<sup>N</sup> <sup>N</sup>**

**N**

**N**

**N**

**L L M**

**b. Network-coordinated polymers** 

Fig. 11.

Fig. 12.

Fig. 13.

Wildi, 1960).

metal ion, resulting in a chelated-type metal complex (Fig. 11).

**L L + M**

**NC CN**

**NC CN**

The free radical initiated polymerization of polar monomers containing pendant nitrile and carbonyl groups, e.g. acrylonitrile and methyl methacrylate, in the presence of metal halides such as ZnCl2 and AlCl3 is characterized by an increased rate of polymerization. On the contrary, the formation of polymers with considerably higher molecular weight is likely in the absence of the metal halide (Bamford et al, 1957; Bovey, 1960; Arthur & Blouin, 1964).

The reaction of methyl methacrylate (MMA) with transition metal bromides gives examples of bidentated polymer complexes (El-Sonbati & Diab, 1988a) as shown in Fig. 15.

M = Cu(II), Co(II) and Ni(II)

Fig. 15.

This behavior is similar to the one suggested (Kabanov, 1969) for the polymerization of MMA in presence of inorganic salts such as ZnCl2 and AlBr3.

The polymerization of acrylonitrile (AN) in presence of Cu(I), Cu(II), Co(II), Ni(II) and Cd(II) bromides was studied (El-Sonbati & Diab, 1988b & 1988c). The IR spectrum of the formed AN-Cu(II) bromide polymer complex shows the absence of the C≡N band and the presence of two new bands corresponding to NH2 and OH groups. These bands are not

Stoichiometry of Polymer Complexes 157

Poly(acrylamido-4-aminoantipyrinyl)(PAA) homopolymer and polymer complexes of acrylamido-4-aminoantipyrinyl (AA) with some transition metal bromides and uranyl acetate have been prepared (El-Sonbat et al., 1989)). Dioxouranium(VI) acetate dehydrate reacts with AA in a 1:2 and with CuBr2, NiBr2 and CoBr2 in 1:1 metal:ligand molar ratios and

the polychelates of the types shown in Fig. 18.

**N**

**O**

CH3COO

**U**

**O O**

**OOCCH**<sup>3</sup>

**C H2**

**O**

**N C O**

H

**HC C H2**

**N**

**N CH3**

**CH3**

**C6H5**

Poly(2-acrylamidophenol)(PAP) homopolymer and polymer complexes of 2 acrylamidophenol (AP) with Cu(II), Ni(II), Co(II), Cd(II) chlorides and uranyl acetate were prepared and characterized (Diab et al., 1988). The phenolic C-O IR band has been shifted of ± 15 cm-1, indicating that it is involved in the coordination of AP-CuCl2 and AP-CdCl2 polymer complexes (Fig. 19). There is a change in the position of NH band to lower frequency, indicating the recruitment of these groups in the coordination of AP-CoCl2 and AP-NiCl2 polymer complexes. The possible structures of AP-Cu(II), AP-Ni(II), AP-Co(II),

**N**

**C**

**M**

**O**

**OH2**

**H C C H2**

**O**

M = Cu(II) and Cd(II)

**H2O**

**N**

**O**

**N C O**

**C H2**

**CH**

**M**

**OH2**

**N CH3**

**CH3**

**C6H5**

**N O C**

H

**HC**

AP-Cd(II) chlorides and uranyl acetate are the following:

**H3C N**

**H3C**

M = Co(II) and Ni(II)

Fig. 18.

**C6H5**

found with the other metal bromide polymer complexes (Fig. 16). It seem that Cu(II) is reduced to the stable Cu(I) during the polymerization of AN-Cu(II) bromide.

Fig. 16.

Poly(8-quinolyl acrylate)(P8-QA) and the polymers of the complexes of 8-quinolyl acrylate (8-QA) with some transition metal bromides and uranyl acetate have been prepared and characterized (El-Sonbati & Diab, 1988d). Dioxouranium(VI) acetate dehydrate reacts with 8-QA monomer in a 1:3 metal:ligand molar ratio. On the other hand, 8-QA reacts with Cu(II), Ni(II) and Co(II) bromides in such a way that the polychelates have 1:2, metal:ligand stoichiometry as shown in Fig. 17.

M = Cu(II), Co(II) and Ni(II)

Fig. 17.

found with the other metal bromide polymer complexes (Fig. 16). It seem that Cu(II) is

Poly(8-quinolyl acrylate)(P8-QA) and the polymers of the complexes of 8-quinolyl acrylate (8-QA) with some transition metal bromides and uranyl acetate have been prepared and characterized (El-Sonbati & Diab, 1988d). Dioxouranium(VI) acetate dehydrate reacts with 8-QA monomer in a 1:3 metal:ligand molar ratio. On the other hand, 8-QA reacts with Cu(II), Ni(II) and Co(II) bromides in such a way that the polychelates have 1:2, metal:ligand

**C HO NH2**

**C O NH2 Cu Br**

**or**

**CH2 CH C O NH2 Cu Br**

reduced to the stable Cu(I) during the polymerization of AN-Cu(II) bromide.

**CuBr2 CH2 CH CH2 CH CH2 <sup>C</sup> CH2 <sup>C</sup>**

**C HO NH**

**C N**

Fig. 16.

**+ H2O**

stoichiometry as shown in Fig. 17.

M = Cu(II), Co(II) and Ni(II)

Fig. 17.

Poly(acrylamido-4-aminoantipyrinyl)(PAA) homopolymer and polymer complexes of acrylamido-4-aminoantipyrinyl (AA) with some transition metal bromides and uranyl acetate have been prepared (El-Sonbat et al., 1989)). Dioxouranium(VI) acetate dehydrate reacts with AA in a 1:2 and with CuBr2, NiBr2 and CoBr2 in 1:1 metal:ligand molar ratios and the polychelates of the types shown in Fig. 18.

M = Co(II) and Ni(II)

Fig. 18.

Poly(2-acrylamidophenol)(PAP) homopolymer and polymer complexes of 2 acrylamidophenol (AP) with Cu(II), Ni(II), Co(II), Cd(II) chlorides and uranyl acetate were prepared and characterized (Diab et al., 1988). The phenolic C-O IR band has been shifted of ± 15 cm-1, indicating that it is involved in the coordination of AP-CuCl2 and AP-CdCl2 polymer complexes (Fig. 19). There is a change in the position of NH band to lower frequency, indicating the recruitment of these groups in the coordination of AP-CoCl2 and AP-NiCl2 polymer complexes. The possible structures of AP-Cu(II), AP-Ni(II), AP-Co(II), AP-Cd(II) chlorides and uranyl acetate are the following:

M = Cu(II) and Cd(II)

Stoichiometry of Polymer Complexes 159

**N**

**CH CH2**

**N**

The IR spectra of AP-CoCl2, AP-NiCl2 and AP-CdCl2 polymer complexes have the characteristic features of coordination between the nitrogen atom of the pyridine ring and the oxygen atom of the hydroxyl group. AP reacts with NiCl2, CoCl2 in a 2:1 ratio and with CdCl2 in a 1:1 ratio. The possible structures of AP-NiCl2, AP-CoCl2 and AP-CdCl2 polymer

It was found that poly[bis(2,6-diaminopyridine sulphoxide)](PDPS) homopolymer and polymer complexes of bis(2,6-diaminopyridine sulphoxide)(DPS) with CuCl2, CuBr2 and CuI2 were prepared and characterized (Diab et al., 1989b). The mode of complexation of the

polymer complexes of PDPS with copper halides is derived as shown in Fig. 23.

**N**

**Cu**

X

**X**

**N H**

**O**

**S**

**NH**

**N**

**CH**

**Cd**

**Cl**

**H2O**

**N**

**Cu**

<sup>X</sup> X = Cl, Br and I

**X**

**HN**

**O**

**S**

**NH**

**N C O**

**H2 C**

**C**

**HO**

**Cl**

**Cl**

Fig. 21.

Fig. 22.

Fig. 23.

complexes (Fig. 22) are the following:

 For M = Ni(II); n = 0 For M = Co(II); n = 4

**Cu**

### Fig. 19.

Poly(2-acrylamidopyridine)(PAP) homopolymer and polymer complexes of 2 acrylamidopyridine (AP) with some transition metal chlorides have been prepared and characterized (Diab et al., 1989a). IR spectrum of PAP homopolymer indicates two tautomeric forms are shown in Fig. 20.

Fig. 20.

The IR spectrum of AP-CuCl2 polymer complex shows a lowering of the OH stretching frequency by about 10-15 cm-1 indicating that the OH group is involved in the coordination (Fig. 21). An increase in the frequency of the pyridine nitrogen indicates that it takes part in the bond formation. Moreover, new bands appeared in the spectrum assigned to υ(M-O), υ(M-N) and υ(M-Cl). It may be deduced that the probable structure of AP-CuCl2 polymer complex is:

Fig. 21.

158 Stoichiometry and Research – The Importance of Quantity in Biomedicine

Poly(2-acrylamidopyridine)(PAP) homopolymer and polymer complexes of 2 acrylamidopyridine (AP) with some transition metal chlorides have been prepared and characterized (Diab et al., 1989a). IR spectrum of PAP homopolymer indicates two

**U**

**O OH2 H2O**

**O**

**NH**

**H C C H2 O C**

**O**

**HN**

**C H**

**C O C H2**

**O**

The IR spectrum of AP-CuCl2 polymer complex shows a lowering of the OH stretching frequency by about 10-15 cm-1 indicating that the OH group is involved in the coordination (Fig. 21). An increase in the frequency of the pyridine nitrogen indicates that it takes part in the bond formation. Moreover, new bands appeared in the spectrum assigned to υ(M-O), υ(M-N) and υ(M-Cl). It may be deduced that the probable structure of AP-CuCl2 polymer

Fig. 19.

Fig. 20.

complex is:

tautomeric forms are shown in Fig. 20.

The IR spectra of AP-CoCl2, AP-NiCl2 and AP-CdCl2 polymer complexes have the characteristic features of coordination between the nitrogen atom of the pyridine ring and the oxygen atom of the hydroxyl group. AP reacts with NiCl2, CoCl2 in a 2:1 ratio and with CdCl2 in a 1:1 ratio. The possible structures of AP-NiCl2, AP-CoCl2 and AP-CdCl2 polymer complexes (Fig. 22) are the following:

Fig. 22.

It was found that poly[bis(2,6-diaminopyridine sulphoxide)](PDPS) homopolymer and polymer complexes of bis(2,6-diaminopyridine sulphoxide)(DPS) with CuCl2, CuBr2 and CuI2 were prepared and characterized (Diab et al., 1989b). The mode of complexation of the polymer complexes of PDPS with copper halides is derived as shown in Fig. 23.

Fig. 23.

Stoichiometry of Polymer Complexes 161

ABA reacts with Cu(II), Co(II), and Ni(II) in a 2:1 molar ratio of monomer unit: metal. The

structure of the polychelates (Fig. 27) is of the type:

**CO**

**NH**

**O**

**O**

**M**

**X**

**O**

**O H2 C**

**C H2**

**X**

**HN**

**O**

**C C H**

M = Cu(II) and Ni(II); X = 0

Poly(5-vinylsalicylidene anthranilic acid)(PVSA) homopolymer and polymer complexes of 5-vinylsalicylidene anthranilic acid (VSA) with some transition metal chlorides and uranyl acetate were prepared (Diab et al., 1990b). The IR spectrum of VSA-uranyl acetate polymer complex shows a change in the position of azomethine nitrogen and carboxylate ion groups indicating their involvement in coordination. Elemental analysis and IR spectrum reveal that VSA reacts with uranyl acetate, NiCl2, CuCl2 and CoCl2 to form the structures shown in

M = Co(II); X = H2O

**O**

**C H**

**O**

**C H** **N**

**Co C O <sup>O</sup> <sup>2</sup>**

**N**

**Cl**

**Ni C O**

**OH**

**4H2O**

**C**

**H C**

**C**

Fig. 27.

Fig. 28.

**CH**

Fig. 28.

**CH2**

**OH**

**C O**

**O**

**U O**

**O**

**N**

**C O**

**O**

**C H** **N**

**Cu <sup>C</sup> O**

**OH2**

**O**

**HO**

**H**

**CH <sup>C</sup>**

**CH2**

**O**

**CH**

**CH**

**H2C**

**CH2**

**C H N**

**HC**

**H2C**

Poly(5-vinyl salicylaldehyde)(PVS) homopolymer and polymer complexes of 5 vinylsalicylaldehyde (VS) with CuCl2, CoCl2, NiCl2 and uranyl acetate were synthesized and characterized (El-Hendawy, 1989). The IR spectrum of VS-CuCl2 polymer complex shows a shift of υ(C=O) to a lower frequency by about 15 cm-1 and the υ(C-O) of the phenolic group is shifted to a higher frequency by about 25 cm-1 indicating that both groups are involved in the complexation. From the spectroscopic data, the magnetic moments and the elemental analysis, it is concluded that VS reacts with CuCl2, CoCl2 and NiCl2 in the ratio 2:1. The possible structure of the polymer complexes VS-CuCl2, VS-CoCl2 and VS-NiCl2 may be as shown in Fig. 24.

Fig. 24.

VS reacts with uranyl acetate in 1:2 metal:ligand stoichiometry (Fig. 25).

### Fig. 25.

Polymer complexes of 2-acrylamidobenzoic acid (ABA) with transition metal chlorides and uranyl acetate were prepared and characterized (Diab et al., 1990a). ABA reacts with uranyl ions in a 2:1 molar ratio. The chelation occurs through one of the two oxygens of the carboxylate ion, which is represented as a tautomeric form as shown in Fig. 26.

ABA reacts with Cu(II), Co(II), and Ni(II) in a 2:1 molar ratio of monomer unit: metal. The structure of the polychelates (Fig. 27) is of the type:

Fig. 27.

160 Stoichiometry and Research – The Importance of Quantity in Biomedicine

Poly(5-vinyl salicylaldehyde)(PVS) homopolymer and polymer complexes of 5 vinylsalicylaldehyde (VS) with CuCl2, CoCl2, NiCl2 and uranyl acetate were synthesized and characterized (El-Hendawy, 1989). The IR spectrum of VS-CuCl2 polymer complex shows a shift of υ(C=O) to a lower frequency by about 15 cm-1 and the υ(C-O) of the phenolic group is shifted to a higher frequency by about 25 cm-1 indicating that both groups are involved in the complexation. From the spectroscopic data, the magnetic moments and the elemental analysis, it is concluded that VS reacts with CuCl2, CoCl2 and NiCl2 in the ratio 2:1. The possible structure of the polymer complexes VS-CuCl2, VS-CoCl2 and VS-NiCl2 may be as shown in Fig. 24.

> = Co (II), X = 2 = Ni (II), X = 4

> > **U**

**O**

Polymer complexes of 2-acrylamidobenzoic acid (ABA) with transition metal chlorides and uranyl acetate were prepared and characterized (Diab et al., 1990a). ABA reacts with uranyl ions in a 2:1 molar ratio. The chelation occurs through one of the two oxygens of the

**HN**

**C C H**

**C**

**O**

**OH2 2H2O**

**O**

**H2O OH2**

VS reacts with uranyl acetate in 1:2 metal:ligand stoichiometry (Fig. 25).

**CH**

**H2C**

**HC O**

**O**

carboxylate ion, which is represented as a tautomeric form as shown in Fig. 26.

**H2 C**

**NH**

**H2O U**

**O**

**O**

**O**

**O**

**O**

**O C H2**

**O C CH**

**C**

Fig. 24.

Fig. 25.

Fig. 26.

M = Cu (II), X = 0

**O CH**

**O CH**

**CH2**

Poly(5-vinylsalicylidene anthranilic acid)(PVSA) homopolymer and polymer complexes of 5-vinylsalicylidene anthranilic acid (VSA) with some transition metal chlorides and uranyl acetate were prepared (Diab et al., 1990b). The IR spectrum of VSA-uranyl acetate polymer complex shows a change in the position of azomethine nitrogen and carboxylate ion groups indicating their involvement in coordination. Elemental analysis and IR spectrum reveal that VSA reacts with uranyl acetate, NiCl2, CuCl2 and CoCl2 to form the structures shown in Fig. 28.

Fig. 28.

Stoichiometry of Polymer Complexes 163

VSA reacts with Ni(II) and Co(II) in a 2:1 molar ratio and with Cd(II) in a 1:1 ratio (Fig. 32).

**CH CH2**

Homopolymer of 5-vinylsalicylidene-2-aminophenol (PVSA) and polymer complexes of 5 vinylsalicylidene-2-aminophenol (VSA) with transition metal acetate have been prepared and characterized (El-Sonbati, 1991a). The absence of the phenolic υ(O-H) in the copper(II), nickel(II), cadmium(II) and zinc(II) polymer complexes indicates the phenolic proton is lost upon metal ion complexation VSA appears to react with Cu(II), Ni(II), Cd(II) and Zn(II) acetate in a 1:1 ratio and with Co(II) and uranyl acetate in a 2:1 molar ratio. A possible

**nH2O**

M =Cu(II); n = 2, M = Ni(II), Cd(II), Zn(II); n = 0 M = UO2(II) or Co(II)

Polymer complexes derived from 5-vinylsalicylidene hydrazine-S-benzyl dithiocarbocarbazate (VSH) with CuCl2, NiCl2, CdCl2 and uranyl acetate were prepared and characterized by elemental analyses, spectroscopic and magnetic measurements (El-Sonbati, 1991b). The IR spectra of VSH-NiCl2 and VSH-CdCl2 polymer complexes show the disappearance of the NH group and the appearance of new bands at 1625-1630 cm-1 which could be attributed to the stretching vibrational mode of the conjugated C=N-N=C group. There is a strong broad band at 3460-3350 cm-1 which is attributable to the associated water molecules. The absence of the phenolic υOH is an indication that the phenolic proton is lost upon complexation. Furthermore, it was found that there is a band around 1495 cm-1, suggesting that the *o*-hydroxy group has entered into the band formation with metal ions. According to these results beside the electronic spectra and elemental analysis, the possible structure of the products of reaction of VSH with NiCl2

**H2O**

**Cl**

**O**

**Cd**

**N**

**CH H2C**

**O**

**HC**

**CH2**

Fig. 32.

**CH**

**H2C**

Fig. 33.

**N**

**Ph OH2**

**M**

**M = Ni(II), Co(II)**

structure for the polymer complexes is shown in Fig. 33.

**N**

**M**

**O**

**H2O**

**O**

and CdCl2 as shown in Fig. 34.

**OH2**

**O**

**Ph**

**N**

Poly(ethylene glycol)(PEG) reacts with Cu(II), Co(II), Ni(II) and Cd(II) chlorides to form polymer complexes in 2:1, ligand:metal molar ratios (Diab & El-Sonbati, 1990). The IR bands due to C-O are shifted to higher frequencies in the formed polymer complexes. This shift may be due to the increased covalence resulting from metal ion coordination. On the basis of the analytical data, electronic and IR spectral data, PEG reacts with CuCl2, CoCl2, NiCl2 and CdCl2 as shown in Fig. 29.

Fig. 29.

Polymer complexes of 5-vinylsalicylidene aniline (VSA) with Cu(II), Co(II), Ni(II), Cd(II) and UO2(II). VSA reacts with uranyl nitrate in a 2:1 ratio and with uranyl acetate in a 1:1 ratio were found (El-Sonbati, 1992). A possible structure for the polymer complexes is shown in Fig. 30.

Fig. 30.

The IR, electronic spectra and elemental analyses data indicate that copper(II) salts react with VSA monomer in a 1:1 molar ratio (Fig. 31).

Fig. 31.

VSA reacts with Ni(II) and Co(II) in a 2:1 molar ratio and with Cd(II) in a 1:1 ratio (Fig. 32).

Fig. 32.

162 Stoichiometry and Research – The Importance of Quantity in Biomedicine

Poly(ethylene glycol)(PEG) reacts with Cu(II), Co(II), Ni(II) and Cd(II) chlorides to form polymer complexes in 2:1, ligand:metal molar ratios (Diab & El-Sonbati, 1990). The IR bands due to C-O are shifted to higher frequencies in the formed polymer complexes. This shift may be due to the increased covalence resulting from metal ion coordination. On the basis of the analytical data, electronic and IR spectral data, PEG reacts with CuCl2, CoCl2, NiCl2 and

> **M O O**

**H C**

> **O O C CH H**

**M**

**Cl**

**nH2O**

**N**

**H O**

**Ph**

**O**

**N**

**X = Cl or Br**

**Cu**

**Ph**

**OH2**

**X**

**U**

**C O O**

**CH3**

**O O**

**C O O**

**CH3**

**H**

**CH**

**H**

Polymer complexes of 5-vinylsalicylidene aniline (VSA) with Cu(II), Co(II), Ni(II), Cd(II) and UO2(II). VSA reacts with uranyl nitrate in a 2:1 ratio and with uranyl acetate in a 1:1 ratio were found (El-Sonbati, 1992). A possible structure for the polymer complexes is

> **CH H2C**

The IR, electronic spectra and elemental analyses data indicate that copper(II) salts react

**C**

**CH3**

**HC CH2**

**O**

**O**

**HC**

**CH2**

**Cl**

CdCl2 as shown in Fig. 29.

Fig. 29.

shown in Fig. 30.

**CH CH2**

**HC**

**CH2**

Fig. 30.

Fig. 31.

**M O O**

**O O C CH H**

**H O**

**Ph**

**N U**

with VSA monomer in a 1:1 molar ratio (Fig. 31).

**O O**

**HO**

**ONO2**

**O**

**Cu**

**Ph**

**N**

**N ONO**

**Ph2**

**H C**

**X 2H2O**

**H**

 M = Cu(II); X = H2O M =Co(II); n = 3 M = Ni(II); X = zero M =Co(II); n = 6

**CH**

**H**

Homopolymer of 5-vinylsalicylidene-2-aminophenol (PVSA) and polymer complexes of 5 vinylsalicylidene-2-aminophenol (VSA) with transition metal acetate have been prepared and characterized (El-Sonbati, 1991a). The absence of the phenolic υ(O-H) in the copper(II), nickel(II), cadmium(II) and zinc(II) polymer complexes indicates the phenolic proton is lost upon metal ion complexation VSA appears to react with Cu(II), Ni(II), Cd(II) and Zn(II) acetate in a 1:1 ratio and with Co(II) and uranyl acetate in a 2:1 molar ratio. A possible structure for the polymer complexes is shown in Fig. 33.

Fig. 33.

Polymer complexes derived from 5-vinylsalicylidene hydrazine-S-benzyl dithiocarbocarbazate (VSH) with CuCl2, NiCl2, CdCl2 and uranyl acetate were prepared and characterized by elemental analyses, spectroscopic and magnetic measurements (El-Sonbati, 1991b). The IR spectra of VSH-NiCl2 and VSH-CdCl2 polymer complexes show the disappearance of the NH group and the appearance of new bands at 1625-1630 cm-1 which could be attributed to the stretching vibrational mode of the conjugated C=N-N=C group. There is a strong broad band at 3460-3350 cm-1 which is attributable to the associated water molecules. The absence of the phenolic υOH is an indication that the phenolic proton is lost upon complexation. Furthermore, it was found that there is a band around 1495 cm-1, suggesting that the *o*-hydroxy group has entered into the band formation with metal ions. According to these results beside the electronic spectra and elemental analysis, the possible structure of the products of reaction of VSH with NiCl2 and CdCl2 as shown in Fig. 34.

Stoichiometry of Polymer Complexes 165

**X2**

**NH**

**Ni**

**NH**

**M**

**OH2**

**OAc 2H2O**

**H C**

**C H2**

**O C**

**N H**

**C H2**

**Cl**

**H2O**

**Cl**

**H C**

**O C**

**N H2**

**NH**

**M O**

**H2 C n**

**O**

M = UO2(II); X = X`

Polymer complexes of 5-vinylsalicylidene semicarbazone (VSSc) with Cu(II), Co(II), Ni(II), Cd(II), Zn(II) and UO2(II) acetates were synthesized by mixing stoichiometric quantities (0.02 mol) of the VSSc in 30 ml DMF, the metal salt (0.01 mol) in 20 ml DMF and adding 0.1 w/v % 2,2`-azobisisobutyronitrile (AIBN) as initiator (El-Sonbati, 1991c). VSSc reacts with metal ions and uranyl acetate in a 2:1 molar ratio and a possible structure for the polymer

**C CH3 X**

= H2O M = Co(II); X = nill M = Cd(II) or Zn(II)

**H C**

**O C**

**N H**

M = Cu(II); X = X` = nill M = Ni(II) ; X = H2O

**HC O**

**CH2**

**HC N**

**NH C O NH2**

**X M X**

M = Cu(II), Co(II), Ni(II), Cd(II) or Zn(II); X = H2O, M = UO2(II); X = nill

**O CH**

**NH C NH2 O**

**<sup>N</sup> CH CH2**

**NH**

**H C** **H2 C**

**O C**

**NH2**

 M = Cu(II) X = Cl X′ = X″ = nill M = Co(II) X = nill X′ = X″ = Cl

**NH**

**X M X'**

**O C H2**

complexes is shown in Fig. 38.

**H2 C**

**HN**

**C C H**

**HN**

**O C CH**

Fig. 37.

Fig. 38.

**NH**

**M X'**

**X'' HN**

**C H2**

**O**

**H2N**

**C CH**

Fig. 34.

The IR spectrum of the VSH-CuCl2 polymer complex shows the disappearance of the bands attributed to C=S and OH groups, suggesting that enolization occurred through the thioketonic group. The shift of the phenolic υ(C-O) to higher frequencies by about 15-20 cm-1 suggests the formation of an oxygen-bridge structure (Fig. 35). The structure appear to be of the following type:

Fig. 35.

The stoichiometry between uranyl acetate and VSH are in agreement with a 1:2 molar ratio and the following type of structure is proposed (Fig. 36).

Fig. 36.

It was found that, 2-acrylamido-1,2-diaminobenzene (AAB) reacts with Cu(II), Ni(II), Zn(II) and UO2(II) chlorides or acetate to give polymer complexes with different stoichiometry (El-Sonbati et.al., 1991), depending on the metal salt and the reaction conditions. The cobalt(II) polymer complexes may be classified into two groups. Those with the 1:1 composition are derived from ADB-Co(II) acetate and those with 1:2 stoichiometry are derived from ADB-Co(II) chloride. All these observations suggest the structures as shown in Fig. 37.

The IR spectrum of the VSH-CuCl2 polymer complex shows the disappearance of the bands attributed to C=S and OH groups, suggesting that enolization occurred through the thioketonic group. The shift of the phenolic υ(C-O) to higher frequencies by about 15-20 cm-1 suggests the formation of an oxygen-bridge structure (Fig. 35). The structure appear to be of

**Cu Cu**

The stoichiometry between uranyl acetate and VSH are in agreement with a 1:2 molar ratio

O

H

C H

Co(II) chloride. All these observations suggest the structures as shown in Fig. 37.

N

S

R

N C

It was found that, 2-acrylamido-1,2-diaminobenzene (AAB) reacts with Cu(II), Ni(II), Zn(II) and UO2(II) chlorides or acetate to give polymer complexes with different stoichiometry (El-Sonbati et.al., 1991), depending on the metal salt and the reaction conditions. The cobalt(II) polymer complexes may be classified into two groups. Those with the 1:1 composition are derived from ADB-Co(II) acetate and those with 1:2 stoichiometry are derived from ADB-

O U O

C N

S

O

H

R = SCH2Ph

H C N

R

**S**

and the following type of structure is proposed (Fig. 36).

HC

CH2

**O N**

CH CH2

**O**

**N S**

Fig. 34.

Fig. 35.

Fig. 36.

the following type:

Polymer complexes of 5-vinylsalicylidene semicarbazone (VSSc) with Cu(II), Co(II), Ni(II), Cd(II), Zn(II) and UO2(II) acetates were synthesized by mixing stoichiometric quantities (0.02 mol) of the VSSc in 30 ml DMF, the metal salt (0.01 mol) in 20 ml DMF and adding 0.1 w/v % 2,2`-azobisisobutyronitrile (AIBN) as initiator (El-Sonbati, 1991c). VSSc reacts with metal ions and uranyl acetate in a 2:1 molar ratio and a possible structure for the polymer complexes is shown in Fig. 38.

M = Cu(II), Co(II), Ni(II), Cd(II) or Zn(II); X = H2O, M = UO2(II); X = nill

Fig. 38.

Stoichiometry of Polymer Complexes 167

**N**

X = Cl− or Br<sup>−</sup>

C CH3

**O**

**N**

**CH2**

**N**

**N**

X = Cl<sup>−</sup> or Br-

 M = Co(II); X = Cl<sup>−</sup> or Br−; X′ = H2O; M = Ni(II); X = nil; X′ = H2O; M =Cd(II), Hg(II), UO2(II); X = X′ = nill

**M**

**O**

**N CH2**

**<sup>X</sup>' CH**

**U**

**O**

**O**

**O H**

**N**

**O**

**O**

**C**

**CH3**

**CH3**

**O**

**C**

**O**

**H2C**

**X**

**X'**

**N**

**Cu X**

**C H2** **N**

**n**

**CH O**

**CH2**

**HC H2C**

O

O

O

Cu

N

**x**

**Pd Pd**

**x <sup>O</sup>**

**O**

**N**

Fig. 42.

Fig. 41.

Polymer complexes of 5-vinylsalicylidene-2-benzothiazoline (VSBH2) with Cu(II), Ni(II), Co(II), Fe(II), Mn(II), Zn(II), Pd(II) and UO2(II) were prepared and characterized (El-Sonbati & Hefni, 1993). Two IR bands of medium intensity at 1580 and 1530 cm-1 can be assigned to the thiazolines ring vibration. Therefore, PVSBH2 homopolymer exists in benzothiazoline form as shown in Fig. 39.

Fig. 39.

The electronic spectral data concluded that the five coordinate polymeric metal complexes of the general formula [M(VSBH2-2H).2H2O]n (M = Ni(II), Co(II), Mn(II) or Fe(II)) are dimetallic with octahedral geometry, while the remained ones are monomeric and present a square or tetrahedral structure (Fig. 40).

Fig. 40.

Polymer complexes derived from 5-vinylsalicylidene-2-aminomethylpyridine (VSAPH) with some transition metal salts were prepared and characterized (El-Bindary et al., 1993). All the IR and analytical data are commensurate with the structure shown in Fig. 41.

VSAPH may also act as a bidentate ligand, coordinating to the metal ion *via* the azomethine nitrogen and phenolic oxygen atoms. Loss in a proton from the latter group would allow formation of a six-membered chelate ring. The uranyl polymer complexes can be formulated as [UO2(VSAP)2] and [UO2(VSAPH)(OAc)2], indicating a probable coordination number of 6 for the uranium(VI) ion. The following structures are suggested (Fig. 42) for the polymer complexes:

Fig. 41.

166 Stoichiometry and Research – The Importance of Quantity in Biomedicine

Polymer complexes of 5-vinylsalicylidene-2-benzothiazoline (VSBH2) with Cu(II), Ni(II), Co(II), Fe(II), Mn(II), Zn(II), Pd(II) and UO2(II) were prepared and characterized (El-Sonbati & Hefni, 1993). Two IR bands of medium intensity at 1580 and 1530 cm-1 can be assigned to the thiazolines ring vibration. Therefore, PVSBH2 homopolymer exists in benzothiazoline

**OH**

**N**

The electronic spectral data concluded that the five coordinate polymeric metal complexes of the general formula [M(VSBH2-2H).2H2O]n (M = Ni(II), Co(II), Mn(II) or Fe(II)) are dimetallic with octahedral geometry, while the remained ones are monomeric and present a

**H**

**O M**

**OH2**

**N**

M = Fe(II), Mn(II), Co(II) or Ni(II) M = Cu(II) or Zn(II)

IR and analytical data are commensurate with the structure shown in Fig. 41.

Polymer complexes derived from 5-vinylsalicylidene-2-aminomethylpyridine (VSAPH) with some transition metal salts were prepared and characterized (El-Bindary et al., 1993). All the

VSAPH may also act as a bidentate ligand, coordinating to the metal ion *via* the azomethine nitrogen and phenolic oxygen atoms. Loss in a proton from the latter group would allow formation of a six-membered chelate ring. The uranyl polymer complexes can be formulated as [UO2(VSAP)2] and [UO2(VSAPH)(OAc)2], indicating a probable coordination number of 6 for the uranium(VI) ion. The following structures are suggested (Fig. 42) for the polymer

**S**

**S**

**<sup>N</sup> <sup>O</sup>**

**M M**

**H2O H2O**

**H2O H2O**

**O**

**S**

**N**

**S**

form as shown in Fig. 39.

Fig. 39.

Fig. 40.

complexes:

**HC**

square or tetrahedral structure (Fig. 40).

**CH CH2** **CH2**

 M = Co(II); X = Cl<sup>−</sup> or Br−; X′ = H2O; M = Ni(II); X = nil; X′ = H2O; M =Cd(II), Hg(II), UO2(II); X = X′ = nill

Fig. 42.

Stoichiometry of Polymer Complexes 169

(cm-1) Assignment µeff (B.M) Geometry

4.31 Octahedral

4.05 Octahedral

3.37 Octahedral

3.21 Octahedral

1.89 Octahedral

dia. Square planner

1.93

4T1g 4T2g(F) υ<sup>1</sup> 4T1g 4A2g(F) υ<sup>2</sup> 4T1g 4T1g(P) υ<sup>3</sup>

4T1g 4T2g(F) υ<sup>1</sup> 4T1g 4A2g(F) υ<sup>2</sup> 4T1g 4T1g(P) υ<sup>3</sup>

3A1g 3T2g(F) 3A2g 3T1g(F) 3A2g 3T1g(P)

3A1g 3T2g(F) 3A2g 3T1g(F) 3A2g 3T1g(P)

2T2g

2T2g

1B1g

1B1g

2Eg

1Ag

2Eg

2Ag

L2(NO3)2] 21730 E <sup>2</sup>π<sup>4</sup> dia. Octahedral

Table 1. Electronic spectral bands, assignments, ligand field parameters and proposed

No Species Band position

10206 15272 22222

10000 15625 24800

13900 – 16900 22200 - 24200

22200 – 24200 29000 - 31000

[Co L2Cl2] 2X

[Co L2Br2] X

[Ni L2Cl2]

[Ni L2 Br 2] X

[Cu L2Cl2] [CuL2 Br 2] X

[Pd LCl2] [Pd L2] Cl2 [Pd L] [PdCl4]

Polymer complexes (1-9) X = Cl or Br.

geometries for the polymer complexes.

<sup>11</sup>[UO2

1

2

3

4

5 6

7 8 9

Poly (cinnamaldehyde)-2-anthranilic acid (PCA) homopolymer and polymer complexes of cinnamaldehyde-2-anthranilic acid with Cu(II), Ni(II), Co(II), Zn(II), Cd(II) and Hg(II) has been synthesized and characterized (Fig. 43) (El- Sonbati et al., 1993a).

Fig. 43.

The analysis of the chelates show their formulae to be [M (PCA)- H)2.2X], where M = Cu (II), Co(II); and M = Zn(II), Hg(II) and Cd(II) at X = nill, [M(PCA)-H]OAc.2X and [Ni(PCA)- H]XY] where M = Cu(II), Co(II), Ni(II) and X = H2O, Y = Cl or Br. Their solubility varies in different common organic solvents. The 1:1 and 1:2 stoichiometries of the polymer complexes have been deduced from their elemental analyses. The presence of coordinated water was confirmed by TG data when a loss in weight corresponding to one water molecule was found for Ni(II) and two water molecules for Cu(II), Co(II) and Ni(II). No coordination water molecules were found in the case of Zn(II), Hg(II) and Cd(II) polymer complexes.

Polymer complexes of N,N`-*o*-phenylenediamine bis(cinnamaldehyde) (L) with Cu(II), Co(II), NiII, ZnII,UO2 II and PdII were prepared and characterized (El-Sonbati et al., 1993b). A bidentate methine nitrogen atoms coordination of the ligand is assigned in the isolated complexes. The µeff values of cobalt(II) and nickel(II) polymer complexes are normal and indicate an octahedral stereochemistry around the metal ion, the moments for the cobalt and nickel complexes are in a range expected for six-coordination metal ions, with much orbital contribution. The electronic spectra are summarized in Table 1, together with the proposed assignments, ligand field parameters, magnetic susceptibilities and suggested geometries.

Mononuclear and binuclear complexes of poly(5-vinylsalicylidene-2-aminopyridine) (PVSA) were prepared by the reaction of the homopolymer with copper(II), cobalt(II), nickel(II), dioxouranium(VI) and palladium(II) salts (El-Sonbati et al., 1994a). Metal(II) acetates and palladium chloride were found to give mononuclear complexes, while cupric chloride gave a binuclear complex. The stereochemistry and the nature of the polymer complexes are markedly dependent upon the molar ratios of the reactants, the pH of the system and the nature of the anions involved. In all of the complexes the homopolymer was chelated to the metal ion through the nitrogen atom of the azomethine group and the oxygen atom of the phenolic group. The stoichiometric of the complexes indicate that the copper(II) complexes fall into two distinct categories. The reaction of metal acetate with the VSP monomer gives compounds with formulae which correspond to [M(VSP-H)2]n while the reaction of CuCl2 with VSP in the presence of an excess of ammonium hydroxide gives a compound with the formula [Cu2(VSP-H)2Cl2]n. The mononuclear and binuclear polymer complexes may be represented as shown in Fig. 44.

Poly (cinnamaldehyde)-2-anthranilic acid (PCA) homopolymer and polymer complexes of cinnamaldehyde-2-anthranilic acid with Cu(II), Ni(II), Co(II), Zn(II), Cd(II) and Hg(II) has

The analysis of the chelates show their formulae to be [M (PCA)- H)2.2X], where M = Cu (II), Co(II); and M = Zn(II), Hg(II) and Cd(II) at X = nill, [M(PCA)-H]OAc.2X and [Ni(PCA)- H]XY] where M = Cu(II), Co(II), Ni(II) and X = H2O, Y = Cl or Br. Their solubility varies in different common organic solvents. The 1:1 and 1:2 stoichiometries of the polymer complexes have been deduced from their elemental analyses. The presence of coordinated water was confirmed by TG data when a loss in weight corresponding to one water molecule was found for Ni(II) and two water molecules for Cu(II), Co(II) and Ni(II). No coordination water molecules were found in the case of Zn(II), Hg(II) and Cd(II) polymer

Polymer complexes of N,N`-*o*-phenylenediamine bis(cinnamaldehyde) (L) with Cu(II),

bidentate methine nitrogen atoms coordination of the ligand is assigned in the isolated complexes. The µeff values of cobalt(II) and nickel(II) polymer complexes are normal and indicate an octahedral stereochemistry around the metal ion, the moments for the cobalt and nickel complexes are in a range expected for six-coordination metal ions, with much orbital contribution. The electronic spectra are summarized in Table 1, together with the proposed assignments, ligand field parameters, magnetic susceptibilities and suggested geometries.

Mononuclear and binuclear complexes of poly(5-vinylsalicylidene-2-aminopyridine) (PVSA) were prepared by the reaction of the homopolymer with copper(II), cobalt(II), nickel(II), dioxouranium(VI) and palladium(II) salts (El-Sonbati et al., 1994a). Metal(II) acetates and palladium chloride were found to give mononuclear complexes, while cupric chloride gave a binuclear complex. The stereochemistry and the nature of the polymer complexes are markedly dependent upon the molar ratios of the reactants, the pH of the system and the nature of the anions involved. In all of the complexes the homopolymer was chelated to the metal ion through the nitrogen atom of the azomethine group and the oxygen atom of the phenolic group. The stoichiometric of the complexes indicate that the copper(II) complexes fall into two distinct categories. The reaction of metal acetate with the VSP monomer gives compounds with formulae which correspond to [M(VSP-H)2]n while the reaction of CuCl2 with VSP in the presence of an excess of ammonium hydroxide gives a compound with the formula [Cu2(VSP-H)2Cl2]n. The mononuclear and binuclear polymer complexes may be

II and PdII were prepared and characterized (El-Sonbati et al., 1993b). A

been synthesized and characterized (Fig. 43) (El- Sonbati et al., 1993a).

Fig. 43.

complexes.

Co(II), NiII, ZnII,UO2

represented as shown in Fig. 44.


Polymer complexes (1-9) X = Cl or Br.

Table 1. Electronic spectral bands, assignments, ligand field parameters and proposed geometries for the polymer complexes.

Stoichiometry of Polymer Complexes 171

M = Cu(II), Co(II), Ni(II), Fe(II), Pd(II), Zn(II) or Cd(II)

M = Cu(II), Co(II), Ni(II), Zn(II) or Cd(II)

Polymer complexes of 2-acrylamido-1-phenyl-2-aminothiourea (APATH) with Rh(II) and Ru(II) ions in the presence and absence of N-heterocyclic bases as mixed ligand have been prepared and characterized through chemical analyses, thermal, electronic and infrared spectral studies (El-Sonbati et al., 1994b). The homopolymer shows three types of coordination behavior. In the mixed valence paramagnetic trinuclear polymer complexes Rh3(APATH)2Cl8 (**1**) and Ru3(APATH)2Cl8 (**2**), and in the mononuclear polymer compound Ru(APATH)2Cl3 (**3**) it acts as a neutral bidentate ligand coordinating through the thiocarbonyl sulphur and carbonyl oxygen atoms. In the mixed ligand paramagnetic polychelates, which are obtained from the reaction of APATH with RuCl3. XH2O in the presence of N-heterocyclic bases [B = H2O, pyridine (Py)/or *o*-phenylendiamine (*o*-phen), DMF] consisting of polymer complexes [Ru(APAT)2(H2O)Py]XCl (**7**) and Ru(APAT)Cl2(*o*phen.) H2O (**8**) and in mononuclear compounds Ru(APAT)2Cl.DMF (**6**) and Ru(APAT)2Cl(H2O)2 (**8**), it behaves as a monobasic bidentate ligand coordinating through the same donor atoms. In mononuclear compounds [Ru(APAT)(APATH)Cl]2H2O (**4**) and [Ru(APAT) (APATH)Cl2]2H2O (**5**) it acts as a monobasic and neutral bidentate ligand coordinating only through the same donor atoms. Monometric distorted octahedral or trimeric chlorine-bridged, approximately octahedral structures are proposed for these polymer complexes. The polychelates are of 1:1, 1:2 and 3:2 (metal: poly-Schiff base)

stoichiometry and exhibit five and six coordination (Fig. 46).

Fig. 45.

**M O N**

**A + MCl2 + Py Py Py**

**N O**

M = Cu(II), Fe(II), Co(II), Ni(II), Pd(II), Cd(II) and Zn (II)

Fig. 44.

Poly(5-vinylsalicylidene)-1,2-diaminobenzene (PVSB) homopolymer behaves as a monobasic tridentate chelating ligand and mixed ligand of PVSB and pyridine as a bidentate species. Polymer complexes of these ligands with Cu(II), Fe(II), Co(II), Ni(II), Pd(II), Cd(II) and Zn(II) were prepared and characterized (El-Sonbati & Hefni, 1994). In PVSB homopolymer, the principal IR bands of interest are two strong bands at 3365 and 3175 cm-1 attributed to the symmetric and asymmetric NH2 stretching vibrations (Fig. 45). The frequencies of these bands are observed at a considerably lower wavenumber in the polymer complexes of the nitrogen atom of the amino group with metal ions. The absence of large systematic shifts of υas(NH2), υs(NH2) and δ(NH2) bands in the spectra of mixed ligand polymer complexes, i.e. 2:1 species, implies that there is no interaction between the amino group nitrogen atom and the metal ions.

M = Cu(II), Fe(II), Co(II), Ni(II), Pd(II), Cd(II) and Zn (II)

Poly(5-vinylsalicylidene)-1,2-diaminobenzene (PVSB) homopolymer behaves as a monobasic tridentate chelating ligand and mixed ligand of PVSB and pyridine as a bidentate species. Polymer complexes of these ligands with Cu(II), Fe(II), Co(II), Ni(II), Pd(II), Cd(II) and Zn(II) were prepared and characterized (El-Sonbati & Hefni, 1994). In PVSB homopolymer, the principal IR bands of interest are two strong bands at 3365 and 3175 cm-1 attributed to the symmetric and asymmetric NH2 stretching vibrations (Fig. 45). The frequencies of these bands are observed at a considerably lower wavenumber in the polymer complexes of the nitrogen atom of the amino group with metal ions. The absence of large systematic shifts of υas(NH2), υs(NH2) and δ(NH2) bands in the spectra of mixed ligand polymer complexes, i.e. 2:1 species, implies that there is no interaction between the amino

Fig. 44.

group nitrogen atom and the metal ions.

Fig. 45.

Polymer complexes of 2-acrylamido-1-phenyl-2-aminothiourea (APATH) with Rh(II) and Ru(II) ions in the presence and absence of N-heterocyclic bases as mixed ligand have been prepared and characterized through chemical analyses, thermal, electronic and infrared spectral studies (El-Sonbati et al., 1994b). The homopolymer shows three types of coordination behavior. In the mixed valence paramagnetic trinuclear polymer complexes Rh3(APATH)2Cl8 (**1**) and Ru3(APATH)2Cl8 (**2**), and in the mononuclear polymer compound Ru(APATH)2Cl3 (**3**) it acts as a neutral bidentate ligand coordinating through the thiocarbonyl sulphur and carbonyl oxygen atoms. In the mixed ligand paramagnetic polychelates, which are obtained from the reaction of APATH with RuCl3. XH2O in the presence of N-heterocyclic bases [B = H2O, pyridine (Py)/or *o*-phenylendiamine (*o*-phen), DMF] consisting of polymer complexes [Ru(APAT)2(H2O)Py]XCl (**7**) and Ru(APAT)Cl2(*o*phen.) H2O (**8**) and in mononuclear compounds Ru(APAT)2Cl.DMF (**6**) and Ru(APAT)2Cl(H2O)2 (**8**), it behaves as a monobasic bidentate ligand coordinating through the same donor atoms. In mononuclear compounds [Ru(APAT)(APATH)Cl]2H2O (**4**) and [Ru(APAT) (APATH)Cl2]2H2O (**5**) it acts as a monobasic and neutral bidentate ligand coordinating only through the same donor atoms. Monometric distorted octahedral or trimeric chlorine-bridged, approximately octahedral structures are proposed for these polymer complexes. The polychelates are of 1:1, 1:2 and 3:2 (metal: poly-Schiff base) stoichiometry and exhibit five and six coordination (Fig. 46).

Stoichiometry of Polymer Complexes 173

Poly[1-acrylamido-2(2-pyridyl)ethane)] (PAEPH) homopolymer and polymer complexes of 1-acrylamido-2(2-pyridyl) ethane AEPH with a number of bi and tetravalent transition metals have been prepared and characterized using spectral (1H and 13C-NMR, IR, UV-Vis) and thermal analysis, and magnetic measurements (El-Sonbati et al., 1995b). The stoiciometries of the polymer complexes have been deduced from their elemental analyses. These indicate that the metal-polymer complexes fall into two distinct categories, namely 1:1 and 1:2 (ligand: metal). PAEPH is mononucleating and hence requires one metal ion for coordination. The formation of the polymer complexes may be represented by the following

MX2 + 2 AEPH [M (AEP)2] + 2HX (M = Pd, Pt or UO2, X = Cl or CH3COO)

(Where AEP represents the anion of the corresponding monofunctional bidentate AEPH). The reactions appear to proceed only up to a 1:2 molar ratio. Even on prolonged refluxing (~ 32 h) of 1:3 or 1:4 reaction mixture, replacement of a third chloride group by the homopolymer was not observed. This is probably due to steric factors. Plausible structures (Fig. 48) are given for the products (**A**, **C**) and (**B**, **D**) obtained from the reaction of 1:1 and

 **(A) (B) (C) (D)**

The zirconium atoms appear to be hexa-(**A**, **B**) and hepta-(**B**, **C**) coordinated. In the polymer complexes of zirconyl isopropoxide, zirconium exhibits a coordination number of 5. The [UO2(AEP)(AcO)(OH2)] polymer complex spectrum exhibits characteristic bands for the monodentate acetate group at 1620 and 1395 cm-1 with Δυ = 235 cm-1. The spectrum also exhibits three bands at 907, 790 and 275 cm-1 assigned to υ3, υ1 and υ2 of the dioxouranium

Trying to deepen the knowledge of this ligand, a studied polymer complexes of AEPH with copper(II), nickel(II), cobalt(II) and Zn(II) (El-Sonbati & El-Bindary, 1996). From IR and elemental analyses, the possible structures of the products of reaction of AEPH with

ZrCl2 + AEPH 1:1 (6h or 9h) [Zr (AEP) Cl3]n **A** or **C**

ZrCl2 + AEPH 1:2 (12h or 15h) [Zr (AEP)2 Cl2]n **B** or **D**

transition metal ions shown in Fig. 49 are as follows:

reactions:

Fig. 48.

ion.

1:2 molar ratios, respectively.

Fig. 46.

In the other hand, mononuclear and hetero bi-trinuclear polymer complexes of nickel(II), copper (II) and oxovanadium(VI) chloride with APATH monomer derived from amidation of acryloyl chloride with 2-amino-1-phenylthiourea have been prepared (El-Sonbati el al., 1995a). The elemental analyses show that these homonuclear polymer complexes have 2:1 and in bimetallic polymer complexes 2:1:1 (homopolymer: metal: metal), stoichiometry. These indicate that they fall into two distinct categories. The first is mononuclear, while the second is heterobinuclear. The following structures shown in Fig. 47 are suggested:

In the other hand, mononuclear and hetero bi-trinuclear polymer complexes of nickel(II), copper (II) and oxovanadium(VI) chloride with APATH monomer derived from amidation of acryloyl chloride with 2-amino-1-phenylthiourea have been prepared (El-Sonbati el al., 1995a). The elemental analyses show that these homonuclear polymer complexes have 2:1 and in bimetallic polymer complexes 2:1:1 (homopolymer: metal: metal), stoichiometry. These indicate that they fall into two distinct categories. The first is mononuclear, while the

second is heterobinuclear. The following structures shown in Fig. 47 are suggested:

Fig. 46.

Fig. 47.

Poly[1-acrylamido-2(2-pyridyl)ethane)] (PAEPH) homopolymer and polymer complexes of 1-acrylamido-2(2-pyridyl) ethane AEPH with a number of bi and tetravalent transition metals have been prepared and characterized using spectral (1H and 13C-NMR, IR, UV-Vis) and thermal analysis, and magnetic measurements (El-Sonbati et al., 1995b). The stoiciometries of the polymer complexes have been deduced from their elemental analyses. These indicate that the metal-polymer complexes fall into two distinct categories, namely 1:1 and 1:2 (ligand: metal). PAEPH is mononucleating and hence requires one metal ion for coordination. The formation of the polymer complexes may be represented by the following reactions:

MX2 + 2 AEPH [M (AEP)2] + 2HX (M = Pd, Pt or UO2, X = Cl or CH3COO) ZrCl2 + AEPH 1:1 (6h or 9h) [Zr (AEP) Cl3]n **A** or **C** ZrCl2 + AEPH 1:2 (12h or 15h) [Zr (AEP)2 Cl2]n **B** or **D**

(Where AEP represents the anion of the corresponding monofunctional bidentate AEPH).

The reactions appear to proceed only up to a 1:2 molar ratio. Even on prolonged refluxing (~ 32 h) of 1:3 or 1:4 reaction mixture, replacement of a third chloride group by the homopolymer was not observed. This is probably due to steric factors. Plausible structures (Fig. 48) are given for the products (**A**, **C**) and (**B**, **D**) obtained from the reaction of 1:1 and 1:2 molar ratios, respectively.

Fig. 48.

The zirconium atoms appear to be hexa-(**A**, **B**) and hepta-(**B**, **C**) coordinated. In the polymer complexes of zirconyl isopropoxide, zirconium exhibits a coordination number of 5. The [UO2(AEP)(AcO)(OH2)] polymer complex spectrum exhibits characteristic bands for the monodentate acetate group at 1620 and 1395 cm-1 with Δυ = 235 cm-1. The spectrum also exhibits three bands at 907, 790 and 275 cm-1 assigned to υ3, υ1 and υ2 of the dioxouranium ion.

Trying to deepen the knowledge of this ligand, a studied polymer complexes of AEPH with copper(II), nickel(II), cobalt(II) and Zn(II) (El-Sonbati & El-Bindary, 1996). From IR and elemental analyses, the possible structures of the products of reaction of AEPH with transition metal ions shown in Fig. 49 are as follows:

Stoichiometry of Polymer Complexes 175

Reaction of ZrCl4 with [Cu(VSR)] give heterobinuclear complexes Cu(VSED)ZrCl4. [Cu(VSR)] has an additional lone pair of electron at each of the coordinated phenolic O-

hence, it acts as a ligand and gets coordinated with UO2(CH3COO)2.2H2O. The Cu(II) band in the binuclear complex shows a shift from its value in mononuclear complex [Cu(VSR)] (Fig. 51). This lowering in the ligand field band of [Cu(VSR)] may be due to exchanges in the planarity of (VSR) and also to reduction in strength of Cu-O bond on the formation of

Novel seven, nine and ten-coordinated rare earth polymer complexes of N-acryloyl-1 phenyl-2-thiourea (APT) of the composition [Ln(NO3)3(APT)2]n (Ln = La, Sm, Tb, Pr and Nd) and [Ln(NCS)3(APT)x]n (where Ln = La or Pr at X = 2 and Ln = Nd, Sm and Tb at X = 3) have been prepared and characterized on the basis of their chemical analyses, magnetic measurements, conductance, visible and IR spectral data (Mubarak & El-Sonbati, 2006). The data of elemental analysis indicate that the stoichiometric ratio for the reaction of monomer with various LnX3 is 1:2 and 1:3 (Ln: monomer). The polymer complexes do not contain any water of coordination are all occupied by donor centers from the ligand groups. Therefore,

LnX3 + nAPT → [Ln(NO3)3(APT)2]n

→ [Ln(NCS)3(APT)2]n

 → [Ln(NCS)3(APT)3]n These data suggest that three nitrato and isothiocyanato ions are within the coordination

The build-up of polymer metallic supramolecules based on homopolymer 1-acrylamido-2- (2-pyridyl)ethane (AEPH) and ruthenium, rhodium, palladium as well as platinum complexes has been pursued with great interest (El-Sonbati et al., 2003a). AEPH is found to be a polyfunctional planar molecule with a delocalized *π* electronic system, with two nitrogen atoms which may act as basic centers and two labile N-H bands. The molecule may present in several tautomers and conformers. The equivalent conformers are the principle contributors to the molecular structure of this molecular in solution; they are in equilibrium and established by intramolecular hydrogen bonds. In the solid state reveals widely used

intramolecular hydrogen bonding, which gives rise to six-membered ring (Fig. 52).

the reaction between LnX3 and ligand can be represented as follows:

second bond with metal(II) halides.

Fig. 51.

sphere.

and

Y = OH2 for Co(AEP)(OH2)2

Fig. 49.

Some binary and ternary novel polymer complexes dioxouranium(VI) with 5 vinylsalicylaldehyde (VSH) have been prepared and characterized by various physicochemical techniques (El-Sonbati et al., 2002). Addition of ammonia to an ethanolic solution of uranyl nitrate give uranyl ammine complex which on treatment with VSA result in the formation of the imine complex (**C**). The reaction of the compound **C** with 1,2 diaminoethane and/or 1,2-diaminobenzene yield symmetrical tetradentate Schiff base complex of type (**1C**) as shown in Fig. 50.

Fig. 50.

Reaction of ZrCl4 with [Cu(VSR)] give heterobinuclear complexes Cu(VSED)ZrCl4. [Cu(VSR)] has an additional lone pair of electron at each of the coordinated phenolic O and hence, it acts as a ligand and gets coordinated with UO2(CH3COO)2.2H2O. The Cu(II) band in the binuclear complex shows a shift from its value in mononuclear complex [Cu(VSR)] (Fig. 51). This lowering in the ligand field band of [Cu(VSR)] may be due to exchanges in the planarity of (VSR) and also to reduction in strength of Cu-O bond on the formation of second bond with metal(II) halides.

Fig. 51.

174 Stoichiometry and Research – The Importance of Quantity in Biomedicine

M = Co(II); X = OAc; Y=OH2 for Co(AEPH))OAc)2(OH2)2

Y = OH2 for Co(AEP)(OH2)2

Some binary and ternary novel polymer complexes dioxouranium(VI) with 5 vinylsalicylaldehyde (VSH) have been prepared and characterized by various physicochemical techniques (El-Sonbati et al., 2002). Addition of ammonia to an ethanolic solution of uranyl nitrate give uranyl ammine complex which on treatment with VSA result in the formation of the imine complex (**C**). The reaction of the compound **C** with 1,2 diaminoethane and/or 1,2-diaminobenzene yield symmetrical tetradentate Schiff base

**NH2 R NH2 CH**

**R =**

**CH CH2** **H2C**

**O C H N U O**

**<sup>C</sup> CH3 or o-C6H5**

**O**

**O C H N R**

**H2**

 M = Zn(II); X = OAc;Y= nil for Zn(AEPH)(OAc)2 M = Co(II); X = NO3; Y= OH2 for Co(AEPH)(NO3)2(OH2)2

 M = Cu(II) for Cu(AEP)2 M = Cu(II), Ni(II) or Zn(II); = Ni(II) for Ni(AEP)2 X = NO3, Y = OH2 for = Zn(II) for Zn(AEP)2 Cu(AEPH)(NO3)2(OH2)2, Ni(AEPH)(NO3)2(OH2)2 and Zn(AEPH)(NO3)2(OH2)2;

Fig. 49.

**CH CH2**

complex of type (**1C**) as shown in Fig. 50.

**O**

**H**

**O**

**H <sup>N</sup> <sup>C</sup> <sup>O</sup>**

**CH CH2**

**O C H N U**

Tran C

Fig. 50.

**H**

Novel seven, nine and ten-coordinated rare earth polymer complexes of N-acryloyl-1 phenyl-2-thiourea (APT) of the composition [Ln(NO3)3(APT)2]n (Ln = La, Sm, Tb, Pr and Nd) and [Ln(NCS)3(APT)x]n (where Ln = La or Pr at X = 2 and Ln = Nd, Sm and Tb at X = 3) have been prepared and characterized on the basis of their chemical analyses, magnetic measurements, conductance, visible and IR spectral data (Mubarak & El-Sonbati, 2006). The data of elemental analysis indicate that the stoichiometric ratio for the reaction of monomer with various LnX3 is 1:2 and 1:3 (Ln: monomer). The polymer complexes do not contain any water of coordination are all occupied by donor centers from the ligand groups. Therefore, the reaction between LnX3 and ligand can be represented as follows:


These data suggest that three nitrato and isothiocyanato ions are within the coordination sphere.

The build-up of polymer metallic supramolecules based on homopolymer 1-acrylamido-2- (2-pyridyl)ethane (AEPH) and ruthenium, rhodium, palladium as well as platinum complexes has been pursued with great interest (El-Sonbati et al., 2003a). AEPH is found to be a polyfunctional planar molecule with a delocalized *π* electronic system, with two nitrogen atoms which may act as basic centers and two labile N-H bands. The molecule may present in several tautomers and conformers. The equivalent conformers are the principle contributors to the molecular structure of this molecular in solution; they are in equilibrium and established by intramolecular hydrogen bonds. In the solid state reveals widely used intramolecular hydrogen bonding, which gives rise to six-membered ring (Fig. 52).

Stoichiometry of Polymer Complexes 177

Monomeric distorted octahedral or trimeric chlorine-bridged, approximately octahedral

Mono, bis and tris-polymer complexes of ruthenium(III) and rhodium(III) chloride with 3 hydroxy-2-N-acrylamidopyridine (H2L) monomer, derived from amidation of acryloyl chloride with 2-amino-3-hydroxypyridine have been proposed (El-Bindary et al., 2003). A few bimetallic mixed ligand polymer complexes have also been obtained by the reaction of rhodium(II) bidentate poly-chelate mixed ligand with palladium(II), platinum(II) or zirconium(IV) chlorides and uranyl acetate. The homopolymer shows three types of coordination behavior. The poly-chelates are of 1:1, 1:2 and 1:3 (metal:homopolymer)

From the spectroscopic investigation of the rhodium complexes, it was concluded that the

rhodium atom in each complex exists in an octahedral environments (Fig. 54).

structures are proposed for these polymer complexes.

stoichiometry and exhibit six coordination.

### Fig. 52.

From the stoichiometries of all complexes, it is clear that the AEPH ligand function as bidentate N-N donors. Construction of molecular models suggest that the formation of a stable six-membered ring system with the central metal ions having N-N donor function taking one of the N-pyridyl ring and the N-imino (NH) of the monomer residue as bonding sites is the most probable proposition as shown in Fig. 53.

Fig. 53.

From the stoichiometries of all complexes, it is clear that the AEPH ligand function as bidentate N-N donors. Construction of molecular models suggest that the formation of a stable six-membered ring system with the central metal ions having N-N donor function taking one of the N-pyridyl ring and the N-imino (NH) of the monomer residue as bonding

M = Pd; X = Cl or Br X = Cl or Br

**N Pd N CH2**

**X Pd X**

**N**

**H2C**

**C O**

**HC**

**CH2**

**H2 C**

 M = Ru(III) or Rh(III) X = Cl or Br M = Ru(III) or Rh(III) Coordination compounds of PAEPH with transition metal ions

**C H2** **N**

**C O** **CH CH2**

**N N**

**M**

**Cl Cl**

**M Cl**

**Cl Cl**

**N H2C C H2**

**Cl**

**C O**

**HC CH2** **H2 C**

**CH2**

**C CH O CH2**

**N**

sites is the most probable proposition as shown in Fig. 53.

**C CH <sup>O</sup> CH2**

M = Pt; X = C

Fig. 52.

**N Pd N CH2**

**N H2C**

**C O**

**HC**

**CH2**

Fig. 53.

**H2 C**

**C H2** **N**

Monomeric distorted octahedral or trimeric chlorine-bridged, approximately octahedral structures are proposed for these polymer complexes.

Mono, bis and tris-polymer complexes of ruthenium(III) and rhodium(III) chloride with 3 hydroxy-2-N-acrylamidopyridine (H2L) monomer, derived from amidation of acryloyl chloride with 2-amino-3-hydroxypyridine have been proposed (El-Bindary et al., 2003). A few bimetallic mixed ligand polymer complexes have also been obtained by the reaction of rhodium(II) bidentate poly-chelate mixed ligand with palladium(II), platinum(II) or zirconium(IV) chlorides and uranyl acetate. The homopolymer shows three types of coordination behavior. The poly-chelates are of 1:1, 1:2 and 1:3 (metal:homopolymer) stoichiometry and exhibit six coordination.

From the spectroscopic investigation of the rhodium complexes, it was concluded that the rhodium atom in each complex exists in an octahedral environments (Fig. 54).

Stoichiometry of Polymer Complexes 179

Two novel supramolecular complexes of types UO2(L)(H2L)(OH2)2 and UO2(HLn)2(OAc)2 (H2L is a potential four-dentate ligand derived from hydrazine hydrate and malonylchloride and HLn is a potential bidentate ligand derived from coupling of allylazo-β-diketone have been synthesized and characterized by elemental analyses, conductance and spectral measurements (El-Sonbati et al., 2004a). Alcoholic solutions of uranyl acetate and malonic dihydrazide were refluxed for 8-9 h forms uranyldihydrazide complex as shown in Fig. 56.

complexes (Fig. 57) were characterized by IR spectroscopy:

macrocyclic uranyl polymer complexes (Fig. 58).

Fig. 56.

Fig. 57.

(A) (B) (C)

To the uranyl complex, an allyl-β-diketone was added using AIBN as initiator; the polymer

Polymer complexes of [UO2(HLn)(OAc)2] were prepared by refluxing a 0.5 M solution of the metal salt with the monomer using AIBN as initiator. The products of condensation reaction of allyl propenyl-2-(4-derivatives phenylazo) butan-3-one polymer complexes with malonyldihydrazide in ethanol/DMF in the presence of sodium acetate results in

**(11)**

Plausible structures are given for the structures obtained from the reaction of 1:1 and 1:2 molar ratios (Fig. 55).

Fig. 55.

Two novel supramolecular complexes of types UO2(L)(H2L)(OH2)2 and UO2(HLn)2(OAc)2 (H2L is a potential four-dentate ligand derived from hydrazine hydrate and malonylchloride and HLn is a potential bidentate ligand derived from coupling of allylazo-β-diketone have been synthesized and characterized by elemental analyses, conductance and spectral measurements (El-Sonbati et al., 2004a). Alcoholic solutions of uranyl acetate and malonic dihydrazide were refluxed for 8-9 h forms uranyldihydrazide complex as shown in Fig. 56.

178 Stoichiometry and Research – The Importance of Quantity in Biomedicine

Plausible structures are given for the structures obtained from the reaction of 1:1 and 1:2

**Rh**

**Cl**

**(9)**

**Rh**

**N**

**(11)**

**Cl**

**Cl**

**O**

**N**

**O**

**N**

**N**

**O**

**Cl**

**Cl**

**Cl**

**Cl**

**(8)**

**N O**

**Rh**

**Cl**

**(10)**

**Cl**

**Rh**

**Cl**

**N**

**N**

**Cl**

**N**

**Rh**

**O**

**O**

**N**

M = UO2; Pt or Pd; X = nil

M = Zr; X = Cl.

Fig. 54.

Fig. 55.

molar ratios (Fig. 55).

**Cl**

**Cl**

To the uranyl complex, an allyl-β-diketone was added using AIBN as initiator; the polymer complexes (Fig. 57) were characterized by IR spectroscopy:

Fig. 57.

Polymer complexes of [UO2(HLn)(OAc)2] were prepared by refluxing a 0.5 M solution of the metal salt with the monomer using AIBN as initiator. The products of condensation reaction of allyl propenyl-2-(4-derivatives phenylazo) butan-3-one polymer complexes with malonyldihydrazide in ethanol/DMF in the presence of sodium acetate results in macrocyclic uranyl polymer complexes (Fig. 58).

Stoichiometry of Polymer Complexes 181

Molecular structures of (a) [ Ru (HL1)2Cl2] Cl, (b) [ Ru (HL2)2Cl2] Cl

Synthesis and characterization of ally propenyl-2-(4-derivatives phenylazo)butan-3-one

coupling 0oc 4-orylaniline

n = 1 R = OCH3 (HL1); n = 2 R = CH3 (HL2); n = 3 R = H (HL3); n = 4 R = Br (HL4); n = 5

The polymer complexes were prepared by mixing the appropriate uranyl acetate with two

UO2(CH3COO)2.2H2O + HLn [UO2(HLn)2(OAc)2] (n = 1-5) (1)

**DMF**

 UO2(CH3COO)2.2H2O + H2L [UO2(HL)2(H2O)2] + 2CH3COOH (2) The magnetic measurements of the dioxouranium(VI) polymer complexes are independent from field strength and temperature and the ground states of dioxouranium(VI) compounds contain no unpaired electrons. Allyl propenyl-2-(4 derivatives phenylazo) butan-3-one (HLn) is a ligand whose reactivity towards metal ions varies as a function of the 4-substituents. The products, which are usually neutral, have two coplanar O,O metal-chelate rings in an O,O(O,O) trans geometry. Consequently, in the UO22+ case, the uranyl atom should be a six-coordinate octahedral with the oxygen

**DMF**

equivalents of HLn/H2L in DMF according to the following reaction scheme.

**N**

**O**

(HLn)

**C**

**CH3**

**C O**

**CH2 O HC CH2**

**O**

**H**

**Ru**

**(b)**

**R N CH**

**N**

**Cl N**

**Cl**

**O**

**H**

**SH**

Fig. 60.

**R NH3 CH2**

atom in the apical position (Fig. 62).

R = NO2 (HL5)

Fig. 61.

**N**

**Ru**

**(a)**

(HLn) are described as shown in Fig. 61 (Mubarak et al., 2006).

**C**

**CH3**

**C O**

**CH2 O HC CH2**

**O**

**Cl N**

**HS**

**Cl**

Fig. 58.

Copper(II) polymer complexes of emprical formula [Cu(ligands)2X2] (Fig. 59) (where X=Cl, Br, I, NO3 and 1/2 SO4 ) and [Cu(ligand)(CH3COO)2] have been prepared with poly(3 phenylacrylidine semicarbazone) (El-Sonbati et al., 2003b). It is propose that the uncomplexed polymer behaves as a bidentate coordinated ligand through the oxygen of the carbonyl and the nitrogen of azomethine.

Fig. 59. Molecular structures proposed for poly(3-phenyl-acrylidine semicarbazone) and [Cu(ligand)2X2] complexes.

Poplymer complexes of N-(3-phenylacrylidene)-2-mercaptoaniline (HL1) and cinnamaldehyde-2-aminophenol (HL2) with Cu(II), Pd(II), Pt(II), UO2(II), Rh(II), Ru(III), and Pd(IV) have been synthesized and characterized (Fig. 60) (El-Sonbati et al., 2003b). The electronic spectra of the derivatives of types [Ru(HLn)Cl3], have four bands in good agreement with the one-electron orbital schemes for trigonal bipyramidal d5 complexes.

Molecular structures of (a) [ Ru (HL1)2Cl2] Cl, (b) [ Ru (HL2)2Cl2] Cl

Fig. 60.

180 Stoichiometry and Research – The Importance of Quantity in Biomedicine

**EtOH/DMF CH3COONa**

**R**

**R' = H2C O CH**

**CH2**

**H N N C** **C N U NC**

**R' <sup>H</sup> N**

**CH3**

**O**

**HN**

**OAc OAc <sup>O</sup>**

**CO**

**CO**

**CH2**

**CONHNH2**

**CONHNH2**

n =1(R = OCH3), n =2(R=CH3), n=3(R=H), n=4(R=Br), n=5(R=NO2)

Copper(II) polymer complexes of emprical formula [Cu(ligands)2X2] (Fig. 59) (where X=Cl, Br, I, NO3 and 1/2 SO4 ) and [Cu(ligand)(CH3COO)2] have been prepared with poly(3 phenylacrylidine semicarbazone) (El-Sonbati et al., 2003b). It is propose that the uncomplexed polymer behaves as a bidentate coordinated ligand through the oxygen of the

X = Cl, Br, I, NO3

Poplymer complexes of N-(3-phenylacrylidene)-2-mercaptoaniline (HL1) and cinnamaldehyde-2-aminophenol (HL2) with Cu(II), Pd(II), Pt(II), UO2(II), Rh(II), Ru(III), and Pd(IV) have been synthesized and characterized (Fig. 60) (El-Sonbati et al., 2003b). The electronic spectra of the derivatives of types [Ru(HLn)Cl3], have four bands in good agreement with the one-electron orbital schemes for trigonal bipyramidal d5 complexes.

Fig. 59. Molecular structures proposed for poly(3-phenyl-acrylidine semicarbazone) and

Fig. 58.

**R'**

**H N N C**

carbonyl and the nitrogen of azomethine.

**C O**

**CH3**

**OC**

**CH2 O H C C H2**

**U**

**O**

**O C**

**O C H CH2**

**CH2**

**O C OAc OAc O**

**CH3**

**H2C**

[Cu(ligand)2X2] complexes.

Synthesis and characterization of ally propenyl-2-(4-derivatives phenylazo)butan-3-one (HLn) are described as shown in Fig. 61 (Mubarak et al., 2006).

n = 1 R = OCH3 (HL1); n = 2 R = CH3 (HL2); n = 3 R = H (HL3); n = 4 R = Br (HL4); n = 5 R = NO2 (HL5)

Fig. 61.

The polymer complexes were prepared by mixing the appropriate uranyl acetate with two equivalents of HLn/H2L in DMF according to the following reaction scheme.

 UO2(CH3COO)2.2H2O + HLn [UO2(HLn)2(OAc)2] (n = 1-5) (1) **DMF**

$$\text{UO}\_2\text{(CH}\_3\text{COO)}\_2\text{2H}\_2\text{O} + \text{H}\_2\text{L} \quad \xrightarrow{\text{DMF}} \quad \text{[UO}\_2\text{(HL)}\_2\text{(H}\_2\text{O)}\_2\text{]} + 2\text{CH}\_3\text{COOH} \tag{2}$$

The magnetic measurements of the dioxouranium(VI) polymer complexes are independent from field strength and temperature and the ground states of dioxouranium(VI) compounds contain no unpaired electrons. Allyl propenyl-2-(4 derivatives phenylazo) butan-3-one (HLn) is a ligand whose reactivity towards metal ions varies as a function of the 4-substituents. The products, which are usually neutral, have two coplanar O,O metal-chelate rings in an O,O(O,O) trans geometry. Consequently, in the UO22+ case, the uranyl atom should be a six-coordinate octahedral with the oxygen atom in the apical position (Fig. 62).

Stoichiometry of Polymer Complexes 183

**N**

**H2N <sup>O</sup>**

**S**

**H**

**N S**

**N**

**N**

**O**

**O**

**,**

**NH**

Fig. 64. Geometrical formula of uranyl polymer complexes

prepared (El-Sonbati et al., 2010b) according to the following scheme.

**U O**

**O**

**S**

**X**

**N**

**N**

**NH R'**

**CH3**

**, <sup>N</sup>**

**O**

HLn + UO2(NO3)2.2H2O → [(UO2)2(HLn)(Ln)(NO3)2(OH2)2]n + 2HNO3

**N**

**HN**

**R**

**S**

**S N**

X = NO3

Novel polymeric complexes with 5-sulphadiazineazo-3-phenyl-2-thioxo-4-thiazolidine (HL1), 5-sulphamethazineazo-3-phenyl-2-thioxo-4- thiazolidine (HL2) and 5 sulphamethoxazoleazo-3-phenyl-2-thioxo-4-thiazolidine (HL3) and various anions were

**<sup>X</sup> <sup>N</sup>**

**O**

**H2O**

**O**

**R**

**U O**

**N**

**R**

**CH3**

**<sup>S</sup> <sup>N</sup>**

**R'**

**N**

**CH3**

**HL1 HL2 HL3 HL4 HL5**

**HN**

**S**

**, <sup>C</sup>**

**O**

**OH2**

**n**

**O**

**<sup>S</sup> <sup>N</sup>**

**O**

**H**

**N S**

**CH3 , <sup>C</sup>**

**O**

**O**

**NH2**

**NH**

**NH R'**

(n=1, R=OCH3 (HL1); n=2, R=CH3 (HL2); n=3, R=H (HL3), n=4,R= Br (HL4), and n=5, R=NO2(HL5)

Fig. 62. Molecular structure proposed for the VO (Ln)2 complexes.

Novel supramolecular rare earth polymeric hydrazone complexes of 5-sulphadiazineazo-3 phenyl-2-thioxo-4-thiazolidinone (HL) of the composition [(Ln)2(HL)3(NO3)6]n where Ln = La(**1**), Y(**2**), Pr(**3**), Nd(**4**), Sm(**5**), Gd(**6**) and Ho(**7**) have been prepared and characterized on the basis of their chemical analyses, magnetic measurements, conductance, visible and IR spectral data (El-Sonbati et al., 2009). The IR spectrum of the ligand leads to assume the structure shown in Fig. 63.

Fig. 63.

The spectral data show that all these act as tetradentate ligand. Electronic spectra indicate weak covalent character in the metal-ligand bond.

Polymer complexes of hydrazone sulphadrugs (HLn) extended to novel five binuclear polymeric dioxouranium(VI) of azosulphadrugs (Fig. 64) (El-Sonbati et al., 2010a). The binding modes of the azosulphadrugs ligands towards uranyl(II) ions were critically assigned and addressed properly on the basis of their IR and their uranyl(II) complexes. 5- Sulphadiazinazo-3-phenyl-2-thioxo-4-thiozolidinone(HL1) and 5-sulphamethineazo-3 phenyl-2-thioxo-4-thiozolidinone (HL2) act as a tetradentate dibasic ligand, binding to the metal ion through nitrogen atom of diimide (N=N) group, nitrogen of azomethine pyridine atom (sulphadrugs moiety) and enolic OH group (sulphonyl oxygen) and through deprotonated hydrogen atom of phenolic oxygen atom (rhodanine). The sulphonamidic NH does not participate in bonding due to structure complication.

**O**

**AcO OAc**

**O**

(n=1, R=OCH3 (HL1); n=2, R=CH3 (HL2); n=3, R=H (HL3), n=4,R= Br (HL4), and n=5,

Novel supramolecular rare earth polymeric hydrazone complexes of 5-sulphadiazineazo-3 phenyl-2-thioxo-4-thiazolidinone (HL) of the composition [(Ln)2(HL)3(NO3)6]n where Ln = La(**1**), Y(**2**), Pr(**3**), Nd(**4**), Sm(**5**), Gd(**6**) and Ho(**7**) have been prepared and characterized on the basis of their chemical analyses, magnetic measurements, conductance, visible and IR spectral data (El-Sonbati et al., 2009). The IR spectrum of the ligand leads to assume the

The spectral data show that all these act as tetradentate ligand. Electronic spectra indicate

Polymer complexes of hydrazone sulphadrugs (HLn) extended to novel five binuclear polymeric dioxouranium(VI) of azosulphadrugs (Fig. 64) (El-Sonbati et al., 2010a). The binding modes of the azosulphadrugs ligands towards uranyl(II) ions were critically assigned and addressed properly on the basis of their IR and their uranyl(II) complexes. 5- Sulphadiazinazo-3-phenyl-2-thioxo-4-thiozolidinone(HL1) and 5-sulphamethineazo-3 phenyl-2-thioxo-4-thiozolidinone (HL2) act as a tetradentate dibasic ligand, binding to the metal ion through nitrogen atom of diimide (N=N) group, nitrogen of azomethine pyridine atom (sulphadrugs moiety) and enolic OH group (sulphonyl oxygen) and through deprotonated hydrogen atom of phenolic oxygen atom (rhodanine). The sulphonamidic NH

**N C NH R C**

**CH3**

**CH2**

.

**O C**

**H2C O C H**

**<sup>N</sup> <sup>U</sup>**

**O**

**C**

**CH3**

Fig. 62. Molecular structure proposed for the VO (Ln)2 complexes.

weak covalent character in the metal-ligand bond.

does not participate in bonding due to structure complication.

**C O**

**CH2 O**

**H C CH2**

**O**

**H**

**R N C**

R=NO2(HL5)

Fig. 63.

structure shown in Fig. 63.

HLn + UO2(NO3)2.2H2O → [(UO2)2(HLn)(Ln)(NO3)2(OH2)2]n + 2HNO3

X = NO3

Fig. 64. Geometrical formula of uranyl polymer complexes

Novel polymeric complexes with 5-sulphadiazineazo-3-phenyl-2-thioxo-4-thiazolidine (HL1), 5-sulphamethazineazo-3-phenyl-2-thioxo-4- thiazolidine (HL2) and 5 sulphamethoxazoleazo-3-phenyl-2-thioxo-4-thiazolidine (HL3) and various anions were prepared (El-Sonbati et al., 2010b) according to the following scheme.

Stoichiometry of Polymer Complexes 185

(**5**).

**H2 C**

(**4**) or SCN-

**NH**

**CO**

**CH**

**S O**

**HN NH**

**PHL**

(**7**), Br-

(**8**)

**Ni**

**X**

**X**

**O**

**N H**

**N H**

**O**

**NH2**

Nickel/iron mixed ligand polymer complexes were obtained by reacting pyridine (Py)/or ethylenediamine (en) with the calculated amount of trans-[Ni(HL)2Cl2] (X = Cl- or Br-) as

**OH2**

**N H**

X = Cl (**1**), Br (**2**), I (**3**), ONO2 (**4**), NCS (**5**), Py (**7,8**)

**H2**

**O SO3**

**H2**

**O N**

**O**

[Ni(HL)2X2]n + Py → [Ni(HL)2(Py)2]nX2 where X = Cl-

[Fe(HL)(SO4)(OH2)]n + en → [Fe(HL)(en)(SO4)(OH2)]n (**9**)

**Fe Fe**

**H N**

Fig. 67. Structure formulae of HL-metal polymer complexes

**O**

**S**

**O**

PdX2 + HL → [Pd(LX)2]n where X = Cl- (**10**), Br- (**11**)

NiX2 + HL → [Ni(HL)2 X2]n

(**1**), Br-

FeSO4 + HL → [Fe(HL)(SO4)(OH2)2]n (**6**)

(**2**) I-

(**3**), NO3-

where X = Cl-

Fig. 66.

shown in Fig. 67.

**OH2**

**O**

**N**

**O**

**O**

**OH2**

2CuCl2 + 3 HLn→ [(Cu)2(HLn)3(Cl)4]n

2CuSO4 + 3 HLn → [(Cu)2(HLn)3(SO4)2]n where HLn = tetradentate hydrazone, n = 1-3

The 2:3 stoichiometries of the polymeric complexes were calculated from their elemental analyses, and molar conductance reveal that three molecules of the ligand and four/two (Cl/SO4) of the anions are coordinated to the two metal atoms in all complexes. The ligands coordinate to Cu(II) ion as an neutral and tetradentate *via* NH (hydrazone), oxygen of the carbonyl group (CO), nitrogen of the NH (3-phenylamine) and thion sulphur (CS) group.

A novel series of nickel(II) polymer complexes of 5-sulphadiazinazo-3-phenylamino-2-thio-4-thiozolidinone (HL1), 5-sulphamethazine-3-phenylamino-2-thioxo-4-thiazolidinone (HL2), 5-sulphamethoxazole-3-phenylamino-2-thioxo-4-thiazolidinone (HL3), 5-sulpacetamide-3 phenyl-2-thioxo-4-thiozalidinone (HL4) and 5-sulphaguanidine-3-phenylamino-2-thioxo-4-thiazolidinone (HL5) were prepared and characterized (El-Sonbati et al., 2010c), IR spectra show that HLn (n = 1-5) is coordinated to the metal ion in a neutral tetradentate manner with NSNO donor sites of NH (hydrazone`s), NH(3-phenylamine), carbonyl group and Ph-NH. The metal-to-ligand ratio of the nickel(II) polymer complexes was found to be 3:2, but all the Ni(II) polymer complexes have two additional bridged coordinated acetate molecules. So the Ni(II) ions appear to be five and hexa-coordinated acetate, and the geometry is octahedral for Ni(II) ion. The title [Ni3(HLn)2(μ-OAc)2(OAc)4]n consists of three Ni(II) atoms linked by interchain π-π interaction observed between aromatic rings of two (HLn) which are further doubly bridged to two adjacent nickel atoms by acetate group. The geometrical structures of these complexes are found to be octahedral. The richness of electronic spectral in these is supporting evidence for the trinuclearity of the Ni(II) polymer complexes (Fig. 65).

Fig. 65.

Polymer complexes of p-acrylamidyl sulphaguandine (HL) with Ni(II), Fe(II) and Pd(II) salts have been prepared (Fig. 66) (El-Sonbati et al., 2011a).

NiX2 + HL → [Ni(HL)2 X2]n

184 Stoichiometry and Research – The Importance of Quantity in Biomedicine

2CuSO4 + 3 HLn → [(Cu)2(HLn)3(SO4)2]n where HLn = tetradentate hydrazone, n = 1-3 The 2:3 stoichiometries of the polymeric complexes were calculated from their elemental analyses, and molar conductance reveal that three molecules of the ligand and four/two (Cl/SO4) of the anions are coordinated to the two metal atoms in all complexes. The ligands coordinate to Cu(II) ion as an neutral and tetradentate *via* NH (hydrazone), oxygen of the carbonyl group (CO), nitrogen of the NH (3-phenylamine) and thion sulphur (CS) group.

A novel series of nickel(II) polymer complexes of 5-sulphadiazinazo-3-phenylamino-2-thio-4-thiozolidinone (HL1), 5-sulphamethazine-3-phenylamino-2-thioxo-4-thiazolidinone (HL2), 5-sulphamethoxazole-3-phenylamino-2-thioxo-4-thiazolidinone (HL3), 5-sulpacetamide-3 phenyl-2-thioxo-4-thiozalidinone (HL4) and 5-sulphaguanidine-3-phenylamino-2-thioxo-4-thiazolidinone (HL5) were prepared and characterized (El-Sonbati et al., 2010c), IR spectra show that HLn (n = 1-5) is coordinated to the metal ion in a neutral tetradentate manner with NSNO donor sites of NH (hydrazone`s), NH(3-phenylamine), carbonyl group and Ph-NH. The metal-to-ligand ratio of the nickel(II) polymer complexes was found to be 3:2, but all the Ni(II) polymer complexes have two additional bridged coordinated acetate molecules. So the Ni(II) ions appear to be five and hexa-coordinated acetate, and the geometry is octahedral for Ni(II) ion. The title [Ni3(HLn)2(μ-OAc)2(OAc)4]n consists of three Ni(II) atoms linked by interchain π-π interaction observed between aromatic rings of two (HLn) which are further doubly bridged to two adjacent nickel atoms by acetate group. The geometrical structures of these complexes are found to be octahedral. The richness of electronic spectral in these is supporting evidence for the

2CuCl2 + 3 HLn→ [(Cu)2(HLn)3(Cl)4]n

trinuclearity of the Ni(II) polymer complexes (Fig. 65).

**S**

**Ni**

**X**

**S**

**NH**

**Ni**

**X**

**X = OAc**

Polymer complexes of p-acrylamidyl sulphaguandine (HL) with Ni(II), Fe(II) and Pd(II) salts

**O**

**O**

**C**

**C**

**O**

**O**

**Ni**

**n**

**X**

**NH**

**<sup>X</sup> <sup>O</sup>**

**NH**

have been prepared (Fig. 66) (El-Sonbati et al., 2011a).

Fig. 65.

where X = Cl- (**1**), Br- (**2**) I- (**3**), NO3- (**4**) or SCN- (**5**).

FeSO4 + HL → [Fe(HL)(SO4)(OH2)2]n (**6**)

Fig. 66.

Nickel/iron mixed ligand polymer complexes were obtained by reacting pyridine (Py)/or ethylenediamine (en) with the calculated amount of trans-[Ni(HL)2Cl2] (X = Cl- or Br-) as shown in Fig. 67.

$$\begin{aligned} \text{[Ni(HL)\_2X\_2]\_n + Py \to [Ni(HL)\_2(Py)\_2]\_nX\_2 \quad &\text{where } X = \text{Cl} \text{ (7), Br (8)} \end{aligned} $$

[Fe(HL)(SO4)(OH2)]n + en → [Fe(HL)(en)(SO4)(OH2)]n (**9**)

PdX2 + HL → [Pd(LX)2]n where X = Cl- (**10**), Br- (**11**)

X = Cl (**1**), Br (**2**), I (**3**), ONO2 (**4**), NCS (**5**), Py (**7,8**)

Fig. 67. Structure formulae of HL-metal polymer complexes

Stoichiometry of Polymer Complexes 187

VOSO4.5H2O + H2L → {[VOL]2}n + H2SO4

VOSO4.5H2O + H2L + B → [VOLB]n + H2SO4

**C O NH**

The molecular structrure shows the presence of a vanadyl group in six-coordinate VNO3/VN2O3 coordination geometry. The N,N-donor heterocyclic and aliphatic base displays an N-donor site *trans* to the vanadyl oxo-group. In all polymeric complexes (**1-4**) the ligand coordinates through oxygen of phenolic/enolic and azodye nitrogen. Formation of the polymer complexes has been done on the basis of their elemental analytical data, molar conductance values and magnetic susceptibilty data. All the complexes show

**H2 <sup>C</sup>**

**AcO**

**C HN O H2N**

**O**

**U**

**C H H2 C**

 **structure IV**

**CH C H2**

**O**

**NH2**

**Fe Cl**

**Cl Cl**

**Cl**

**structure V**

**Fe Cl**

**Cl O**

**NH2**

**O NH H2N**

**OAc**

**O**

**N**

**V O**

**H C C**

**AcO Cu H2N OAc**

**<sup>H</sup> H2 <sup>2</sup> <sup>O</sup>**

 **structure III**

1:1{[VOL]2}n/1:1:1[VOLB]n metal:ligand/metal:ligand:base stoichiometry (Fig. 70).

**N**

**O**

Recently, a novel ligand of N-[2-(6-aminopyridino)] acrylamide (APA) was prepared via amidation of 2,6-diaminopyridine with acryloyl chloride in dry benzene as solvent (El-Sonbati et al., 2011c). Metal-polymer complexes are reported and characterized. The formation of these polymer complexes proceeds according to the following equations:

Fig. 70. Ternary structure of [VOLB] n (**2-4**) and the bases (B) used Tentative structure of

**V O**

**N**

**O**

**O**

**N**

MCl2 + APA → [M(APA)Cl.OH2]n M = Cu(II) or Cd(II)

MCl2 + APA → [M(APA)(OH2)3Cl]n M = Co(II) or Ni(II)

**O**

**V**

**O**

**N**

UO2(OAc)2 + APA → [UO2(APA)2(OH2)2]n

The proposed strucrure for the polychelates is shown in Fig. 71.

**O**

**C CH H2C**

**C**

**OH2**

**C N O N**

**H2O**

**Co**

**C H C H2**

Fig. 69. Proposed structures of polymer complexes

**H C C H2 O N N**

**O N Cl M N**

**OH2**

 **M = Cu(II) and Cd(II)**

 **structure I structure II**

polymer complex {[VOL] 2}n (**1**)

**H2**

Novel polymer complexes of N-[3-(5-amino-1,2,4-triazolo)]acrylamide (ATA), formed by amidation of 3,5-diamino-1,2,4-triazole with acryloyl chloride were synthesized and characterized (Diab et al., 2011). Spectral studies reveal that the free ligand coordinates to the metal ion in a bidentate fashion through the oxygen of carbonyl group and a nitrogen azomethine of heterocyclic ring (Fig. 68). Elemental analyses of the polychelates indicate that the metal to ligand ratio was 1:1 and 1:2.

M = Cu(II) or Cd(II) M = Co(II) or Ni(II)

Fig. 68.

The amidation of acryloyl chloride with hydrazine hydrate in dry benzene forms acryloyl hydrazine (AH) monomer [(El-Bindary et al., 2011). Polymer complexes of AH with Cu(II), Ni(II), Co(II), Cd(II), UO2(II) and Fe(III) salts have been prepared and characterized. AH has been shown to behave as a bidentate ligand via its nitrogen (NH2 of the hydrazine group) and C-O/C=O (acryloyl) group in the polymer complexes, all of which exhibit supramolecular architectures assembled through weak interactions including hydrogen bonding and *π-π* staking. The elemental analyses, IR and electronic spectra data indicate that AN reacts with CuCl2, Cu(OAc)2, FeCl3 and CdCl2 in a 1:1 ratio (Structure I, III and V) and with CoCl2 and UO2(OAc)2 in 2:1 molar ratios (Structure II and IV). The AH-NiCl2 polymer complex is a mixture of both structure I and II. The magnetic and spectral data indicate a square planar geometry for Cu2+ complexes and an octahedral geometry for Co(II) and UO2(II) complexes (Fig. 69). The ESR spectral data of the Cu(II) complexes showed that the metal-ligand bonds have considerable covalent character.

Oxovandium(IV) polymer complexes of formulation {[(VO)L]2}n(1) and [(VO)LB]n (2-4), where H2L is tridentate and dianionic ligand, 3-allyl-2-thioxo-1,3-triazolidine-4,5-dione-5[*o*hydroxylphenyl] and B is planar heterocyclic and aliphatic bases, bipyridyl (bipy); pyridine (py) and ethylenediamine (en) have been prepared and characterized (El-Sonbati et al., 2011b).

Novel polymer complexes of N-[3-(5-amino-1,2,4-triazolo)]acrylamide (ATA), formed by amidation of 3,5-diamino-1,2,4-triazole with acryloyl chloride were synthesized and characterized (Diab et al., 2011). Spectral studies reveal that the free ligand coordinates to the metal ion in a bidentate fashion through the oxygen of carbonyl group and a nitrogen azomethine of heterocyclic ring (Fig. 68). Elemental analyses of the polychelates indicate

MCl2 + ATA P[M(ATA)Cl2] M = Cu(II) or Cd(II)

MCl2 + ATA P[M(ATA)(OH2)2Cl2] M = Co(II) or Ni(II)

**C O NH**

**OH2**

**N N**

**N**

M = Cu(II) or Cd(II) M = Co(II) or Ni(II)

The amidation of acryloyl chloride with hydrazine hydrate in dry benzene forms acryloyl hydrazine (AH) monomer [(El-Bindary et al., 2011). Polymer complexes of AH with Cu(II), Ni(II), Co(II), Cd(II), UO2(II) and Fe(III) salts have been prepared and characterized. AH has been shown to behave as a bidentate ligand via its nitrogen (NH2 of the hydrazine group) and C-O/C=O (acryloyl) group in the polymer complexes, all of which exhibit supramolecular architectures assembled through weak interactions including hydrogen bonding and *π-π* staking. The elemental analyses, IR and electronic spectra data indicate that AN reacts with CuCl2, Cu(OAc)2, FeCl3 and CdCl2 in a 1:1 ratio (Structure I, III and V) and with CoCl2 and UO2(OAc)2 in 2:1 molar ratios (Structure II and IV). The AH-NiCl2 polymer complex is a mixture of both structure I and II. The magnetic and spectral data indicate a square planar geometry for Cu2+ complexes and an octahedral geometry for Co(II) and UO2(II) complexes (Fig. 69). The ESR spectral data of the Cu(II) complexes showed that the

Oxovandium(IV) polymer complexes of formulation {[(VO)L]2}n(1) and [(VO)LB]n (2-4), where H2L is tridentate and dianionic ligand, 3-allyl-2-thioxo-1,3-triazolidine-4,5-dione-5[*o*hydroxylphenyl] and B is planar heterocyclic and aliphatic bases, bipyridyl (bipy); pyridine (py) and ethylenediamine (en) have been prepared and characterized (El-Sonbati et al.,

**C HN O**

**OAc**

**O**

**NH2**

**U**

**OAc**

**H2N**

**C <sup>O</sup> NH**

**O**

**CH**

**H2 C**

**N N**

**N**

**C H**

**C H2**

**N N**

**N**

**M**

**Cl Cl H2O**

metal-ligand bonds have considerable covalent character.

**H2N**

**H C H2C**

that the metal to ligand ratio was 1:1 and 1:2.

**AIBN**

**AIBN** 

**C O NH**

**<sup>M</sup> <sup>N</sup> <sup>N</sup>**

**H2N**

Fig. 68.

2011b).

**Cl**

**Cl**

**N**

**H C C H2**

UO2(OAc)2 + ATA P[UO2(ATA)(OAc)2

**AIBN** 

$$\begin{array}{rcl} \text{VOSO4.5H\_2O + H\_2L} & \rightarrow \text{([VOL]\_2]\_n + H\_2SO\_4} \\\\ \text{VOSO4.5H\_2O + H\_2L + B} & \rightarrow \text{[VOL.B]\_n + H\_2SO\_4} \end{array}$$

Fig. 69. Proposed structures of polymer complexes

The molecular structrure shows the presence of a vanadyl group in six-coordinate VNO3/VN2O3 coordination geometry. The N,N-donor heterocyclic and aliphatic base displays an N-donor site *trans* to the vanadyl oxo-group. In all polymeric complexes (**1-4**) the ligand coordinates through oxygen of phenolic/enolic and azodye nitrogen. Formation of the polymer complexes has been done on the basis of their elemental analytical data, molar conductance values and magnetic susceptibilty data. All the complexes show 1:1{[VOL]2}n/1:1:1[VOLB]n metal:ligand/metal:ligand:base stoichiometry (Fig. 70).

Fig. 70. Ternary structure of [VOLB] n (**2-4**) and the bases (B) used Tentative structure of polymer complex {[VOL] 2}n (**1**)

Recently, a novel ligand of N-[2-(6-aminopyridino)] acrylamide (APA) was prepared via amidation of 2,6-diaminopyridine with acryloyl chloride in dry benzene as solvent (El-Sonbati et al., 2011c). Metal-polymer complexes are reported and characterized. The formation of these polymer complexes proceeds according to the following equations:

$$\begin{array}{c} \text{MCl}\_{2} + \text{APA} \rightarrow & [\text{M(APA)(C.OH)}\_{2}\text{]}\_{n} \text{} \text{} \text{M} = \text{Cu(II)} \text{ or } \text{Cd(II)} \\\\ \text{MCl}\_{2} + \text{APA} \rightarrow & [\text{M(APA)(OH)}\_{2}\text{]}\_{5}\text{Cl}]\_{n} \text{} \text{} \text{M} = \text{Co(II)} \text{ or } \text{Ni(II)} \\\\ \text{UO}\_{2}\text{(OAc)}\_{2} + \text{APA} \rightarrow & [\text{UO}\_{2}\text{(APA)}\_{2}\text{(OH}\_{2})\_{n}] \text{n} \end{array}$$

The proposed strucrure for the polychelates is shown in Fig. 71.

Stoichiometry of Polymer Complexes 189

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*radiation*, Nature 209, 292-295.

58.

45-48.

M = Cu(II) or CdII) M = Co(II) or Ni(II)

Fig. 71. Proposed structure of the polymer complexes

### **3. Conclusions**

The coordination polymer research field of study is a vast and one of the fastest growing areas of chemistry in recent times, with important work being done on a large variety of different aspects. Polymer complexes are an important class of new materials due to the coupling of the chemical, optical and electronic properties of the metal moiety to those of the polymer. This review, however, provides a uniquely broad overview of the stoichiometry of polymer complexes by using elemental analyses, FT-IR and IR spectra. The geometry of the polymer complexes was evaluated by electronic spectra (UV.-Vis.) and magnetic moment measurements.

### **4. Acknowledgement**

The authors are grateful to Dr. M.M. El-Halawany, Department of Mathematics and Physics Sciences, Faculty of Engineering, Mansoura University for his patience and neat diligent drawing all the structures of the review.

### **5. References**


**N**

The coordination polymer research field of study is a vast and one of the fastest growing areas of chemistry in recent times, with important work being done on a large variety of different aspects. Polymer complexes are an important class of new materials due to the coupling of the chemical, optical and electronic properties of the metal moiety to those of the polymer. This review, however, provides a uniquely broad overview of the stoichiometry of polymer complexes by using elemental analyses, FT-IR and IR spectra. The geometry of the polymer complexes was evaluated by electronic spectra (UV.-Vis.) and magnetic moment

The authors are grateful to Dr. M.M. El-Halawany, Department of Mathematics and Physics Sciences, Faculty of Engineering, Mansoura University for his patience and neat diligent

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**C O M Cl**

**CH**

**H2N**

**H2O**

**H2O**

**N**

**H2 C**

**OH2 <sup>N</sup>**

**N**

**CH C H2**

**H2N**

**O**

**O**

**H2O**

**O**

**C**

**C H**

**N**

**N**

**C H2**

**C O U**

**NH2**

**OH2**

**N**

M = Cu(II) or CdII) M = Co(II) or Ni(II)

Fig. 71. Proposed structure of the polymer complexes

**C O M Cl**

**H C**

**H2N**

**H2O**

**3. Conclusions** 

measurements.

**5. References** 

**4. Acknowledgement** 

drawing all the structures of the review.

Chem. Ed. 14, 2819-2830.

*cellulose*, J. Appl. Polym. Sci. 8 (6*),* 2813-2824.

505, 85 - 88.

241, 364-375.

**N**

**C H2**


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**8** 

**Dermatological Application of PAMAM –** 

Stoichiometry of reaction describes the quantitative relationships among substances as they participate in chemical reactions. Furthermore the term stoichiometry is used to describe the quantitative relationship among elements in compounds. This is also valid in the quantitative description of so-called weak complexes formed between molecules through non-covalent and non-ionic interactions. They generally arise from hydrogen bonding or Van der Waals interactions and are very common in biological chemistry, like in the case of enzyme-substrate, enzyme-inhibitor, or enzyme-coenzyme complexes. In less specific systems, stoichiometry may be referred to the number of small molecules interacting with one macromolecule to form complex structure. Depending on the interaction type between the components of the complex they are often desribed as host (macromolecule, H) – guest (small molecule, g) complexes. The host-guest complexes can sometimes be isolated as compounds of defined strochiometry, however their dissolution always leads to establishing an equilibrium between complexes and free guest, according

Hgn ⇔ Hgn-1 + g ⇔ Hgn-2 + 2g ⇔ Hgn-3 + 3g ……. ⇔ H + ng (1)

This weak interaction between H and g leads to the formation of multiple complexes Hgn, with n = 1, 2, 3, …. n, depending on g concentration, which is in excess compared to H one. Its larger amount is necessary to determine nmax, i.e. the maximum amount of guest

**1. Introduction** 

to the scheme:

described by overall formation constant:

**Vitamin Bioconjugates and Host-Guest** 

**Complexes – Vitamin C Case Study** 

Stanisław Wołowiec1, Marek Laskowski1, Barbara Laskowska1, Agnieszka Magoń2, Bogdan Mysliwiec2 and Marek Pyda2

*University of Information Technology and Management, 2Faculty of Chemistry, Rzeszów University of Technology,* 

K = [Hgn]/[H][g]n (2)

*1Department of Cosmetology,* 

*Rzeszów Poland* 


## **Dermatological Application of PAMAM – Vitamin Bioconjugates and Host-Guest Complexes – Vitamin C Case Study**

Stanisław Wołowiec1, Marek Laskowski1, Barbara Laskowska1, Agnieszka Magoń2, Bogdan Mysliwiec2 and Marek Pyda2 *1Department of Cosmetology, University of Information Technology and Management, 2Faculty of Chemistry, Rzeszów University of Technology, Rzeszów Poland* 

### **1. Introduction**

194 Stoichiometry and Research – The Importance of Quantity in Biomedicine

Wertz, D.L. & Tyroll, L. (1974). *The coordination of Cu(II) in a nearly saturated solution of CuCl2*

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*in hydrochloric acid,* J. Inorg. & Nucl. Chem. 36 (12), 3713-3717.

*and allyl monomers*, J. Polym. Sci., Part C 23 (1), 147-155.

Stoichiometry of reaction describes the quantitative relationships among substances as they participate in chemical reactions. Furthermore the term stoichiometry is used to describe the quantitative relationship among elements in compounds. This is also valid in the quantitative description of so-called weak complexes formed between molecules through non-covalent and non-ionic interactions. They generally arise from hydrogen bonding or Van der Waals interactions and are very common in biological chemistry, like in the case of enzyme-substrate, enzyme-inhibitor, or enzyme-coenzyme complexes. In less specific systems, stoichiometry may be referred to the number of small molecules interacting with one macromolecule to form complex structure. Depending on the interaction type between the components of the complex they are often desribed as host (macromolecule, H) – guest (small molecule, g) complexes. The host-guest complexes can sometimes be isolated as compounds of defined strochiometry, however their dissolution always leads to establishing an equilibrium between complexes and free guest, according to the scheme:

$$\mathrm{Hg}\_{\mathrm{n}} \Leftrightarrow \mathrm{Hg}\_{\mathrm{p}\cdot 1} + \mathrm{g} \Leftrightarrow \mathrm{Hg}\_{\mathrm{p}\cdot 2} + 2\mathrm{g} \Leftrightarrow \mathrm{Hg}\_{\mathrm{p}\cdot 3} + 3\mathrm{g} \cdot \dots \dots \Leftrightarrow \mathrm{H} + \mathrm{ng} \tag{1}$$

described by overall formation constant:

$$\mathbf{K} = [\mathbf{H} \mathbf{g}\_n] / [\mathbf{H}] [\mathbf{g}]^n \tag{2}$$

This weak interaction between H and g leads to the formation of multiple complexes Hgn, with n = 1, 2, 3, …. n, depending on g concentration, which is in excess compared to H one. Its larger amount is necessary to determine nmax, i.e. the maximum amount of guest

Dermatological Application of PAMAM –

**<sup>N</sup> <sup>N</sup>**

**O OMe**

**O**

**N <sup>H</sup> <sup>N</sup>**

**NH**

**O**

**N**

**O**

**2NH NH2**

**OMe**

**O OMe**

**O**

**O**

**MeO**

to G1.5, G2, G2,5, G3 and so on.

**MeO**

**2.2 Medical applications of PAMAM dendrimers** 

**O**

**MeO**

**O**

**O**

**G-0.5**

**MeO**

**MeO**

Vitamin Bioconjugates and Host-Guest Complexes – Vitamin C Case Study 197

**<sup>N</sup> <sup>N</sup>**

**O**

**O N H**

> **O OMe**

**NH2**

**G0**

**O**

**NH**

**NH2**

**O**

**O N H** **N**

**O**

**G0.5**

**OMe**

**OMe**

**O**

**O**

**N <sup>H</sup> 2NH**

**2NH NH2**

**<sup>N</sup> <sup>N</sup>**

**O**

**NH**

**O N**

**O**

**OMe**

Scheme 1. The scheme of synthesis of PAMAM dendrimers on ethylenediamine (en) core. Addition of methyl acrylate to en results in formation of -0.5 half-generation PAMAM dendrimer (G-0.5) with four methyl ester groups on surface. The condensation of G-0.5 with four en equivalents leads to full-generation PAMAM dendrimer (G0). Further addition of methyl acrylate gives G0.5 PAMAM dendrimer, which upon next condensation with eight en equivalents results in obtaining full generation PAMAM dendrimer G1 (not shown). Repeated sequence of addition/condensation protocol leads

PAMAM dendrimers are relatively low toxic (Jain et al., 2010, Mukherjee et al., 2010, Kolhatkar et al., 2007, Hans & Lowman, 2002). Therefore they are extensively studied as drug carriers. There are two strategies commonly applied: 1) diffusion of prodrug covalently bound to the dendrimer, and 2) diffusion of drug encapsulated in the dendrimer. Thus, the PAMAM dendrimers act as solubilizers for anti-inflamatory drugs *ketoprofen* (Yiyun et al., 2005), *ibuprofen* (Milhem et al., 2000) and *indomethacin* (Chauhan et al., 2003) and promote

**NH**

**NH2**

**MeO OMe**

molecules which are able to interact with one host macromolecule. Thus the nmax is often referred to as host-guest complex stoichiometry or host capacity in relation to specific guest.

Commonly employed molecular complex is the one used in iodometric titration, where the equivalent point is determined by the deeply blue color of starch (macromolecular host) and iodine (guest) complex disappearance with the iodine completely consumed by thiosulfate (Rundle & Frank, 1943).

Starch is a glucose polymer containing mainly α(1-4) glycosidic bonds with an amylose moiety forming polyiodide complexes with maximum absorbance at 620 nm. Being starch a polydisperse polymer, the equilibrium constant for the blue iodine complex formation is actually the averaged value (Saenger, 1984).

More adequate formation constants can be determined for monodisperse macromolecules, such as dendritic polymers. The dendrimer chemistry developed very fast over the last two decades, and it has been the subject of many reviews due to dendrimers numerous applications, such as: nanomaterials for molecular electronics, photonics, sensors (Astruc et al., 2010, Lo & Burn, 2007) and nanomedicine (D'Emanuele & Attwood, 2005, Caruthers et al., 2007). Polyethyleneimine (PEI), polyester (PES) and polyamidoamine (PAMAM) dendrimers invented in Frechet's and Tomalia's group macromolecules own a signifficant position among dendrimeric molecules (Frechet et al., 1995, Tomalia , 2005a and b).

### **2. Polyamidoamine dendrimers (PAMAM)**

### **2.1 General characteristics of PAMAM dendrimers**

The dendritic molecules are globular shaped monodisperse objects. The polyamidoamine dendrimers (PAMAM) were synthesized in Tomalia's group (Tomalia et al., 2003, Tomalia, 2005). The PAMAM dendrimers of full generation posses several surface amine groups which make them perfectly soluble in water. They can be obtained by alternate addition of methyl acrylate to amine (in our study ethylenediamine has been used as starting diamine core) resulting in doubling the surface methyl propionate groups, followed by condensation of ester groups with diamine (ethylenediamine being the best choice). The latter step introduces further amine function on surface. Thus the full generation (Gn) PAMAM dendrimers posses: 8, 16, 32, and 64 surface amine groups in G1, G2, G3, and G4, respectively. The synthetic pattern is shown in Scheme 1. The hydrodynamic diameters of full generation PAMAM dendrimers are: 1.5, 2.2, 2.9, 3.6, and 4.5 nm for G0, G1, G2, G3, and G4, respectively. The surface structure of full generation dendrimers can be widely modified by surface amine groups conversion, resulting in change in their solubility and permeability properties (Jevprasesphant et al., 2003, Imae et al., 2000). The PAMAM dendrimers are molecules with inner cavities, which are able to absorb small molecules to form host-guest complexes. During the synthesis of PAMAM dendrimers in methanol, the final removal of this solvent from the dendrimer spherical macromolecule requires prolonged vacuum evaporation. PAMAM dendrimers ability to encapsulate hydrophobic guests was extensively used as a strategy for promoting water insoluble drugs transportation into tissues and cells (vide infra).

molecules which are able to interact with one host macromolecule. Thus the nmax is often referred to as host-guest complex stoichiometry or host capacity in relation to specific guest. Commonly employed molecular complex is the one used in iodometric titration, where the equivalent point is determined by the deeply blue color of starch (macromolecular host) and iodine (guest) complex disappearance with the iodine completely consumed by thiosulfate

Starch is a glucose polymer containing mainly α(1-4) glycosidic bonds with an amylose moiety forming polyiodide complexes with maximum absorbance at 620 nm. Being starch a polydisperse polymer, the equilibrium constant for the blue iodine complex formation is

More adequate formation constants can be determined for monodisperse macromolecules, such as dendritic polymers. The dendrimer chemistry developed very fast over the last two decades, and it has been the subject of many reviews due to dendrimers numerous applications, such as: nanomaterials for molecular electronics, photonics, sensors (Astruc et al., 2010, Lo & Burn, 2007) and nanomedicine (D'Emanuele & Attwood, 2005, Caruthers et al., 2007). Polyethyleneimine (PEI), polyester (PES) and polyamidoamine (PAMAM) dendrimers invented in Frechet's and Tomalia's group macromolecules own a signifficant position among dendrimeric molecules (Frechet et al., 1995, Tomalia , 2005a

The dendritic molecules are globular shaped monodisperse objects. The polyamidoamine dendrimers (PAMAM) were synthesized in Tomalia's group (Tomalia et al., 2003, Tomalia, 2005). The PAMAM dendrimers of full generation posses several surface amine groups which make them perfectly soluble in water. They can be obtained by alternate addition of methyl acrylate to amine (in our study ethylenediamine has been used as starting diamine core) resulting in doubling the surface methyl propionate groups, followed by condensation of ester groups with diamine (ethylenediamine being the best choice). The latter step introduces further amine function on surface. Thus the full generation (Gn) PAMAM dendrimers posses: 8, 16, 32, and 64 surface amine groups in G1, G2, G3, and G4, respectively. The synthetic pattern is shown in Scheme 1. The hydrodynamic diameters of full generation PAMAM dendrimers are: 1.5, 2.2, 2.9, 3.6, and 4.5 nm for G0, G1, G2, G3, and G4, respectively. The surface structure of full generation dendrimers can be widely modified by surface amine groups conversion, resulting in change in their solubility and permeability properties (Jevprasesphant et al., 2003, Imae et al., 2000). The PAMAM dendrimers are molecules with inner cavities, which are able to absorb small molecules to form host-guest complexes. During the synthesis of PAMAM dendrimers in methanol, the final removal of this solvent from the dendrimer spherical macromolecule requires prolonged vacuum evaporation. PAMAM dendrimers ability to encapsulate hydrophobic guests was extensively used as a strategy for promoting water insoluble drugs transportation into

(Rundle & Frank, 1943).

and b).

actually the averaged value (Saenger, 1984).

**2. Polyamidoamine dendrimers (PAMAM)** 

tissues and cells (vide infra).

**2.1 General characteristics of PAMAM dendrimers** 

Scheme 1. The scheme of synthesis of PAMAM dendrimers on ethylenediamine (en) core. Addition of methyl acrylate to en results in formation of -0.5 half-generation PAMAM dendrimer (G-0.5) with four methyl ester groups on surface. The condensation of G-0.5 with four en equivalents leads to full-generation PAMAM dendrimer (G0). Further addition of methyl acrylate gives G0.5 PAMAM dendrimer, which upon next condensation with eight en equivalents results in obtaining full generation PAMAM dendrimer G1 (not shown). Repeated sequence of addition/condensation protocol leads to G1.5, G2, G2,5, G3 and so on.

### **2.2 Medical applications of PAMAM dendrimers**

PAMAM dendrimers are relatively low toxic (Jain et al., 2010, Mukherjee et al., 2010, Kolhatkar et al., 2007, Hans & Lowman, 2002). Therefore they are extensively studied as drug carriers. There are two strategies commonly applied: 1) diffusion of prodrug covalently bound to the dendrimer, and 2) diffusion of drug encapsulated in the dendrimer. Thus, the PAMAM dendrimers act as solubilizers for anti-inflamatory drugs *ketoprofen* (Yiyun et al., 2005), *ibuprofen* (Milhem et al., 2000) and *indomethacin* (Chauhan et al., 2003) and promote

Dermatological Application of PAMAM –

cosmetic creams.

**3.1 Materials and methods** 

used without further purification.

**3.1.2 Syntheses of PAMAM dendrimers**

based on 1-D and 2-D NMR experiments.

**3.1.1 Reagents** 

Vitamin Bioconjugates and Host-Guest Complexes – Vitamin C Case Study 199

matrix of intercellular lipid due to its low water content. This also demonstrated that the rapid permeation of vitamin C when released from delivering formulation is not necessarily a cosmetic target. Macromolecular carriers can be used for controlling the transdermal diffusion rate of cosmetic ingredients; polyamidoamine (PAMAM) dendrimers, widely used as transdermal carriers for drugs have been shown to be amongst the best candidates (Svenson, 2009). For water-insoluble vitamins, like A and E, they can serve as solubilizers, while for water soluble vitamins, like ascorbic acid (**1**), they might allow to increase the skin load. In such a case the PAMAM dendrimers could be used as valuable additives for

Here we present the results on simple host-guest chemistry between PAMAM dendrimers and **1** in solution and in neat dendrimers **G2,5**, **G3**, **G3,5**, and **G4** studied by the 1H NMR and differential scanning calorimetry (DSC) methods in order to establish the proper stochiometry of host-guest complexes available for cream formulation. The preliminary *in vitro* studies on diffusion of **1** absorbed in PAMAM dendrimers through artificial model

**O**

**1**

**OH O**

**OH OH**

**1**

Ascorbic acid (vitamin C, **1**, MW = 176.12 g/mol, m.p. = 190 - 194°C with decomposition) was used as received. All solvents and reagents were of reagent grade purity (Aldrich) and

PAMAM dendrimers of generation 2, 2,5, 3, 3,5, and 4 (**G2**, **G2,5**, **G3**, **G3,5**, and **G4**, respectively) on ethylenediamine core were synthesized according to the published method by alternate addition of methyl acrylate to **Gn** and condensation of ethylenediamine with **Gn,5** [Tomalia et al., 2003]. The dendrimers were characterized by the 1H and 13C NMR spectra in deuterium oxide and in methanol-*d*4 using standard 1-D and 2-D COSY, HMBC, and HSQC methods with 500 MHz Bruker UltraShield spectrometer to confirm their purity.

The solubility of **1** in methanol-*d4*, estimated by reference chloroform addition into the saturated solution is 0.36 mol dm-3. 1H and 13C resonances assignement has been performed

**3.1.3 Solubilization of 1 in methanol containing host dendrimers**

**3 2**

membrane (polyvinydifluoride, PVDF) and pig ear skin (PES) were also performed.

**OH**

**H**

**4 5 6**

their prolonged release both *in vitro* and *in vivo* (Na et al., 2006, Kolhe et al., 2003). Similar concept was used to increase solubility and uptake flux of several anticancer drugs, like *methoxyestradiol* (Wang et al., 2011), *adriamycin* and *methotrexate* (Kojima et al., 2000), a plant alkaloid *camptothecin* (Cheng et al., 2008), *doxorubicidin* (Papagiannaros et al., 2005), and *dimethoxycurcumin* (Markatou et al. 2007). Moreover, *nifedipine* - a calcium channel blocking agent (Devarakonda et al., 2004, 2005), a loop diuretic *furosemide* (Devarakonda et al., 2007, antipsychotic drug *risperidone* (Prieto et al., 2011), a hypolipidemic drug (Kulhari et al., 2011), antibiotic *quinolones* (Cheng et al., 2007), antibacterial *sulfamethoxazole* (Ma et al., 2007), as well as ophtalmic drugs *pilocarpine nitrate* and *tropicamide* (Vandamme & Brobeck, 2005) were also supported by PAMAM dendrimers as carrier. Surprisingly PAMAM – drug complexes were proven to be effectively transdermal increasing the flux of *5-fluorouracil* - a drug for treatment of psoriasis, premalignant and malignant skin conditions (Venuganti & Perumal, 2008, Bhadra et al., 2003) of dermatologically important vitamins, like *nicotinic acid* Cheng & Xu, 2005) and *riboflavin* (Filipowicz & Wołowiec, 2011) as well as of *psoralene* – the photosensitizer used for treatment of psoriasis (Borowska et al., 2010).

A more advanced strategy is based on a covalent bonding of the prodrug, bioconjugates being extremely promising for site-directed therapy. Thus, the PAMAM bioconjugates with drugs synthesized and tested *in vitro* so far are the one with *methotrexate* and *folate* (Patri et al., 2005, Chandrasekar et al., 2009), *ibuprofen* (Kolhe et al., 2006, Kurtoglu et al., 2010), *methylprednisolone* (Khandare et al., 2005)*, adriamycin* (Kono et al., 2008)*, triamcinolone* (Ma et al., 2009), *propranolol* (D'Emanuele et al., 2004), *5-aminosalicylic acid* (Wiwattanapatapee et al., 2003), and especially important for skin treatment *phosphorylcholine* (Jia et al., 2011), *cholic acid* (Zhang et al., 2011), *biotin* (Yang et al., 2009), and *riboflavin* (Thomas et al., 2010). Similar studies are currently being performed in our laboratory to clarify the skin penetration of vitamins supported by PAMAM dendrimers. In some cases PAMAM dendrimers act as solubilizers and enhance the skin load, while in other cases the vitamin flux decreases. Here we present the latest results on vitamin C permeation in the presence of PAMAM dendrimers.

### **3. PAMAM dendrimers as carriers for vitamin C**

Ascorbic acid (vitamin C) is an essential nutrient protecting living tissues from oxidation processes by free radicals and reactive oxygen derived species. It is also an important cofactor in collagen synthesis, hence present in most cosmetic products. The bioavailability of topically applied vitamin C is very high compared with other dermatologically important vitamins and depends on the specific delivery system, like o/w, w/o emulsions and hydrogels (Rozman et al., 2009) and liposomes, niosomes or solid lipid nanoparticles as dispergents (Kaur et al., 2007) as well as microemulsions (Kogan and Garbi, 2006). Due to its instability vitamin C is usually present in cosmetics as ester derivatives which are thermally and oxidatively more stable. Besides they also promote diffusion through epidermis. Though ascorbic palmitate is generally used, recently some other esters (Shibayama et al., 2008, Kumano et al., 1998, Tai et al., 2004) and even tandem retinyl ascorbate (Abdulmayed and Herda, 2004) were synthesized and their skin bioavailability tested.

The permeation rate through whole mouse skin was estimated as 3.43 (± 0.74) μg/cm2/h (Lee and Tojo, 1998) assuming that the least permeable barrier of *stratum corneum* was a matrix of intercellular lipid due to its low water content. This also demonstrated that the rapid permeation of vitamin C when released from delivering formulation is not necessarily a cosmetic target. Macromolecular carriers can be used for controlling the transdermal diffusion rate of cosmetic ingredients; polyamidoamine (PAMAM) dendrimers, widely used as transdermal carriers for drugs have been shown to be amongst the best candidates (Svenson, 2009). For water-insoluble vitamins, like A and E, they can serve as solubilizers, while for water soluble vitamins, like ascorbic acid (**1**), they might allow to increase the skin load. In such a case the PAMAM dendrimers could be used as valuable additives for cosmetic creams.

Here we present the results on simple host-guest chemistry between PAMAM dendrimers and **1** in solution and in neat dendrimers **G2,5**, **G3**, **G3,5**, and **G4** studied by the 1H NMR and differential scanning calorimetry (DSC) methods in order to establish the proper stochiometry of host-guest complexes available for cream formulation. The preliminary *in vitro* studies on diffusion of **1** absorbed in PAMAM dendrimers through artificial model membrane (polyvinydifluoride, PVDF) and pig ear skin (PES) were also performed.

### **3.1 Materials and methods**

### **3.1.1 Reagents**

198 Stoichiometry and Research – The Importance of Quantity in Biomedicine

their prolonged release both *in vitro* and *in vivo* (Na et al., 2006, Kolhe et al., 2003). Similar concept was used to increase solubility and uptake flux of several anticancer drugs, like *methoxyestradiol* (Wang et al., 2011), *adriamycin* and *methotrexate* (Kojima et al., 2000), a plant alkaloid *camptothecin* (Cheng et al., 2008), *doxorubicidin* (Papagiannaros et al., 2005), and *dimethoxycurcumin* (Markatou et al. 2007). Moreover, *nifedipine* - a calcium channel blocking agent (Devarakonda et al., 2004, 2005), a loop diuretic *furosemide* (Devarakonda et al., 2007, antipsychotic drug *risperidone* (Prieto et al., 2011), a hypolipidemic drug (Kulhari et al., 2011), antibiotic *quinolones* (Cheng et al., 2007), antibacterial *sulfamethoxazole* (Ma et al., 2007), as well as ophtalmic drugs *pilocarpine nitrate* and *tropicamide* (Vandamme & Brobeck, 2005) were also supported by PAMAM dendrimers as carrier. Surprisingly PAMAM – drug complexes were proven to be effectively transdermal increasing the flux of *5-fluorouracil* - a drug for treatment of psoriasis, premalignant and malignant skin conditions (Venuganti & Perumal, 2008, Bhadra et al., 2003) of dermatologically important vitamins, like *nicotinic acid* Cheng & Xu, 2005) and *riboflavin* (Filipowicz & Wołowiec, 2011) as well as of *psoralene* – the

A more advanced strategy is based on a covalent bonding of the prodrug, bioconjugates being extremely promising for site-directed therapy. Thus, the PAMAM bioconjugates with drugs synthesized and tested *in vitro* so far are the one with *methotrexate* and *folate* (Patri et al., 2005, Chandrasekar et al., 2009), *ibuprofen* (Kolhe et al., 2006, Kurtoglu et al., 2010), *methylprednisolone* (Khandare et al., 2005)*, adriamycin* (Kono et al., 2008)*, triamcinolone* (Ma et al., 2009), *propranolol* (D'Emanuele et al., 2004), *5-aminosalicylic acid* (Wiwattanapatapee et al., 2003), and especially important for skin treatment *phosphorylcholine* (Jia et al., 2011), *cholic acid* (Zhang et al., 2011), *biotin* (Yang et al., 2009), and *riboflavin* (Thomas et al., 2010). Similar studies are currently being performed in our laboratory to clarify the skin penetration of vitamins supported by PAMAM dendrimers. In some cases PAMAM dendrimers act as solubilizers and enhance the skin load, while in other cases the vitamin flux decreases. Here we present the latest results on vitamin C permeation in the presence of PAMAM

Ascorbic acid (vitamin C) is an essential nutrient protecting living tissues from oxidation processes by free radicals and reactive oxygen derived species. It is also an important cofactor in collagen synthesis, hence present in most cosmetic products. The bioavailability of topically applied vitamin C is very high compared with other dermatologically important vitamins and depends on the specific delivery system, like o/w, w/o emulsions and hydrogels (Rozman et al., 2009) and liposomes, niosomes or solid lipid nanoparticles as dispergents (Kaur et al., 2007) as well as microemulsions (Kogan and Garbi, 2006). Due to its instability vitamin C is usually present in cosmetics as ester derivatives which are thermally and oxidatively more stable. Besides they also promote diffusion through epidermis. Though ascorbic palmitate is generally used, recently some other esters (Shibayama et al., 2008, Kumano et al., 1998, Tai et al., 2004) and even tandem retinyl ascorbate (Abdulmayed

The permeation rate through whole mouse skin was estimated as 3.43 (± 0.74) μg/cm2/h (Lee and Tojo, 1998) assuming that the least permeable barrier of *stratum corneum* was a

photosensitizer used for treatment of psoriasis (Borowska et al., 2010).

**3. PAMAM dendrimers as carriers for vitamin C** 

and Herda, 2004) were synthesized and their skin bioavailability tested.

dendrimers.

Ascorbic acid (vitamin C, **1**, MW = 176.12 g/mol, m.p. = 190 - 194°C with decomposition) was used as received. All solvents and reagents were of reagent grade purity (Aldrich) and used without further purification.

### **3.1.2 Syntheses of PAMAM dendrimers**

PAMAM dendrimers of generation 2, 2,5, 3, 3,5, and 4 (**G2**, **G2,5**, **G3**, **G3,5**, and **G4**, respectively) on ethylenediamine core were synthesized according to the published method by alternate addition of methyl acrylate to **Gn** and condensation of ethylenediamine with **Gn,5** [Tomalia et al., 2003]. The dendrimers were characterized by the 1H and 13C NMR spectra in deuterium oxide and in methanol-*d*4 using standard 1-D and 2-D COSY, HMBC, and HSQC methods with 500 MHz Bruker UltraShield spectrometer to confirm their purity.

### **3.1.3 Solubilization of 1 in methanol containing host dendrimers**

The solubility of **1** in methanol-*d4*, estimated by reference chloroform addition into the saturated solution is 0.36 mol dm-3. 1H and 13C resonances assignement has been performed based on 1-D and 2-D NMR experiments.

Dermatological Application of PAMAM –

**[vit.C] [mol dm-3**

**]**

**0,30 0,35 0,40 0,45 0,50 0,55 0,60 0,65 0,70 0,75 0,80**

> **1 : Gn ratio**

> > 6:1 250 7:1 225

**3.1.5** *In vitro* **permeation of Gn-1 and Gn,5-1 complexes** 

G3.5.

Vitamin Bioconjugates and Host-Guest Complexes – Vitamin C Case Study 201

**0,0000 0,0005 0,0010 0,0015 0,0020 0,0025 0,0030**

**G2,5 G3 G3,5 G4** 

Fig. 2. The dependence of solubility of 1 in methanol containing variable concentration of

0:1 229 253 224 248 1:1 243 265 240 263 2:1 243 268 251 269 3:1 247 267 255 259 4:1 246 257 224 249 5:1 244 254 248

Table 1. Glass transition temperatures [K] for Gn dendrimers and mixtures of Gn and 1.

Permeation of **Gn**-**1** and **Gn,5**-**1** complexes was studied using Franz diffusion assembly (Thermo Scientific (UK) model DC 600 equipped with 6 cm3 acceptor compartments). The o/w emulsion was used as donor. The emulsion was prepared using cetearyl alcohol (1.5 g), Brij 72 (1.2 g), Brij 58 (0.3 g) as emulsifiers, vaseline (5.0 g), stearine (0.5 g), glycerin (1.5 g) and water (40.0 g). The samples containing **Gn**-**1** complexes were prepared on 1 g scale by dissolving **1 (***ca* 5 mg) and **Gn** (*ca* 50 mg) in 1 g of the emulsion. Preliminary samples were obtained by dissolving the host-guest complexes **Gn**-**1** (prepared by mixing **1** and **Gn** in methanol followed by vacuum evaporation) in emulsion on the same scale. No difference in the permeation studies were noticed related to the protocols. For the analysis ca 250 mg samples were mounted over commercial polyvinydifluoride membrane (PVDF, 0.125 mm thickness) or prepared pig ear skin membrane (PES, 0.55 mm thickness), with 0.067 M phosphate buffer pH = 7.4 : ethanol 7:3 v/v. as receptor medium. The progress of diffusion was monitored spectrophotometrically at 264 nm using the extinction coefficient calculated for the solution of **1** in receptor solution (1.1⋅104, Figure 3). The receiving solution was

**[C] = C0**

**R = 0.999**

**C0**

 **+ B [G3,5]**

 **= 0.35 (0.01); B = 160 (12)**

**[G3,5] [mol dm-3]**

1H NMR (chemical shift [ppm], intensity, multiplicity, assignment): 4.88 ([1H], d, H4); 3.90 ([1H], d of t, H5); 3.68 ([2H], d, H6); 13C NMR: 172.1 (C1); 153.4 (C3); 118.5 (C2); 75.5 (C4); 69.2 (C5); 62.2 (C6).

The solubilization of **1** in presence of dendrimers was studied by straight addition of solid **1** into 700 μL of **G3**, **G4**, **G2,5** or **G3,5** solutions at variable concentration in methanol-*d*4 after added a measured amount of chloroform as quantitative reference. The H4 doublet of (**1**) shifted from 4.88 to 4.73 ppm upon dissolving in solution containing **G3** or **G4** dendrimers. Partial precipitation of the complex occurred when added amount of **1** added reached **1**:**G3** and **1**:**G4** ratio equal to 3:1. The analysis of separated solid indicated that the composition of water-soluble solid complex was 3:1, independently on dendrimers concentration. Solubilization of **1** in methanol-*d*4 in presence of **G2,5** or **G3,5** showed no complexes precipitation within studied range of dendrimer concentration (up to 0.003 mol⋅dm-3); the solubility of **1** depending linearly on it.

 Linear regression of **1** versus **G2,5** and **G3,5** concentrations are shown in Figure 1 and 2, respectively. The proton resonances in the 1H NMR spectrum of **1** in solutions containing **G2,5** or **G3,5** were not shifted compared with **1** in pure methanol-*d*4.

### **3.1.4 Differential scanning calorimetric studies on PAMAM-1 stoichiometry**

Glass transition temperature Tg was examined using heat-flux differential scanning calorimeter DSC, Q1000™ from TA Instruments, Inc., equipped with a mechanical refrigerator from temperatures 183.15 K (-90°C ) to 393.15 K (120°C) (dry nitrogen gas with a flow rate of 50 cm3⋅min-1 was purged through the DSC cell in the instrument and cooling was accomplished with a refrigerated cooling system). Samples of neat **G2,5**, **G3**, **G3,5**, and **G4** dendrimers were examined as well as host-guest complexes prepared by dissolving **Gn** or **Gn,5** in methanol followed by addition of measured amount of **1** and extensive vacuum evaporation. The oily samples of **1** and **Gn** or **Gn,5** exhibited a higher Tg value than the neat dendrimers (Table 1) within **1**:**PAMAM** ratio 6:1 for **G2,5** and 3:1 for other generations of PAMAM dendrimer. The original Tg of pure dendrimers was recovered once exceeded these molar ratios, with a subsequent lost of the sample homogeneity.

Fig. 1. The dependence of solubility of 1 in methanol containing variable concentration of G2.5.

1H NMR (chemical shift [ppm], intensity, multiplicity, assignment): 4.88 ([1H], d, H4); 3.90 ([1H], d of t, H5); 3.68 ([2H], d, H6); 13C NMR: 172.1 (C1); 153.4 (C3); 118.5 (C2); 75.5 (C4); 69.2

The solubilization of **1** in presence of dendrimers was studied by straight addition of solid **1** into 700 μL of **G3**, **G4**, **G2,5** or **G3,5** solutions at variable concentration in methanol-*d*4 after added a measured amount of chloroform as quantitative reference. The H4 doublet of (**1**) shifted from 4.88 to 4.73 ppm upon dissolving in solution containing **G3** or **G4** dendrimers. Partial precipitation of the complex occurred when added amount of **1** added reached **1**:**G3** and **1**:**G4** ratio equal to 3:1. The analysis of separated solid indicated that the composition of water-soluble solid complex was 3:1, independently on dendrimers concentration. Solubilization of **1** in methanol-*d*4 in presence of **G2,5** or **G3,5** showed no complexes precipitation within studied range of dendrimer concentration (up to 0.003 mol⋅dm-3); the

 Linear regression of **1** versus **G2,5** and **G3,5** concentrations are shown in Figure 1 and 2, respectively. The proton resonances in the 1H NMR spectrum of **1** in solutions containing

Glass transition temperature Tg was examined using heat-flux differential scanning calorimeter DSC, Q1000™ from TA Instruments, Inc., equipped with a mechanical refrigerator from temperatures 183.15 K (-90°C ) to 393.15 K (120°C) (dry nitrogen gas with a flow rate of 50 cm3⋅min-1 was purged through the DSC cell in the instrument and cooling was accomplished with a refrigerated cooling system). Samples of neat **G2,5**, **G3**, **G3,5**, and **G4** dendrimers were examined as well as host-guest complexes prepared by dissolving **Gn** or **Gn,5** in methanol followed by addition of measured amount of **1** and extensive vacuum evaporation. The oily samples of **1** and **Gn** or **Gn,5** exhibited a higher Tg value than the neat dendrimers (Table 1) within **1**:**PAMAM** ratio 6:1 for **G2,5** and 3:1 for other generations of PAMAM dendrimer. The original Tg of pure dendrimers was recovered once exceeded these

**0,0000 0,0005 0,0010 0,0015 0,0020 0,0025 0,0030**

Fig. 1. The dependence of solubility of 1 in methanol containing variable concentration of G2.5.

**[C] = C0**

**R = 0.990**

**C0**

 **+ B [G2,5]**

**[G2,5] [mol dm-3**

**]**

 **= 0.36 (0.02); B = 144 (12)**

**G2,5** or **G3,5** were not shifted compared with **1** in pure methanol-*d*4.

molar ratios, with a subsequent lost of the sample homogeneity.

**0,30 0,35 0,40 0,45 0,50 0,55 0,60 0,65 0,70 0,75 0,80**

**[vit.C] [mol dm**

**-3**

**]**

**3.1.4 Differential scanning calorimetric studies on PAMAM-1 stoichiometry** 

(C5); 62.2 (C6).

solubility of **1** depending linearly on it.

Fig. 2. The dependence of solubility of 1 in methanol containing variable concentration of G3.5.


Table 1. Glass transition temperatures [K] for Gn dendrimers and mixtures of Gn and 1.

### **3.1.5** *In vitro* **permeation of Gn-1 and Gn,5-1 complexes**

Permeation of **Gn**-**1** and **Gn,5**-**1** complexes was studied using Franz diffusion assembly (Thermo Scientific (UK) model DC 600 equipped with 6 cm3 acceptor compartments). The o/w emulsion was used as donor. The emulsion was prepared using cetearyl alcohol (1.5 g), Brij 72 (1.2 g), Brij 58 (0.3 g) as emulsifiers, vaseline (5.0 g), stearine (0.5 g), glycerin (1.5 g) and water (40.0 g). The samples containing **Gn**-**1** complexes were prepared on 1 g scale by dissolving **1 (***ca* 5 mg) and **Gn** (*ca* 50 mg) in 1 g of the emulsion. Preliminary samples were obtained by dissolving the host-guest complexes **Gn**-**1** (prepared by mixing **1** and **Gn** in methanol followed by vacuum evaporation) in emulsion on the same scale. No difference in the permeation studies were noticed related to the protocols. For the analysis ca 250 mg samples were mounted over commercial polyvinydifluoride membrane (PVDF, 0.125 mm thickness) or prepared pig ear skin membrane (PES, 0.55 mm thickness), with 0.067 M phosphate buffer pH = 7.4 : ethanol 7:3 v/v. as receptor medium. The progress of diffusion was monitored spectrophotometrically at 264 nm using the extinction coefficient calculated for the solution of **1** in receptor solution (1.1⋅104, Figure 3). The receiving solution was

Dermatological Application of PAMAM –

experiments on skin-model membranes (see below).

**dendrimers** 

3:1; 4:1.

**3.2.3 Permeation studies** 

Vitamin Bioconjugates and Host-Guest Complexes – Vitamin C Case Study 203

Recently we have used DSC method to evaluate the stoichiometry of host-guest complexes between PAMAM dendrimers and *8-methoxypsoralene* (Borowska et al., 2010). Water insoluble host formed oily host-guest complexes which revealed higher temperature of glass transition (Tg) than PAMAM dendrimers. When the guest amount was increased above the host maximum capacity, the separation of PAMAM dendrimers and guest took place, followed by Tg returning to its original value. Similar phenomenon was observed in all cases studied here. However, the results on Tg were slightly surprising, because the limit of encapsulation for dendrimers **G3**, **G3,5** and **G4** was 3 molecules of **1** per macromolecule, i.e. lower in comparison with **G2,5**, for which 6 molecules of **1** per molecule of **G2,5**, showed increased value of Tg. However it confirms the 1H NMR results on solubilization in methanol, which also showed that **G2,5** interacts with more molecules of guest than larger hosts. This might be due to different types of interaction between host and **1**. Vitamin C, unlike hydrophobic *8-methoxypsoralene* is able to form ion-pair complex, this interaction prevailing in case of full-generation dendrimers **G3** and **G4**. The ion-pairs decompose when solvent is removed from solution upon preparation of neat samples. Besides, the larger dendrimers are used, the more dense are the cavities of host and self organization of vitamin C crystals prevails over weak intramolecular interaction within host-guest complex. Furthermore we noticed that homogeneous samples of host-guest complexes formed between PAMAM dendrimers and **1** can be obtained in every case when the stoichiometry is maintained as 3:1. These complexes were then used to perform transdermal permeability

Fig. 4. The DSC curves for **1** : **G4** mixtures at molar ratio (from bottom to top): 0:1; 1:1; 2:1;

The permeation experiments of **1** through PVDF and PES membranes using **1** dispersed in o/w emulsion indicated a typical change in the flux of **1**; after 0.5 hr induction time, the flux

rapidly grew finally stabilizing within 1.5 hour of experiment.

**3.2.2 Differential scanning calorimetric studies of neat complexes of 1 with** 

stirred magnetically with 1000 rpm at 32°C. 10 ml aliquots of receptor solution were taken at 0.5 hour or longer time intervals and the receiver compartment was filled with 6 ml portion of a new receptor solution. The experiments were carried on until at least 10% of initial amount of **1** was received in receptor solution. The results were analyzed calculating the flux in [μmol⋅hour-1⋅cm-2]. The active area of membrane determined by size of the ring in Franz cell was 0.176 cm2. The cumulated amount of **1** received as a function of diffusion time was crucial to determine the diffusion properties of **Gn**-**1** complexes. The time of 10% diffused **1** (τ**0.1**) was used as quantitative parameter to compare diffusion efficency. Permeation experiments were repeated 7 times. The mean standard deviation and workup of data were performed as previously (Filipowicz and Wołowiec, 2011).

Fig. 3. The UV-Vis spectrum of **1** in receptor solution.

### **3.2 Results and discussion**

### **3.2.1 Solubilization of 1 in presence of dendrimers studied by the 1 H NMR**

Ascorbic acid (**1**) is well soluble in water, while its solubility in methanol-*d4*, determined by 1H NMR spectroscopy is 0.35 mol⋅dm-3. It increases when bound to PAMAM dendrimers **G2**, **G3**, **G4**, **G2,5** and **G3,5**, respectively. When **1** is dissolved in methanol-*d4*, the doublet resonance of H4 shifts considerably from 4.80 into 4.62 ppm when **1**:**G4** ratio is 1:1. The species formed between **1** and **G3** or **G4** dendrimers become insoluble when the **1**:**Gn** ratio reaches 3:1 and 6:1 for **1**:**G3** and **1**:**G4**, respectively. The isolated complexes are readily water soluble. Presumably their stoichiometry does not correspond to the dendrimers ability to absorb small molecules of ascorbic acid, rather than to the limit of their solubility in methanol.

Opposite to **G3** or **G4** the **G2,5** and **G3,5** dendrimers which have similar sizes and molecular weights act as effective solubilizers of **1** in methanol. They are able to solubilize *ca* 144-160 molecules of **1** per molecule of dendrimer, almost independently on the host size. When methanol is evaporated from such a samples, the separation of **1** from dendrimer is observed resulting in formation of non-homogeneous mixture. In order to establish the stoichiometry of neat host-guest complexes another method was used.

stirred magnetically with 1000 rpm at 32°C. 10 ml aliquots of receptor solution were taken at 0.5 hour or longer time intervals and the receiver compartment was filled with 6 ml portion of a new receptor solution. The experiments were carried on until at least 10% of initial amount of **1** was received in receptor solution. The results were analyzed calculating the flux in [μmol⋅hour-1⋅cm-2]. The active area of membrane determined by size of the ring in Franz cell was 0.176 cm2. The cumulated amount of **1** received as a function of diffusion time was crucial to determine the diffusion properties of **Gn**-**1** complexes. The time of 10% diffused **1** (τ**0.1**) was used as quantitative parameter to compare diffusion efficency. Permeation experiments were repeated 7 times. The mean standard deviation and workup

**200 250 300 350 400 450 500**

Ascorbic acid (**1**) is well soluble in water, while its solubility in methanol-*d4*, determined by 1H NMR spectroscopy is 0.35 mol⋅dm-3. It increases when bound to PAMAM dendrimers **G2**, **G3**, **G4**, **G2,5** and **G3,5**, respectively. When **1** is dissolved in methanol-*d4*, the doublet resonance of H4 shifts considerably from 4.80 into 4.62 ppm when **1**:**G4** ratio is 1:1. The species formed between **1** and **G3** or **G4** dendrimers become insoluble when the **1**:**Gn** ratio reaches 3:1 and 6:1 for **1**:**G3** and **1**:**G4**, respectively. The isolated complexes are readily water soluble. Presumably their stoichiometry does not correspond to the dendrimers ability to absorb small molecules of ascorbic acid, rather than to the limit of their solubility in

Opposite to **G3** or **G4** the **G2,5** and **G3,5** dendrimers which have similar sizes and molecular weights act as effective solubilizers of **1** in methanol. They are able to solubilize *ca* 144-160 molecules of **1** per molecule of dendrimer, almost independently on the host size. When methanol is evaporated from such a samples, the separation of **1** from dendrimer is observed resulting in formation of non-homogeneous mixture. In order to establish the

**3.4 10-5**

 **mol dm-3**

**Spectrum of vitamin C in receiving solution**

**Wavelength [nm]**

**H NMR** 

of data were performed as previously (Filipowicz and Wołowiec, 2011).

<sup>λ</sup>**max = 264nm;** ε**264 = 1.1 x 104**

**0,0**

**3.2 Results and discussion** 

methanol.

Fig. 3. The UV-Vis spectrum of **1** in receptor solution.

**3.2.1 Solubilization of 1 in presence of dendrimers studied by the 1**

stoichiometry of neat host-guest complexes another method was used.

**0,1**

**0,2**

**0,3**

**Absorbance**

**0,4**

### **3.2.2 Differential scanning calorimetric studies of neat complexes of 1 with dendrimers**

Recently we have used DSC method to evaluate the stoichiometry of host-guest complexes between PAMAM dendrimers and *8-methoxypsoralene* (Borowska et al., 2010). Water insoluble host formed oily host-guest complexes which revealed higher temperature of glass transition (Tg) than PAMAM dendrimers. When the guest amount was increased above the host maximum capacity, the separation of PAMAM dendrimers and guest took place, followed by Tg returning to its original value. Similar phenomenon was observed in all cases studied here. However, the results on Tg were slightly surprising, because the limit of encapsulation for dendrimers **G3**, **G3,5** and **G4** was 3 molecules of **1** per macromolecule, i.e. lower in comparison with **G2,5**, for which 6 molecules of **1** per molecule of **G2,5**, showed increased value of Tg. However it confirms the 1H NMR results on solubilization in methanol, which also showed that **G2,5** interacts with more molecules of guest than larger hosts. This might be due to different types of interaction between host and **1**. Vitamin C, unlike hydrophobic *8-methoxypsoralene* is able to form ion-pair complex, this interaction prevailing in case of full-generation dendrimers **G3** and **G4**. The ion-pairs decompose when solvent is removed from solution upon preparation of neat samples. Besides, the larger dendrimers are used, the more dense are the cavities of host and self organization of vitamin C crystals prevails over weak intramolecular interaction within host-guest complex. Furthermore we noticed that homogeneous samples of host-guest complexes formed between PAMAM dendrimers and **1** can be obtained in every case when the stoichiometry is maintained as 3:1. These complexes were then used to perform transdermal permeability experiments on skin-model membranes (see below).

Fig. 4. The DSC curves for **1** : **G4** mixtures at molar ratio (from bottom to top): 0:1; 1:1; 2:1; 3:1; 4:1.

### **3.2.3 Permeation studies**

The permeation experiments of **1** through PVDF and PES membranes using **1** dispersed in o/w emulsion indicated a typical change in the flux of **1**; after 0.5 hr induction time, the flux rapidly grew finally stabilizing within 1.5 hour of experiment.

Dermatological Application of PAMAM –

**0,0**

**0**

**2**

**4**

**6**

**8**

**10**

**<sup>12</sup> PVDS**

 **PES**

PES membranes in function of PAMAM dendrimer generation.

was 2.8 (± 0.2) mg in every case.

**[hr]** τ**0.1**

**0,1**

**0,2**

**0,3**

**0,4**

**Total amount of 1 [mg]**

**0,5**

Vitamin Bioconjugates and Host-Guest Complexes – Vitamin C Case Study 205

useful for controlling transdermal diffusion of dermatologically important agents. Finally the emulsion containing vitamin and dendrimeic carrier can be easily prepared by addition of pre-formed host-guest complex in ethanol and addition of oily complex to the prepared emulsion. Such prepared creams may carry both water-soluble and water-insoluble vitamins, as well as some vitamin derivatives bonded covalently, like retinal, pyridoxal or

**0 1 2 3 4 5 6 7 8 9 10 11**

**01234**

Fig. 6. The dependence of τ**0.1** in experiments of transdermal diffusion through PVDS and

**Generation**

Fig. 5b. The cumulated amount of **1** diffused through PES membrane vs time. The load of **1**

**Time [hr]**

biotin. These bioconjugates are currently under investigation in our laboratory.

**0,6 NONE**; mean SD = 0.012  **G2**; mean SD = 0.011  **G2.5**; mean SD = 0.004  **G3**; mean SD = 0.003  **G3.5**; mean SD = 0.003  **G4**; mean SD = 0.010

Addition of PAMAM dendrimers of **G2**, **G2,5**, **G3**, **G3,5**, and **G4** only slightly influenced the rate of diffusion through PVDS membrane. The experiments were conducted until ca 50% of **1** was transferred through PVDS and the time of 10% transfer, τ**0.1**. was used as reference in all the experiments. Addition of smaller size dendrimers **G2**, **G2,5**, **G3** caused elongation of τ**0.1**, presumably due to host-guest complexes diffusion or diffusion of **1** preliminarily released from them in emulsion. The larger size dendrimers **G3,5**, and **G4** had no such impact (Figure 5a). Generally the diffusion of **1** through PVDF was fast, with 10% of **1** transferred within ca 1 hour. Unlikely, the diffusion through much thicker PES membrane occurred slower being strongly affected by the added dendrimer (Figure 5b). This influence could be clearly demonstrated by comparison of τ**0.1** (Figure 6 and Table 2). The slowest diffusion was found in case of **1**-**G2,5** composition. The diffusion rate was diminished by a factor of 4 if compared with **1** itself. **G3** considerably decreased the rate by a factor of 3.7, while other dendrimers, larger **G3,5** and **G4** and smaller **G2**, showed lower impact. The results obtained for diffusion experiments through PES confirm the PVDF ones, nevetheless remarkable differentiation of diffusion efficiency was found in case of PES.

Fig. 5a. The cumulated amount of **1** diffused through PVDF membrane vs time. The load of **1** was 2.8 (± 0.2) mg in every case.

Comparing the supposed stoichiometry of host-guest complexes based on DSC measurements as well as remarkable solubilization of **1** in methanol containing **G2,5** and **G3,5** we can assume that these dendrimers form the most stable host-guest complexes, with **1** encapsulated within macromolecule, while **G3** and **G4** encapsulate **1** weakly to give the 3:1 **1**: **Gn** complexes. Moreover, **1** interacts with **G2**, **G3** and **G4** surface amine groups with this interaction prevailing on encapsulation. When **1** is released from ionic complexes with **Gn**, it diffuses similarly like from emulsion. When the whole host-guest complex diffuse, the rate is considerably lower. This phenomenon is quite opposite to what was observed for the systems in which PAMAM dendrimers were used as solubilizers of water-insoluble *psoralene* or *riboflavin* (Borowska et al, 2010, Filipowicz and Wołowiec, 2011); in these cases the transdermal diffusion of these compounds was enhanced. Both of these behaviors are

Addition of PAMAM dendrimers of **G2**, **G2,5**, **G3**, **G3,5**, and **G4** only slightly influenced the rate of diffusion through PVDS membrane. The experiments were conducted until ca 50% of **1** was transferred through PVDS and the time of 10% transfer, τ**0.1**. was used as reference in all the experiments. Addition of smaller size dendrimers **G2**, **G2,5**, **G3** caused elongation of τ**0.1**, presumably due to host-guest complexes diffusion or diffusion of **1** preliminarily released from them in emulsion. The larger size dendrimers **G3,5**, and **G4** had no such impact (Figure 5a). Generally the diffusion of **1** through PVDF was fast, with 10% of **1** transferred within ca 1 hour. Unlikely, the diffusion through much thicker PES membrane occurred slower being strongly affected by the added dendrimer (Figure 5b). This influence could be clearly demonstrated by comparison of τ**0.1** (Figure 6 and Table 2). The slowest diffusion was found in case of **1**-**G2,5** composition. The diffusion rate was diminished by a factor of 4 if compared with **1** itself. **G3** considerably decreased the rate by a factor of 3.7, while other dendrimers, larger **G3,5** and **G4** and smaller **G2**, showed lower impact. The results obtained for diffusion experiments through PES confirm the PVDF ones, nevetheless

**01234567**

**Time [hr]**

Fig. 5a. The cumulated amount of **1** diffused through PVDF membrane vs time. The load of

Comparing the supposed stoichiometry of host-guest complexes based on DSC measurements as well as remarkable solubilization of **1** in methanol containing **G2,5** and **G3,5** we can assume that these dendrimers form the most stable host-guest complexes, with **1** encapsulated within macromolecule, while **G3** and **G4** encapsulate **1** weakly to give the 3:1 **1**: **Gn** complexes. Moreover, **1** interacts with **G2**, **G3** and **G4** surface amine groups with this interaction prevailing on encapsulation. When **1** is released from ionic complexes with **Gn**, it diffuses similarly like from emulsion. When the whole host-guest complex diffuse, the rate is considerably lower. This phenomenon is quite opposite to what was observed for the systems in which PAMAM dendrimers were used as solubilizers of water-insoluble *psoralene* or *riboflavin* (Borowska et al, 2010, Filipowicz and Wołowiec, 2011); in these cases the transdermal diffusion of these compounds was enhanced. Both of these behaviors are

 **None**; mean SD = 0.015  **G2**; mean SD = 0.016  **G3**; mean SD = 0.015  **G2.5**; mean SD = 0.014  **G3.5**; mean SD = 0.017  **G4**; mean SD = 0.014

remarkable differentiation of diffusion efficiency was found in case of PES.

**0,2**

**1** was 2.8 (± 0.2) mg in every case.

**0,3**

**0,4**

**Total amount of 1 [mg]**

**0,5**

**0,6**

**0,7**

**0,8**

useful for controlling transdermal diffusion of dermatologically important agents. Finally the emulsion containing vitamin and dendrimeic carrier can be easily prepared by addition of pre-formed host-guest complex in ethanol and addition of oily complex to the prepared emulsion. Such prepared creams may carry both water-soluble and water-insoluble vitamins, as well as some vitamin derivatives bonded covalently, like retinal, pyridoxal or biotin. These bioconjugates are currently under investigation in our laboratory.

Fig. 5b. The cumulated amount of **1** diffused through PES membrane vs time. The load of **1** was 2.8 (± 0.2) mg in every case.

Fig. 6. The dependence of τ**0.1** in experiments of transdermal diffusion through PVDS and PES membranes in function of PAMAM dendrimer generation.

Dermatological Application of PAMAM –

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Table 2. The time of 10% transfer of **1** (τ**0.1**) from emulsions containing dendrimers.

### **4. Conclusions**


### G2,5≅G3 > G3,5 >> G2≅G4 >none

5. Finally, the **G2,5** and **G3** dendrimers can be applied as transdermal carriers to control vitamin C release kinetics from emulsions or hydrogels. Vitamin C retardation is surprisingly in contrast with previously studied water insoluble 8-methoxypsoralene or riboflavin which showed a promotion of the diffusion process.

### **5. Acknowledgment**

The work was supported by the Grant no N N302 432839, obtained from Ministry of Higher Education and Research, Poland.

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[hr]

Table 2. The time of 10% transfer of **1** (τ**0.1**) from emulsions containing dendrimers.

1. PAMAM dendrimers influence the solubility of ascorbic acid (**1**) in methanol. The solubility of ionic complexes between **1** and full-generation PAMAM dendrimers in methanol is lower in comparison with **1** itself. 3:1 stoichiometry adducts between vitamin **1** : **G3** and **1** : **G4**, can be isolated from methanolic solutions as homogeneous,

2. Half-generation PAMAM dendrimers: **G2,5** and **G3,5** solubilize **1** in methanol due to non-specific interaction up to *ca* 150 molecules of **1** per molecule of dendrimer. 3. The ionic interactions, encapsultation, and surface absorption of **1** by PAMAM dendrimers result in host-guest complexes formation. Based upon DSC measurements the stoiochiometry of the homogeneous, oily complexes was determined as 6:1 (for **1** :

4. When 10% of **1** per dendrimer compositions are placed in o/w emulsions, the permeation profile of **1** through the polyvinyldifluoride (PVDF) and pig ear skin (PES) membranes depends on the presence and size of dendrimer used as vitamin carrier in the emulsion. Transdermal diffusion through PES is considerably slowed down by

G2,5≅G3 > G3,5 >> G2≅G4 >none 5. Finally, the **G2,5** and **G3** dendrimers can be applied as transdermal carriers to control vitamin C release kinetics from emulsions or hydrogels. Vitamin C retardation is surprisingly in contrast with previously studied water insoluble 8-methoxypsoralene or

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**1** 0.9 (±0.12) 3.0 (±0.21) **1-G2** 1.3 (±0.15) 4.5 (±0.26) **1-G2.5** 1.3 (±0.15) 12.0 (±0.29) **1-G3** 1.0 (±0.13) 11.0 (±0.28) **1-G3.5** 0.9 (±0.12) 8.2 (±0.20) **1-G4** 0.9 (±0.12) 3.7 (±0.22)

τ**0.1**

PVDS PES

Sample (o/w)

**4. Conclusions** 

solvent-free oily complexes.

**G2,5**) and 3:1 (for **1** : **G3**, **1** : **G3,5** and **1** : **G4**).

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dendrimers according to the order:

**5. Acknowledgment** 

**6. References** 

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**Part 4** 

**The Role of Stoichiometry** 

**in the Determination of Protein Interactions** 

