Aminoalkylphosphonic Acids Research Articles

Inducing differences in modification degree and binding mode of organophosphonic acid grafted titania by changing pH and hydrocarbon chain length

Organically modified metal oxide surfaces are of interest in many applications since they combine the advantages of metal oxide supports (structural properties, chemical and mechanical stability) and organic functionalities (for specific surface interactions). Although surface modification with organophosphonic acids (PAs) with an alkyl or aminoalkyl functional group on TiO2 has been investigated previously, knowledge of the synthesis-properties correlation (e.g. the binding mode of the PAs) is still lacking, especially for functional group-surface interactions. These are however important as they can influence functional group availability in applications such as (metal) sorption. In this work, the dependence of modification degree and phosphorus chemical environment on pH and chain length (C1 to C6) was investigated with TGA, ICP-OES, nitrogen/argon sorption, XPS, and solid-state 31P NMR and DFT calculations. The TGA and the ICP-OES results showed a clear impact of pH on surface modification degrees, with a different response for modification with alkyl- and aminoalkylphosphonic acids, featuring a more rapid decrease in modification degrees from pH 2 upwards for the alkylphosphonic acids compared to the aminoalkylphosphonic acids. Moreover, a clear correlation can be found between the aminoalkyl chain length and the NH2/NH3+ ratio. In addition, a positive correlation between the modification degree and the protonation degree of the amine group is observed for aminomethylphosphonic acid (AMPA) and 2-aminoethylphosphonic acid (2AEPA) modified samples, while this is absent for longer alkyl chains. This is supported by DFT calculations that indicate that the most stable binding modes of AMPA and 2AEPA grafted on the anatase (101) surface include hydrogen bonds between NH3+ and the surface oxygen atoms, in contrast, the most stable binding modes for 3-aminopropylphosphonic acid (3APPA), 4-aminobutylphosphonic acid (4ABPA), and 6-aminohexylphosphonic acid (6AHPA) grafted on the anatase (101) surface involve a Lewis acid-base interaction between NH2 and a surface Ti site.

Deamination of 1-Aminoalkylphosphonic Acids: Reaction Intermediates and Selectivity.

Deamination of 1-aminoalkylphosphonic acids in the reaction with HNO2 (generated "in situ" from NaNO2) yields a mixture of substitution products (1-hydroxyalkylphosphonic acids), elimination products (vinylphosphonic acid derivatives), rearrangement and substitution products (2-hydroxylkylphosphonic acids) as well as H3PO4. The variety of formed reaction products suggests that 1-phosphonoalkylium ions may be intermediates in such deamination reactions.

Synthesis and stability of 1-aminoalkylphosphonic acid quaternary ammonium salts.

An effective protocol for the quaternization of simple 1-aminoalkylphosphonic acids under basic conditions using Me2SO4 as a convenient alkylating agent is reported. During the course of the reaction, phosphonic acid quaternary ammonium derivatives, along with their corresponding monoesters are formed. Subsequent direct acidic hydrolysis of the crude reaction mixture leads to the desired novel N,N,N-trialkyl-N-(1-phosphonoalkyl)ammonium salts with overall yields of up to 88%. The developed protocol is general in scope and the products are purified by simple crystallization to give stable solids. Novel quaternary ammonium salts bearing a phosphonic group are generally unreactive in acidic and alkaline media. However, some of them undergo Hofmann elimination and substitution reactions in the presence of a base.

Synthetic Methods of Phosphonopeptides.

Phosphonopeptides are phosphorus analogues of peptides and have been widely applied as enzyme inhibitors and antigens to induce catalytic antibodies. Phosphonopeptides generally contain one aminoalkylphosphonic acid residue and include phosphonopeptides with C-terminal aminoalkylphosphonic acids and phosphonopeptides with a phosphonamidate bond. The phosphonamidate bond in the phosphonopeptides is generally formed via phosphonylation with phosphonochloridates, condensation with coupling reagents and enzymes, and phosphinylation followed by oxidation. Pseudo four-component condensation reaction of amides, aldehydes, alkyl dichlorophosphites, and amino/peptide esters is an alternative, convergent, and efficient strategy for synthesis of phosphonopeptides through simultaneous construction of aminoalkylphosphonic acids and formation of the phosphonamidate bond. This review focuses on the synthetic methods of phosphonopeptides containing a phosphonamidate bond.

Selective and clean synthesis of aminoalkyl-H-phosphinic acids from hypophosphorous acid by phospha-Mannich reaction.

Aminoalkyl-H-phosphinic acids, also called aminoalkylphosphonous acids, are investigated as biologically active analogues of carboxylic amino acids and/or as valuable intermediates for synthesis of other aminoalkylphosphorus acids. Their synthesis has been mostly accomplished by phospha-Mannich reaction of a P–H precursor, an aldehyde and an amine. The reaction is rarely clean and high-yielding. Here, reaction of H3PO2 with secondary amines and formaldehyde in wet AcOH led to aminomethyl-H-phosphinic acids in nearly quantitative yields and with almost no by-products. Surprisingly, the reaction outcome depended on the basicity of the amines. Amines with pKa > 7–8 gave the desired products. For less basic amines, reductive N-methylation coupled with oxidation of H3PO2 to H3PO3 became a relevant side reaction. Primary amines reacted less clearly and amino-bis(methyl-H-phosphinic acids) were obtained only for very basic amines. Reaction yields with higher aldehydes were lower. Unique carboxylic–phosphinic–phosphonic acids as well as poly(H-phosphinic acids) derived from polyamines were obtained. Synthetic usefulness of the aminoalkyl-H-phosphinic was illustrated in P–H bond oxidation and its addition to double bonds, and in selective amine deprotection. Compounds with an ethylene-diamine fragment, e.g. most common polyazamacrocycles, are not suitable substrates. The X-ray solid-state structures of seventeen aminoalkyl-phosphinic acids were determined. In the reaction mechanism, N-hydroxyalkyl species R2NCH2OH and [R2N(CH2OH)2]+, probably stabilized as acetate esters, are suggested as the reactive intermediates. This mechanism is an alternative one to the known phospha-Mannich reaction mechanisms. The conditions can be utilized in syntheses of various aminoalkylphosphorus compounds.

Reactivity of aminophosphonic acids. 2. Stability in solutions of acids and bases

The stability of the representative series of ω-aminoalkylphosphonic acids (ω-AAP: 2-AlaP and 3-AlaP), 1-aminoalkylphosphonic acids (AAP: GlyP; AlaP and PglP) and quaternary 1-aminoalkylphosphonic acids (AAP: MalP), 1-(N-alkylamino)alkylphosphonic acids (R-AAP: tBu-GlyP; tBu-AlaP; Me-HalP; Et-HalP and Et-MalP) and 1-(N,N-dialkylamino)alkylphosphonic acids (R2-AAP: Me2-GlyP and Me2-HalP) being exposed to acidic (2 M H2SO4) and/or basic (2 M KOH) solutions in the temperature range of 25-100 °C, was investigated.

Reactivity of aminophosphonic acids. 3. Reaction with hydrogen peroxide

The reactions of aminoalkylphosphonic acids with hydrogen peroxide in 2 M KOH and 2 M H2SO4 solutions were investigated. The formation of phosphate ion (Pi), as a result of the hydrogen peroxide-promoted cleavage of the Cα-P bond, was observed in a few cases. The dephosphonylation of aminoalkylphosphonic and 1-(N-alkylamino)alkylphosphonic acids were found to occur at a moderate rate in basic solution and was not observable in acidic solution. 1-(N,N-dialkylamino)-alkylphosphonic acids in alkaline solutions were oxidized into the corresponding N,N-dialkyl-N-oxide derivatives.

1-(N-Acylamino)alkylphosphonic acids—Deacylation in aqueous solutions

GRAPHICAL ABSTRACT

Penicillin G acylase-mediated kinetic resolution of racemic 1-(N-acylamino)alkylphosphonic and 1-(N-acylamino)alkylphosphinic acids and their esters

Extensive studies on the penicillin G acylase-mediated kinetic resolution of N-acylated 1-aminoalkylphosphonic and 1-aminoalkylphosphinic acids as well as their esters were carried out to recognise the relationships between the substrate structure, reaction conditions, and the enzymatic hydrolytic deacylation efficiency and stereoselectivity. Reactivity of 1-(N-acylamino)alkylphosphonic and 1-(N-acylamino)alkylphosphinic acids and their esters in the penicillin G acylase-mediated hydrolytic deacylation reaction depends strongly on the kind of their N-acyl group, with high preference to the hydrolytic splitting of the N-phenylacetyl moiety. The initial hydrolysis rates of 1-(N-phenylacetylamino)alkylphosphonic acid dimethyl esters 2 are mostly distinctly lower in comparison with the corresponding free acids 3 and rapidly decrease with the increasing steric effect of the substituent at the α-position. In contrary to the substituents at the α-carbon, bulky substituents at the phosphorus hinder the enzymatic hydrolysis to a much lesser degree. The penicillin G acylase-mediated stereospecific hydrolysis of N-acyl group of both racemic 1-(N-acylamino)alkylphosphonic acids 3 and their dimethyl esters 2 proved to be, in most cases, a highly effective method for the kinetic resolution of these compounds. High enzyme enantioselectivity E-values exceeding 100, or synthetically useful E-values exceeding 20 (in two cases) were obtained for the N-acylated phosphonic acid analogues of alanine, phenylalanine, valine, leucine, and asparagine, as well as for their dimethyl esters, with the exception of the dimethyl ester of phosphonic analogue of valine 2e, that E-value was low (E=1.2). Also for the N-acylated H-phosphinic acid analogues of alanine, as well as phenylphosphinic acid analogue of alanine, high enzyme enantioselectivity values exceeding 100 were obtained. In contrary, E-values for both diastereomers of ethyl ester of phenylphosphinic analogue of alanine 2k were low (E=7 and 13). For the all accomplished assignments penicillin G acylase exhibited stereochemical preference for the (R)-substrate.

Reactivity of aminophosphonic acids. Oxidative dephosphonylation of 1-aminoalkylphosphonic acids by aqueous halogens.

The reactions of 1-aminoalkylphosphonic acids with bromine-water, chlorine-water and iodine-water were investigated. The formation of phosphoric(v) acid, as a result of a halogen-promoted cleavage of the Cα-P bond, accompanied by nitrogen release, was observed. The dephosphonylation of 1-aminoalkylphosphonic acids was found to occur quantitatively. In the reactions of 1-aminoalkylphosphonic acids with other halogen-water reagents investigated by (31)P NMR, scission of the Cα-P bond was also observed, the reaction rates being comparable for bromine and chlorine, but much slower for iodine.

Convergent and Facile Synthesis of Hybrid Sulfonophosphonodipeptides

A convergent and facile method has been developed for the preparation of hybrid sulfonophosphonodipeptides composed of 2-aminoalkanesulfonic acid and 1-aminoalkylphosphonic acid residues. A series of hybrid sulfonophosphonodipeptides were synthesized in satisfactory yields via the Mannich-type reaction of 2-(Cbz-amino)alkanesulfonamides, aldehydes, and phosphorus trichloride, followed by sequential hydrolysis. The reaction mechanism was proposed and verified by NMR tracing experiments.

The nomenclature of 1-aminoalkylphosphonic acids and derivatives: evolution of the code system.

The approach for the unification of published proposals for the nomenclature and abbreviations of aminoalkylphosphonic acids and their derivatives is presented. Their modification was made on the basis of the IUPAC-IUB rules concerning the nomenclature and code system of proteinogenic amino acids. Our present proposal formulates the supplementary code and nomenclature system allowing unambiguous description of phosphonic analogs of proteinogenic amino acids, their analogs, homologs, metabolites, and derivatives including phosphonopeptides.

Catabolism and Detoxification of 1-Aminoalkylphosphonic Acids: N-Acetylation by the phnO Gene Product

In Escherichia coli uptake and catabolism of organophosphonates are governed by the phnCDEFGHIJKLMNOP operon. The phnO cistron is shown to encode aminoalkylphosphonate N-acetyltransferase, which utilizes acetylcoenzyme A as acetyl donor and aminomethylphosphonate, (S)- and (R)-1-aminoethylphosphonate, 2-aminoethyl- and 3-aminopropylphosphonate as acetyl acceptors. Aminomethylphosphonate, (S)-1-aminoethylphosphonate, 2-aminoethyl- and 3-aminopropylphosphonate are used as phosphate source by E. coli phn+ strains. 2-Aminoethyl- or 3-aminopropylphosphonate but not aminomethylphosphonate or (S)-1-aminoethylphosphonate is used as phosphate source by phnO strains. Neither phn+ nor phnO strains can use (R)-1-aminoethylphosphonate as phosphate source. Utilization of aminomethylphosphonate or (S)-1-aminoethylphosphonate requires the expression of phnO. In the absence of phnO-expression (S)-1-aminoethylphosphonate is bacteriocidal and rescue of phnO strains requires the simultaneous addition of d-alanine and phosphate. An intermediate of the carbon-phosphorus lyase pathway, 5′-phospho-α-d-ribosyl 1′-(2-N-acetamidoethylphosphonate), a substrate for carbon-phosphorus lyase, was found to accumulate in cultures of a phnP mutant strain. The data show that the physiological role of N-acetylation by phnO-specified aminoalkylphosphonate N-acetyltransferase is to detoxify (S)-1-aminoethylphosphonate, an analog of d-alanine, and to prepare (S)-1-aminoethylphosphonate and aminomethylphosphonate for utilization of the phosphorus-containing moiety.

Systematic Investigation of Zinc Aminoalkylphosphonates: Influence of the Alkyl Chain Lengths on the Structure Formation

With the high-throughput (HT) methodology, the bifunctional aminoalkylphosphonic acids (AAPA) linker molecules 2-aminoethyl- (AEPA), 3-aminopropyl- (APPA), and 4-aminobutylphosphonic acid (ABPA) [HO(3)P-C(n)H(2n)-NH(2) (n = 2-4)] and zinc nitrate were used to synthesize new metal phosphonates in order to investigate the influence of the alkyl chain length on the structure formation. The systematic investigations led to one known (ZnO(3)PC(2)H(4)NH(2)) and six new compounds: one using AEPA, three using APPA, and two using ABPA. The crystal structures of five compounds were determined by single crystal X-ray diffraction, using X-ray powder diffraction (XRPD) data as well as structure modeling employing force field methods. For compound 1, Zn(O(3)P-C(2)H(4)-NH(3))(NO(3))(H(2)O) (monoclinic, Cc, a = 4.799(1) Å, b = 29.342(6) Å, c = 5.631(1) Å, β = 91.59(3)°, V = 792.7(3) Å(3), Z = 4), and compound 2, Zn(2)(OH)(O(3)P-C(3)H(6)-NH(3))(NO(3)) (monoclinic, P2/c, a = 12.158(2) Å, b = 5.0315(10) Å, c = 13.952(3) Å, β = 113.23(3)°, V = 784.3(3) Å(3), Z = 2), the structures were determined using single crystal X-ray diffraction data. The crystal structures of [Zn(O(3)P-C(3)H(6)-NH(2))]·H(2)O (3) (monoclinic, P2(1)/c, a = 9.094(2) Å, b = 5.0118(7) Å, c = 16.067(4) Å, β = 90.38(2)°, V = 732.3(2) Å(3), Z = 4) and Zn(O(3)P-C(4)H(8)-NH(2)) (5) (monoclinic, P2(1)/c, a = 8.570(7) Å, b = 8.378(4) Å, c = 9.902(6) Å, β = 90.94(5)°, V = 710.9(8) Å(3), Z = 4) were determined using XRPD data. The structural model for compound 6, Zn(O(3)P-C(4)H(8)-NH(3))(NO(3))(H(2)O), was established using lattice parameters from XRPD data and following crystal structure modeling employing force field methods. The structures depend strongly on the alkyl chain length n. For n = 2 and 4 isoreticular compounds are observed, while n = 3 leads to new structures. Larger amounts of all compounds were obtained employing scale-up syntheses in a conventional oven as well as in a microwave reactor system. In addition, in situ energy dispersive X-ray diffraction (EDXRD) experiments at 130 °C were performed at beamline F3 at HASYLAB, DESY, Hamburg, to investigate the formation of compounds 2 and 3 as well as the phase transformation of 2 into 3 upon addition of NaOH. All compounds were characterized in detail using X-ray powder diffraction, IR/Raman spectroscopy, and thermogravimetric and elemental analysis.

ChemInform Abstract: Thioureidoalkylphosphonates in the Synthesis of 1‐Aminoalkylphosphonic Acids. The Ptc‐aminophosphonate Method

AbstractReview: 195 refs.

Thioureidoalkylphosphonates in the synthesis of 1-aminoalkylphosphonic acids. The Ptc-aminophosphonate method

Thioureidoalkylphosphonates in the synthesis of 1-aminoalkylphosphonic acids. The Ptc-aminophosphonate method

Tritylamine (triphenylmethylamine) in organic synthesis; III. The synthesis of 1-aminoalkylphosphonic acids in the reaction of N-(triphenylmethyl)alkanimines with phosphorus trichloride in acetic acid or with phosphonic acid in acetic anhydride.

Tritylamine (triphenylmethylamine) in organic synthesis; III. The synthesis of 1-aminoalkylphosphonic acids in the reaction of N-(triphenylmethyl)alkanimines with phosphorus trichloride in acetic acid or with phosphonic acid in acetic anhydride.

ChemInform Abstract: Methods of Synthesis of Organophosphorus Nitro Compounds and Aminoalkylphosphonic Acids.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Preparation of Optically Active 1-Aminoalkylphosphonic Acids by Stereoselective Enzymatic Hydrolysis of Racemic N-Acylated 1- Aminoalkylphosphonic Acids.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform Abstract: Preparation of N-Acylated Phosphonopeptides with Free Phosphonic Group.

Abstract Aminoalkylphosphonic acids on heating with hexamethyldisilazane yield tris(trimethylsilyl) derivatives, which are used as amino components for the synthesis of N-acylated phosphonopeptides with free phosphonic group. These transformations proceed with complete retention of the stereoconfiguration of aminophosphonate moiety.