Polyphosphoesters: Chemistry and Application

Elsevier

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First edition 2012

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Preface

Phosphorus chemistry has contributed in various ways to the present progress in biology, biochemistry, medicine, and industry, providing new, highly specified materials. Phosphorus is a key element in polymer chemistry. Polymeric materials have the potential to simulate the mechanical and chemical behavior of biological tissues better than metals or ceramics. The contribution of phosphorus chemistry in this area is significant. The discovery in the early 1950s that the incorporation of phosphorus into a polymer’s backbone gives it flame-retardant properties sparked great interest in phosphorus polymer chemistry. However, because of the high cost of synthesizing these polymers in comparison to carbon analogues, their low molecular weight, and their perceived hydrolytic instability, research interests have faded since the 1960s. The versatility of the phosphorus atom was exploited to be synthesized into a wide range of polymers. The most important feature of phosphorus chemistry is the methods of synthesis of polymers that allow the main chain and the side group to be varied over a very broad range. Different main chain and side groups generate different properties such that the characteristics may vary from those of linear to cross-linked, from water-soluble to hydrophobic polymers, and from bioinert to bioactive materials. This is crucially important for developing new multifunctional materials. Recently, organophosphorus polymers, especially polyphosphoesters with phosphoester bonds (POC) in the main chain, have regained our interest due to these properties:

• Excellent thermal stability

• Fire resistance

• Excellent adhesion to glass and metals

• Excellent binding properties

• High refractivity (invisible cements for glass)

• Good resistance to abrasion

• High resistance to acids

• Attractive mechanical properties

Among these polymers, polyphosphates, structurally related to the natural biopolymers, play a key role as a new class of polymers with the following properties:

• Biodegradable

• Biocompatible

• Thermoresponsive

• Nontoxic

• Water soluble

These properties can be modified to match a specific application as a carrier of drugs and genes. In the last 10 years, especially, poly(alkylene H-phosphonate)s and poly(alkylene phosphate)s are considered to be one of the most promising polymers for medicine and pharmacy. A number of papers were published devoted to the application of these polymers as carriers of drugs and genes.

The main goal of this book is to provide knowledge for the advantageous properties of polyphosphoesters. They are polyesters of the corresponding phosphorus acids. There are five types of organophosphorus acids; three of them are of the pentavalent phosphorus and two of the tervalent phosphorus atoms. In this book, their chemistry and application are discussed in detail.

In polyesters of phosphorous and phosphonous acids, the phosphorus atom is a tervalent:

With regard to synthetics, polyesters of the pentavalent phosphorus are most important.

Acknowledgment

I take a great pleasure in gratefully acknowledging Tokyo University of Science for providing the access to all literature references needed. The support of Action CM08902 of the European Cooperation in Science and Technology (COST) Framework Programme is also acknowledged. I am heartily thankful to my wife, Krassimira, who was very supportive in my efforts to write and complete the book.

About the Author

Kolio Dimov Troev was born in Rupkite, in the district of Chirpan, Bulgaria, 1944. He did his undergraduate work at the Higher Institute of Chemical Technology, Sofia, and received his doctorate in the field of organophosphorus chemistry in 1974 from the Institute of Organic Chemistry, Bulgarian Academy of Sciences, with Prof. Georgy Borissov. In 1985, he received the scientific degree Doctor of Science from the Institute of Polymers, where he worked. In 1988, he became Professor of Chemistry at the same Institute. Since 1989, he has been head of the laboratory Phosphorus-containing monomers and polymers, which he established in 1989. His research interests are in the areas of organophosphorus chemistry, especially esters of H-phosphonic acid; aminophosphonates; biodegradable, biocompatible phosphorus-containing polymers; polymer conjugates; and drug delivery systems. He has taught in the United States (Marquette University, Tulane University), Japan (Tokyo Institute of Technology, University of Tokyo, Tohoku University, Tokyo University of Science), and Germany (Düsseldorf University). He is an author of more than 125 papers in this field published in the Phosphorus, Sulfur, Silicon and Related Elements; Heteroatom Chemistry; Journal of American Chemical Society; European Polymer Journal; Polymer; Bioorganic & Medicinal Chemistry; Journal of Medicinal Chemistry; Macromolecular Rapid Communication; Polymer Degradation and Stability; Journal of Polymer Science, Part A: Polymer Chemistry; European Journal of Medicinal Chemistry; Amino Acids; and Tetrahedron Letters. In October 2006, Elsevier published his book Chemistry and Application of H-phosphonates. Since 2003, he has been director of the Institute of Polymers, Bulgarian Academy of Sciences.

He and his wife, Krassimira, have a daughter, who is a notary public in British Columbia, Canada, and a son, who is an economist.

TABLE OF CONTENTS

Cover Image

Title

Copyright

Preface

Acknowledgment

About the Author

1. Poly(alkylene H-phosphonate)s

1 Methods for Preparation

2 Characterization of Poly(alkylene H-phosphonate)s

3 Copolymers

4 Application

Appendix

2. Poly[alkylene (arylene) phosphate]s

1 Methods for Preparation

2 Hydrogels

3 Application

Appendix

3. Poly[alkylene(arylene) alkyl or arylphosphonate]s

1 Methods for Preparation

Appendix

4. Poly[alkylene(arylene) phosphite]s and Poly[alkylene(arylene) phosphonite]s

1 Methods for Preparation

Appendix

1

Poly(alkylene H-phosphonate)s

Poly(alkylene H-phosphonate)s are polyesters of the H-phosphonic acid.

They are one of the most interesting classes of polyphosphoesters because both the polymer backbone and phosphorus substituents can be modified.

The most important feature of poly(alkylene H-phosphonate) chemistry is the methods of synthesis that allow the main chain and the side group to be varied over a very broad range. Different main chain and side groups generate different properties such that the characteristics may vary from those of linear to cross-linked, from water soluble to hydrophobic polymers, and from bioinert to bioactive materials. In particular, these polymers might possess potential as a new class of degradable biomaterials whose properties can be modified to match a specific application. Polymeric materials have the potential to simulate the mechanical and chemical behavior of biological tissues better than metals or ceramics. Poly(alkylene H-phosphonate)s are particularly interesting due to the fact that the PH group in the repeating unit is highly reactive and permits a number of chemical transformations, proceeding in mild conditions with practically quantitative yield. Poly(alkylene H-phosphonate)s are a versatile starting material for preparation of various polymer derivatives. Oxidative chlorination of these polymers using chlorine, Atherton–Todd reaction conditions, copper dichloride, or trichloroacetic acid in carbon tetrachloride followed by reaction with alcohols and amines yields the corresponding polymeric phosphate esters or amides. Oxidation with N2O4 furnishes poly(hydroxyalkylene phosphate)s (Scheme 1.1). The interest in the chemistry and application of poly(alkylene H-phosphonate)s has dramatically increased over recent years because they show promise as new biodegradable, water-soluble, polymer–drug carriers.

Scheme 1.1 Chemical transformations of the PH group in the repeating unit of poly(alkylene H-phosphonate)s.

1 Methods for Preparation

A number of synthetic methods have been explored for the synthesis of these polymers, including ring-opening, bulk, and enzymatic polymerization. Bulk polycondensation is often used as a preferred method for large-scale production of poly(alkylene H-phosphonate)s. The advantages of the polycondensation method are the possibility of preparing polymers with different structure and composition, the short reaction time, minimal purification steps, and feasibility for scale-up. For laboratory purposes, poly(alkylene H-phosphonate)s can be obtained by other methods.

1.1 Polymerization of Cyclic H-phosphonates

The ring-opening polymerization of five- (phospholane) and six-membered (phosphorinane) cyclic H-phosphonates furnished high molecular poly(alkylene H-phosphonate)s.

1.1.1 Methods for Preparation of Cyclic H-phosphonates

One of the best methods for the preparation of cyclic H-phosphonates includes the synthesis of cyclic chlorophosphites, reacting phosphorus trichloride and diols, and their hydrolysis [1–8].

A general method for the synthesis of cyclic chlorophosphites starting from phosphorus trichloride and aliphatic glycols has been described by Lucas (see Appendix) [9], in which the corresponding 1,2- or 1,3-glycol is added to phosphorus trichloride, dissolved in methylene chloride. Hydrolysis of chlorophosphites is realized in dioxane. 4-Methyl-2-hydro-2-oxo-2-1,3,2-dioxaphospholane was obtained in two stages: (1) during the first stage, 1,2-propanediol reacts with PCl3, yielding 2-chloro-4-methyl-1,3,2-dioxaphospholane; (2) at the second stage, 2-chloro-4-methyl-1,3,2-dioxaphospholane was hydrolyzed to give 4-methyl-2-hydro-2-oxo-1,3,2-dioxaphospholane [9].

Hydrolysis was carried out in CH2Cl2 solution with a mixture of water and 1,4-dioxane. It was essential to use slightly less than the stoichiometric amount of water (1:0.8); otherwise, premature, undesirable polymerization will occur [10].

The molecular weight, determined cryometrically in dioxane solution, was about 980, which indicates the presence of a relatively short polymer chain consisting of 8–9 units. It was found that when this polymer is heated at low pressure, ring closure occurs, and the polymer reverts to the monomeric state.

4-(Acethoxymethyl)-2-chloro-1,3,2-dioxaphospholane 1 was prepared by cyclization of glycerol acetate with PCl3. Hydrolysis of 1 resulted in the formation of 4-acethoxymethyl-2-hydro-2-oxo-1,3,2-dioxaphospholane 2 [11]. Water used in excess caused a premature spontaneous polymerization of 2.

In the ³¹P{H} NMR spectrum of 2, the signal for the phosphorus atom appears at δ=23.8 ppm, but in the ¹H NMR spectrum there are two types of PH protons at δ=6.08 ppm with ¹ J(P,H)=730.0 Hz and at δ=6.06 ppm with ¹ J(P,H)=727.5 Hz. These two types of PH protons can be assigned to the cis and trans isomers. It is known that in the 2-oxo-1,3,2λ⁵-dioxaphospholanes, differences between ¹ J(P,H) in both diastereoisomers are small [10]. Usually, substitution in the ring causes an important decrease of differences between axial and equatorial ¹ J(P,H) [12].

2-Hydro-2-oxo-1,3,2-dioxaphosphorinanes or 4-methyl-2-hydro-2-oxo-1,3,2-dioxaphosphorinane were obtained following the same procedure, starting with 1,3-propanediol or 1,3-butanediol and PCl3. Hydrolysis was carried out in the presence of triethylamine [9].

The transesterification of H-phosphonate diesters with 1,2- and 1,3-glycols resulted in the formation of 1,3,2-dioxaphospholane,

or 1,3,2-dioxaphosphorinane, respectively, in 75–85% yield [13].

The reaction was carried out between 130°C and 140°C. When the liberation of alcohol ceased, the remaining crude product was fractionated at vacuum between 2 and 3 mmHg. This compound results from the nucleophilic attack of the end hydroxyl group of the monotransesterificated product at the phosphorus atom. The purified 2-hydro-2-oxo-1,3,2-dioxaphospholanes are liquids (Table 1.1), whereas 5,5-dimethyl-2-hydro-2-oxo-1,3,2-dioxaphosphorinane is a solid product (see Table 1.2).

Table 1.1. Properties of 2-Hydro-2-oxo-1,3,2-dioxaphospholanes

Table 1.2. Properties of 2-Hydro-2-oxo-1,3,2-dioxaphosphorinanes

It was found that the transesterification of dimethyl H-phosphonate with 1,2-propanediol yields 4-methyl-2-hydro-2-oxo-1,3,2-dioxaphospholane [14].

Obviously, the first stage of the reaction furnished methyl-2-hydroxypropyl H-phosphonate 1. Subsequent intramolecular transesterification of the methyl-2-hydroxypropyl phosphonate yielded 4-methyl-2-hydro-2-oxo-1,3,2-dioxaphospholane 2. The specific reactivity of these esters of H-phosphonic acid is determined by the presence of the β-hydroxyl group. The role of the β-hydroxyl group may be regarded as an intramolecular catalysis. The reactivity enhancement of β-hydroxyethyl esters of H-phosphonic acid may probably be explained through hydrogen bonding, which favors the intramolecular transesterification reaction. In the ³¹P{H} NMR (Figure 1.1) spectrum of 4-methyl-2-hydro-2-oxo-1,3,2-dioxaphospholane, measured immediately after distillation, there are only two signals at δ=23.92 and 23.10 ppm in ratio 1:1 [14]. After 6 h in the ³¹P{H} NMR spectrum, two new signals appear at 8.50 and 7.38 ppm. The ratio between the signals at 23.90–23.11 ppm is 1:1, and at 8.50–7.38 ppm is 1:1 too. The presence of the signals at 8.50 and 7.38 ppm in the ³¹P{H} NMR spectrum can be explained by the existence of two tautomeric forms: I and II of the 4-methyl-2-hydro-2-oxo-1,3,2-dioxaphospholane with PO and POH bonds. Ovchinnikov et al. [15] were the first to believe that a new type of tautomerization existed at the cyclic H-phosphonate, connected with the migration of a proton to the phosphorus atom. The chemical shift of the phosphorus nucleus in form I is at 23.90 ppm, and for form II is at 8.50 ppm.

Figure 1.1 The ³¹ P{H} NMR spectrum of 4-methyl-2-hydro-2-oxo-1,3,2-dioxaphospholane.

It is known that cyclic H-phosphonates may have the PH atom in cis or trans positions to the ring substituents [3].

The data from the ¹H and ³¹P{H} NMR spectra can be assigned as follows: the chemical shift of the phosphorus nucleus in the cis form of I was 23.11 ppm, and for the trans form of I was 23.90 ppm. The difference in δp is 0.79 ppm. The signals at 8.50 and 7.38 ppm can be assigned to the phosphorus nucleus of the cis form of II, and those at 8.50 ppm, for the phosphorus nucleus of the trans form of II.

In the ³¹P{H} NMR spectrum of 2-hydro-2-oxo-1,3,2-dioxaphospholane, there is only one signal at 24.75 ppm. The POH form is not observed. A mobile proton is not present in the ring.

Polymerization of 2-Hydro-2-oxo-1,3,2-dioxaphosphorinanes

Klosinski et al. are the first who studied the polymerization of the 2-hydro-2-oxo-1,3,2-dioxaphosphorinane 1, initiated anionically. The resulting polymer is poly(propylene H-phosphonate) 2 [16].

Anionic polymerization of 1 proceeds very easily, even at low temperatures (down to −80°C). Other polar solvents (DMSO, HMPA) can be used. The polymerization in bulk or in CH2Cl2 or THF is widely used. Poly(propylene H-phosphonate) 2 with molecular weight (M n, high-speed osmometry) in the range of 1.1×10⁴ to 10×10⁴ was obtained in 55–75% yield. The ¹H NMR spectrum of 2 consists of a doublet at δ=6.85 ppm with ¹ J(P,H)=705.0 Hz, which can be assigned to the PH proton; a multiplet at δ=4.01–4.50 ppm for POCH2 protons; and a quintet at δ=2.18 ppm for POCH2CH2 protons. The ³¹P{H} NMR revealed a signal at δ=8.8 ppm, which appears as a doublet of quintets in the ³¹P NMR spectrum. Researchers did not discuss the signal with low intensity at approximately 4.9 ppm, which can be assigned to the phosphorus atom in the end groups. In the ¹³C{H} NMR spectrum, there are one doublet at δ=59.6 ppm with ² J(P,C)=5.5 Hz and one triplet at δ=29.3 ppm with ³ J(P,C)=6.7 Hz, which can be assigned to the POCH2 and POCH2 CH2CH2OP carbon atoms, respectively.

Penczek et al. have chosen 4-methyl-2-hydro-2-oxo-1,3,2-dioxaphospholane [17a] for the model for the study of the stereochemistry of ring-opening polymerization [17b,c].

In the ³¹P{H} NMR spectrum of the reaction product, there are signals at δ=5.7, 6.5, 7.15, 7.45, 7.7, and 8.5 ppm. These data indicate that the ring-opening polymerization of 4-methyl-2-hydro-2-oxo-1,3,2-dioxaphospholane does not proceed specifically. These six lines correspond to six units in which phosphorus atoms are with different substituents and different configurations.

Based on ³¹P{H} NMR spectroscopy, polymerization proceeded with formation of all three kinds of dyads. Their proportions are as 1:2:1, with the highest proportion being the head-to-tail structures, formed in two different consecutive ring openings, namely α, α and β, β. The α, β ring opening leads to tail-to-tail structures, and β, α leads to head-to-head structures.

Polymerization of 4-acethoxymethyl-2-hydro-2-oxo-1,3,2-dioxaphospholane resulted in the formation of the following poly(alkylene H-phosphonate) [17b].

Polymerization of 4-acethoxymethyl-2-hydro-2-oxo-1,3,2-dioxaphospholane is the equilibrium process (70% polymer and 30% starting monomer).

Anionic polymerization of α (and β)-methyl-2-deoxy-D-ribofuranoside cyclic diethylphosphoramidite-bicyclic monomer initiated by t-BuOK resulted in poly(α and β)-methyl-2-deoxy-D-ribofuranose H-phosphonate) (Scheme 1.2) [18]. The starting bicyclic monomer was synthesized, reacting α (and β)-methyl-2-deoxy-D-ribofuranose with phosphorus hexaethyltriamide.

Scheme 1.2 Synthesis of poly[α (and β)-methyl-2-deoxy- D -ribofuranose H-phosphonate] 3 and the corresponding phosphate derivatives.

The product 1 was isolated via distillation. The product is very sensitive to moisture. Polymerization of 1 was performed in bulk at room temperature. The resulting polymer 2 was converted to the corresponding poly(alkylene H-phosphonate) bearing in the chain methyl-2-deoxy-D-ribofuranoside 3 via acetolysis. The structure of 3 was proved by NMR spectroscopy. The ¹H NMR spectrum shows signals at δ=4.75–5.45, multiplet that can be assigned for CH protons; δ=2.09–2.60 ppm for CH2 protons in the deoxyribose ring; δ=3.74–4.75 ppm for POCH2 protons; δ=3.30 ppm singlet for OCH3 protons; and at δ=6.96 ppm with ¹ J(P, H)=718.8 Hz for PH protons in the repeating units. The ³¹P{H} NMR spectrum of 3 shows one broad signal at δ=6.75 ppm with ¹ J(P, H)=718.8 Hz. The oxidation of 3 furnished the corresponding polyphosphate 4. After removing the blocking methoxy group and esterification, polyacid 5 was converted into polyester 6. The final molecular weight was found to be 4300.

1.2 Polytransesterification of Diesters of H-phosphonic Acid with Dihydroxy Aliphatic or Aromatic Compounds

Arbuzov and Vinogradova were the first to establish that dialkyl H-phosphonates can be prepared by a transesterification reaction between another dialkyl H-phosphonate and higher alcohol homologues [19, 20]. When transesterification is realized by diols, the resulting product is polymer. That is why commercially available and low-cost H-phosphonate diesters, alkyl or aryl, are used as starting compounds for the preparation of poly(alkylene H-phosphonate)s.

Polycondensation as a process for the preparation of poly(alkylene H-phosphonate)s has a big advantage compared to the polymerization process, namely:

1. Poly(alkylene H-phosphonate)s with different structure can be obtained; different hydroxyl-containing compounds can be used, from linear to cross-linked, from water-soluble to hydrophobic polymers, and from bioinert to bioactive materials.

2. The hydrophilic/hydrophobic balance can be controlled using hydrophilic and hydrophobic starting diols.

3. Polymers with different molecular weight can be synthesized, depending on the reaction conditions.

4. Polymers with narrow molecular distribution can be obtained.

5. Copolymers can be obtained.

6. Commercially available starting monomers are available.

1.2.1 Methods for Preparation of Diesters of H-phosphonic Acid

The diesters of H-phosphonic acid occupy a major position in organophosphorus chemistry because they are frequently intermediates in the synthesis of a variety of bioactive products, including aminophosphonate, aminophosphonic acids, bisphosphonates, PC phosphonates, hydroxyalkyl phosphonates, phosphates, amidophosphates, nucleoside H-phosphonates, poly(alkylene H-phosphonate)s and poly(alkylene phosphate)s, phosphorus-containing polyesters, polyurethanes (PUs), and so on. The strongy polar character of the phosphoryl group of the H-phosphonates is responsible to a great extent for the reactivity of this class of compounds. The versatility of these compounds is determined by the presence of two types of reaction centers in their molecule, the phosphorus atom and the α-carbon atom of the alkoxy groups, and of three functional groups—alkoxy, PH, and PO. This fact uniquely defines the chemical reactivity of dialkyl phosphonates and their usefulness in various synthetic applications. The diesters of H-phosphonic acid can be obtained by several synthetic procedures. This chapter outlines the most commonly used approaches in that respect.

Dialkyl H-phosphonates are produced on an industrial scale in the United States, Japan, Germany, and other countries, primarily from phosphorus trichloride and alcohols. The general procedure for the preparation of dialkyl H-phosphonates is given in the Appendix.

Addition of an alcohol to the phosphorus trichloride at about 0°C leads to rapid stepwise alkoxylation of phosphorus, followed by dealkylation of the trialkyl phosphite to dialkyl H-phosphonate [21, 22]. The initial procedures for this reaction, which include cooling of the reaction mixture, have been modified many times [22–26]. It has been established that the cooling step is not necessary for large alkoxy substituents with more than four carbon atoms in the chain [27]. It was shown that when some water is added to the reaction mixture together with the alcohol, the yield of dialkyl H-phosphonates increases significantly [28–31]. Another approach for synthesis of dialkyl H-phosphonates has been proposed that does not include cooling of the reaction mixture but uses a solvent instead [32]. Methods have also been developed for hydrogen chloride elimination from the reaction mixture [33, 34] by washing it with water. Mixed dialkyl H-phosphonates can be obtained when the above reaction is carried out with an equimolar mixture of two different alcohols [35]. Depending on the reaction conditions and the type of alcohol, the residue, obtained after distillation, ranges between 5% and 30% and consists mainly of a monoester of H-phosphonic acid and H-phosphonic acid. A new method for the preparation of diesters of H-phosphonic acid has been developed, according to which the residue is treated with phosphorus trichloride at 10–40°C, and the resulting product is treated with alcohol or alcohol and water at temperatures from –10°C to 80°C [36].

The synthesis of higher dialkyl H-phosphonate homologues usually includes the initial treatment of phosphorus trichloride with methyl alcohol, and then the transesterification of the so-formed dimethyl H-phosphonate with higher alcohols [37, 38].

Saks et al. pioneered the use of H-phosphonic acid for the preparation of dialkyl H-phosphonates [39]. There are a few patents devoted to the preparation of dialkyl H-phosphonates via direct esterification of H-phosphonic acid with alcohols [40–44].

The process consists of heating under reflux a mixture of H-phosphonic acid, an excess of an alcohol over that required stoichiometrically to form the dialkyl H-phosphonate, and a substantial proportion of an inert solvent, such as toluene. The water that forms during the esterification is removed continuously. An improved process for the preparation of dialkyl H-phosphonates by means of refluxing H-phosphonic acid with alcohols having at least four carbon atoms, in an excess of at least 45% over the stoichiometrical amount, under azeotropic separation of the reaction water, is described in the US Pat. [45] (see Appendix). In comparison to known processes, the dialkyl H-phosphonates are obtained according to the instant process, in higher yield and with higher purity. Mixtures of two different alcohols are also used in this process. It has been shown that the yield of dialkyl H-phosphonates increases when the synthesis is carried out in the presence of sulfonic acid [42] or trialkyl phosphates [46, 47].

Diphenyl H-phosphonate is obtained by treatment of H-phosphonic acid with a twofold excess of triphenyl phosphite [48–50].

Another approach employs treatment of H-phosphonic acid or its monoalkyl ester with a carboxylic acid anhydride and an alcohol at 20–50°C. Dimethyl H-phosphonate is obtained according to this procedure in quantitative yield based on phosphonic acid, acetic anhydride, and methyl alcohol [51].

Dialkyl H-phosphonates can be prepared by oxidation of white phosphorus, followed by treatment of the intermediate with alcohols [52].

This method is for laboratory-scale preparation of diesters of H-phosphonic acid.

1.2.2 Properties (Physical and Chemical) of the Diesters of H-phosphonic Acid

I decided to include in this chapter some physical and chemical properties of the diesters of H-phosphonic acid, such as acidity, thermal stability, disproportionation, and IR and NMR (¹H, ³¹P, ¹³C) data because they are directly connected with the synthesis and characterization of poly(alkylene H-phosphonate)s and are useful for the reader. Dialkyl H-phosphonates are liquids under normal conditions, soluble in alcohols, diethyl ether, acetone, chloroform, tetrahydrofurane, benzene, and other common organic solvents. Table 1.3 summarizes some characteristic physical constants: boiling point, refraction, dipole moment, and density for a number of diesters of H-phosphonic acid.

Table 1.3. Physical Constants of Some H-phosphonic Acid Diesters

aDipole moments taken from Ref. [58].

Thermal Stability

Under normal conditions, dialkyl phosphonates are stable compounds. At elevated temperatures (above 160°C), they begin to decompose. Dimethyl H-phosphonate is the most unstable homologue in that respect. At a temperature of 173°C, it pyrolyzes to monomethyl H-phosphonate and dimethyl methyl phosphonate [59, 60].

Moreover, the monomethyl ester of H-phosphonic acid undergoes further rearrangement, yielding monomethyl ester of the methyl phosphonic acid.

Another decomposition product observed in these studies [59, 60] is tetramethyl pyrophosphonate. Its formation is probably due to the condensation of two molecules of the monomethyl ester of methyl phosphonic acid.

Furthermore, the generated phosphonic acid further decomposes to phosphoric acid and phosphine.

The oxidation of the phosphine that is generated in the above reaction takes place as a radical chain process, and at a certain PH3/O2 ratio the mixture may ignite.

Methyl phosphonic acid is obtained in a high degree of purity and a theoretical yield of almost 100% by pyrolysis of dimethyl H-phosphonate in liquid phase [61– 63]. The condensation of the latter to pyromethyl phosphonic acid takes place at about 250–270°C.

These reactions occur rapidly on addition of dimethyl H-phosphonate to a reaction medium having a temperature of about 290–300°C. The reaction can be carried out rapidly and with good yield when high boiling heavy paraffin oil (such as Nujol) is employed.

Higher dialkyl H-phosphonate homologues, such as butyl and amyl, usually decompose at higher temperatures.

Reactivity of H-phosphonates

Acidity of H-phosphonate Diesters

H-phosphonate diesters are tautomeric systems in which the phosphite–phosphonate equilibrium is almost entirely shifted to the four coordinated phosphonate forms [64, 65].

This implies that these compounds have PH-type acidity and are therefore considerably less acidic than the corresponding POH-type acids. It was established by means of ³¹P NMR spectroscopy that in dimethoxy ethane, the acidity of dibutyl hydrogen phosphonate is close to that of ethanol, and that these PH acids are stronger than the corresponding N–H acids [66]. The pK a values of a series of H-phosphonate diesters have been calculated by the so-called premetallization method [67], according to the following equation:

where AR is an indicator-type CH acid.

These results are summarized in Table 1.4, together with some other calculated [68] and experimental [69] pK a values for phosphonic acid and its esters, as well as for phosphorus acid and its esters. The data in Table 1.4 provide a direct comparison of the strengths of the PH and POH types of acids and indicate the significant difference in their acidities. The substitution of one OH group in the molecule of both phosphonic and phosphorus acids with an ethoxy group leads to an increase in the acidity of the remaining OH groups.

Table 1.4. p K a Values of Phosphonic, Phosphorus Acids, and Some of Their Esters [67] a, [68] b, [69] c

apKa values determined by the premetallization method.

bpKa values determined by potentiometric titration.

cpKa values calculated from thermodynamic data for aqueous solution at 25°C.

The pKa value of 13.0 for diethyl phosphonate in Table 1.4 has been calculated from thermodynamic data, based on the following scheme [69]:

This calculated pKa value for diethyl phosphonate is 7.8 pKa units lower than that obtained by the premetallization method [67]. Both results, however, indicate that a diethyl phosphonate is a very weak acid, so the equilibrium outlined below is almost completely shifted toward the neutral phosphonate form:

Disproportionation

The disproportionation is characteristic for the asymmetric dialkyl H-phosphonates [70].

The process has been shown to be reversible [71, 72]. The equilibrium is established already at room temperature. This disproportionation reaction can be used as a method for the synthesis of optically active asymmetric or symmetric dialkyl phosphonates.

Hydrolysis

Hydrolysis of diesters of H-phosphonic acid is of fundamental importance because compounds containing the [P(O)(OH)2] group have myriad medicinal applications. However, H-phosphonic acid possesses poor biological transport properties. At physiological pH, the acid is strongly ionized—pK a (1) values are typically of the order 1–2 [68], which in turn inhibits passage of the compound through cell membranes. The process of H-phosphonate diesters hydrolysis can be illustrated as follows:

Two hydrolytic transformations are possible: (1) primary and (2) secondary hydrolyses. Hydrolysis of H-phosphonate diesters to H-phosphonate monoesters (primary hydrolysis) is found to occur much more readily under basic than acidic conditions. It has been established that hydrolysis of dialkyl H-phosphonates is generally base-catalyzed and generally acid-catalyzed [73]. By contrast, conversion of H-phosphonate monoesters to H-phosphonic acid (secondary hydrolysis) occurs more easily under acidic conditions [74]. The hydrolytic behavior of diesters of H-phosphonate acid in aqueous acidic and basic media has been studied previously. Hydrolysis of H-phosphonate diesters and phosphate esters are believed to proceed via pentacoordinated intermediates and transition structures that are formed by nucleophilic attack of the tetracoordinated phosphorus atom [75, 76]. These intermediates undergo further pseudorotation [77] and elimination of alcohol from the apical position to form the final products of the nucleophilic substitution. Thermodynamic calculations by Guthrie [78] of pKa values for phosphate esters in aqueous solution predict that water addition to these compounds more likely occurs via a concerted cyclic proton-transfer process to neutral adducts.

Mitchell et al. published an excellent paper devoted to hydrolysis of dimethyl H-phosphonate [79]. Using ³¹P NMR spectroscopy, they studied hydrolysis of dimethyl H-phosphonate with ¹⁸O-enriched water under base-catalyzed conditions (Scheme 1.3). They discussed the possibility of both [PO] and [CO] bond cleavage occurring during hydrolysis. Why? There are two reasons. First, hydrolysis represents a nucleophilic substitution at the phosphorus atom. The nucleophile attacks the electrophile center. In the molecule of the dialkyl esters of H-phosphonic acid, there are two electrophilic centers—the phosphorus and the α-carbon atoms. Second, acid-catalyzed hydrolysis of phosphate trimesters occurs with both [PO] and [CO] bond cleavage. Hydrolysis of dimethyl H-phosphonate in basic conditions is illustrated in Scheme 1.3. In [PO] bond cleavage (a), the nucleophile attacks the phosphorus atom, whereas in [CO] cleavage (b), the nucleophile attacks the α-carbon atom. The results from the ³¹P NMR studies of base-catalyzed hydrolysis revealed that only [PO] bond cleavage occurs.

Scheme 1.3 Hydrolysis of dimethyl H-phosphonate under basic conditions with (A) [PO] and (B) [CO] bond cleavage.

In acid-catalyzed hydrolysis (Scheme 1.4), ³¹P NMR studies support a process involving exclusive [PO] bond cleavage.