Phosphoric acid, C14-15-branched and linear alkyl esters, potassium salts

Hydrolysis

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

hydrolysis

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Reference 2

Endpoint:

hydrolysis

Type of information:

other: publication

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

abstract

Qualifier:

no guideline followed

GLP compliance:

no

Phosphate ester (Organophosphorus)

Organophosphorus or phosphate esters can be represented as R1OP(=O)(R2)(R3), where the oxygen of OR1 is bonded to a sp2 or sp3 carbon (R1). R2 and R3 represent additional leaving groups or substituents of the perturber structure. Depending on the local environment, these compounds hydrolyze via three distinct mechanisms: acid, base and neutral hydrolysis [1, 2].

Base Catalyzed Hydrolysis of Phosphate ester

The base-catalyzed (alkaline) hydrolysis of phosphate esters follows the same general mechanism as carboxylic acid ester base hydrolysis. BP2 stands for base-catalyzed, phosphoyl-oxygen fission, bimolecular reaction, and is similar to the SN2 reaction that occurs when a hydroxide ion attacks the carbonyl carbon of an ester to yield a carboxylic acid and an alcohol.

The hydroxide ion attacks the phosphorus atom in the rate-controlling step of the sequence. Formation of an intermediate addition product of hydroxide ion and the ester that is in equilibrium with the reactants and decomposes to give the products is excluded by the failure of the phosphorus group to exchange oxygen with the solvent prior to chemical hydrolysis. Therefore, the reaction cannot, proceed by an addition-elimination sequence analogous to that believed to represent the course of hydrolysis of carboxylic acid esters, but must consist either of a one-step process in which the leaving group is being expelled at the same time the substituent group is entering, or a two step process in which the intermediate decomposes so very rapidly that it cannot equilibrate with the solvent. Alkaline hydrolysis of phosphate esters also occurs through other mechanisms, such as: BP1 (base-catalyzed, phosphoryl-oxygen fission, unimolecular), BAL1 (base-catalyzed, alkyloxygen fission, unimolecular), and BAL2 (base-catalyzed, alkyl-oxygen fission, bimolecular). However, the BP2 mechanism usually dominates and these other mechanisms are masked.

Acid Catalyzed Hydrolysis

Acid-catalyzed hydrolysis of phosphoric acid esters can occur by direct nucleophilic attack at the phosphorus atom without the formation of a pentavalent intermediate. The reaction takes place via an AAC2 mechanism as shown in the following equation. AAC2 stands for acidcatalyzed, acyl-oxygen fission, bimolecular reaction. It is similar to the SN2 reaction, occurring when a positive hydrogen ion catalyzes the ester and a water molecule attacks the carbonyl carbon of the ester to produce a carboxylic acid and an alcohol. Acid-catalyzed hydrolysis of esters also takes place by other mechanisms such as phosphoryl-oxygen or alkyl-oxygen fission unimolecular and alkyl-oxygen fission bimolecular. However, AAC2 is the general mechanism for acid-catalyzed hydrolysis of esters and usually masks all other possible mechanisms.

General Base Catalyzed (Neutral) Hydrolysis

Neutral hydrolysis of phosphoric acid esters occurs by direct nucleophilic substitution of water at the carbon atom, causing C-O cleavage, , as is the case for trialkyl phosphates such as trimethyl phosphate. This reaction is analogous to the base catalyzed SN2 reaction; however neutral and base hydrolysis may not yield the same products. This difference in products is primarily because toward phosphorous, OH− is a better nucleophile than H2O by about a factor of 108 [3]. This usually causes the base catalyzed reaction to occur at the phosphorous atom with the hydroxide causing the best leaving group to dissociate (P-O cleavage). However, depending on the leaving groups present, the neutral (general base) reaction may occur where water acts as the nucleophilic substituent at the carbon atom (C-O cleavage). If a good leaving group is present, the reaction may proceed simultaneously by both neutral and base hydrolysis reaction mechanisms with C-O and P-O cleavage. Multiple researchers [4] have found higher temperatures cause the proportion of C-O to P-O cleavage to be greater; while at lower temperatures, P-O cleavage dominates. For example, at 70° C and pH = 5.9 parathion reacted 90% by C-O cleavage, while at a lower temperature, higher proportion of the neutral reaction occurred by P-O cleavage [5]. This observation is explained because the reaction involving CO cleavage requires a greater activation energy than that involving P-O cleavage [6].

Conclusion:

Taking into account the reaction mechanisms presented, hydrolysis of the test item based on the reaction mechanisms provided will finally result in inorganic phosphates and fatty alcohols. Taking into account the rationale for testing according to Chapter R.7b: Endpoint specific guidance to provide information on abiotic degradation that can help in classification, persistence testing and in determining the fate of a substance in environmental surface waters can be considered when assessing the environmental impact of the test item.

[1] Wolfe, N.L., Chemosphere, 1980. 9: 571 – 579.

[2] Murakami, Y.; Sunamoto, J., J. Chem. Soc. Perk. T 2, 1973. 9: 1235.

[3] Barnard, P.W.C.;Bunton, C.A.; Llewellyn, D.R.; Vernon, C.A.; Welch, V.A., J. Chem. Soc., 1961: 2670–2676.

[4] Heath, F.F., J. Chem. Soc., 1956: 3796.

[5] Weber, K., Water Res., 1976. 10: 237.

[6] Schwarzenbach, R.P.; Gschwend, P.M.; Imboden, D.M., Environmental Organic Chemistry. First ed. 1993, New York: John Wiley & Sons, Inc.

Reference 3

Endpoint:

hydrolysis

Type of information:

other: publication

Adequacy of study:

supporting study

Study period:

2014

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

abstract

Qualifier:

no guideline followed

GLP compliance:

no

Mono-ester Hydrolysis

Phosphate esters are of considerable interest as they are of great biological importance. Mono substituted phosphate esters are capable of losing two protons depending on the dissociation constant and pH; hydrolysis could involve the undissociated acid, monoanion, di-anion or a mixture of species. Generally phosphate mono-esters in strongly acidic media, one may expect the major reactive species to be the neutral acid. An acid catalysed hydrolysis may also be observed by the addition of a hydrogen-ion usually to the phosphoryl oxygen and may be more reactive than the neutral acid. At high pH, where the dominant species may be the di-anion and hydroxide ion attack would be made less favourable due to electrostatic repulsion.

An example of a simple but well studied phosphate mono-ester is methyl phosphate. Hydrolysis of methyl phosphate in acid is very slow - at pH 0 at 100 °C it shows an observed first-order rate constant (kobs) = 5.09 x 10^-6s^-1 which increases as the acid concentration increases suggesting an acid catalysed reaction of the neutral species. [27, 32]. Using isotopically labelled water (18O) in these acidic conditions shows both C-O and P-O bond fission occurs most likely through an associative mechanism. Isotopically labelled 18O showed that hydrolysis proceeds via P-O bond fission.[32]

Di-ester hydrolysis

Phosphate di-esters are generally very stable towards hydrolysis. The hydrolysis of di-methyl phosphate as a function of pH is significantly different to that of mono-methyl phosphate. Mono-methyl phosphate shows a hydrolysis rate maximum at pH 4.17 where the major reactive species is the mono-anion but the reactivity of the di-methyl mono-anion is low at pH’s where the mono-anion concentration also dominates. Decreasing the pH converts the mono-anionic species to the neutral species and in solutions which are not more acidic than pH 0 the only substrate involved in hydrolysis is the neutral species. Hydrolysis using

isotopically labelled water (18O) at pH 1.24 where the major reactive species is the neutral dimethyl phosphate as the substrate, the reaction proceeds mainly through C-O bond fission (78%) and a small amount via P-O bond fission in a concerted mechanism. The rate of hydrolysis of di-benzyl phosphate was investigated by Westheimer in 1954 who found that the di-ester anion at 75.6 °C and an ionic strength of 1.0 M has a very slow hydrolysis rate constant = 4.17 x 10^-8 ^s-1 and the neutral species = 3.17 x 10^-5s^-1. [37] The acid catalysed hydrolysis of di-methyl phosphate may involve protonation on either the phosphoryl oxygen or the methoxy oxygen with both C-O and P-O bond cleavage occurring by nucleophilic attack by a water molecule on the carbon or phosphorus atom of the conjugate acid. [36]

Dialkyl phosphates are not readily hydrolysed under basic conditions. Westheimer et al. investigated the hydrolysis of di-methyl phosphate in strongly basic conditions at high temperature. The major mechanism of base-catalysed hydrolysis involved C-O bond fission compared to P-O bond fission as shown by using isotopically labelled solvent. [38] Kirby in 1970 investigated the hydrolysis of a series of diaryl phosphate anions; for example diphenyl phosphate at 100 °C at pH 10 remained unchanged after 5 hours and the half-life of bis-p-nitrophenyl phosphate at pH 3-4 and at 100 °C is unchanged after more than 4 months. The hydrolysis of bis-2,4-dinitrophenyl phosphate, bis-4-nitrophenyl phosphate and bis-3-nitrophenyl phosphate was investigated over a wide pH range and it was found that between pH 2 and 6 the rate of hydrolysis of 2,4-dinitrophenyl phosphate is pH independent and at low and high pH there is an acid and base catalysed reaction of all three compounds. [39]

Hydrolysis of the P-O-P bond

Phosphate esters and condensed phosphates (phosphate anhydrides) which contain a P-O-P bond are also subject to hydrolysis. The pH of the solution greatly influences the hydrolytic rate of simple condensed phosphates such as pyrophosphate to give the

corresponding phosphate. The stability of the P-O-P bond of condensed phosphates at neutral pH and at room temperature is in the order of magnitude of years.[41] At higher temperatures e.g. 100 °C pyrophosphate hydrolyses in water to give two mole equivalents of phosphoric acid is near completion within a few hours.[42]

Unsymmetrical pyrophosphate di-esters are difficult to isolate probably because they are very unstable and hydrolyse rapidly in water. The hydrolysis of P1,P1-diethyl pyrophosphate is pH dependent and above pH 6 diethyl pyrophosphate exists as the di-anion and hydrolyses rapidly with a first-order rate constant = 1.15 x 10^-3s^-1, whereas the mono-anion below pH 6 hydrolyses more slowly with a first-order rate constant = 3.0 x 10^-5s^-1. [46] The mechanism of hydrolysis resembles that of phosphate mono-esters where a metaphosphate intermediate is formed.[28]

[27] C. A. Bunton, Journal of Chemical Education, 1968, 45, 21.

[28] J. Florián and A. Warshel, The Journal of Physical Chemistry B, 1998, 102, 719-734.

[32] C. A. Bunton, D. R. Llewellyn, K. G. Oldham and C. A. Vernon, Journal of the Chemical Society (Resumed), 1958, 3574-3587.

[36] C. A. Bunton and S. J. Farber, The Journal of Organic Chemistry, 1969, 34, 767-772.

[37] J. Kumamoto and F. H. Westheimer, Journal of the American Chemical Society, 1955, 77, 2515-2518.

[38] N. H. Williams and P. Wyman, Chemical Communications, 2001, 1268-1269.

[39] A. J. Kirby and M. Younas, Journal of the Chemical Society B: Physical Organic, 1970, 510-513.

[41] E. Karl-Kroupa, C. F. Callis and E. Seifter, Industrial & Engineering Chemistry, 1957, 49, 2061-2062.

[42] G. A. Abbott, Journal of the American Chemical Society, 1909, 31, 763-770.

[46] D. L. Miller and T. Ukena, Journal of the American Chemical Society, 1969, 91, 3050-3053.

Validity criteria fulfilled:

not applicable

Conclusions:

Abiotic hydrolitic cleavage is not a relevant degradative pathway for alkyl diphosphoric acid esters (pyroesters) and alkyl diesters of phosphoric acid at neutral to moderately high pH values under environmental conditions. At higher temperatures abiotic hydrolysis can be oberved for both substance groups.

Executive summary:

Abiotic hydrolitic cleavage is not a relevant degradative pathway for alkyl diphosphoric acid esters (pyroesters) and alkyl diesters of phosphoric acid at neutral to moderately high pH values under environmental conditions. At higher temperatures abiotic hydrolysis can be oberved for both substance groups.

Reference 4

Endpoint:

hydrolysis

Type of information:

other: publication

Adequacy of study:

supporting study

Study period:

2006

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

abstract

Qualifier:

no guideline followed

GLP compliance:

no

Radiolabelling:

no

Analytical monitoring:

yes

Details on sampling:

The progress of reaction was followed by monitoring the disappearance of starting material by proton NMR. The integrated intensities of the resonances of the reactants and products were compared with those of pyrazine, a known concentration of which had been added just before analysis as an integration standard. Each of these reactions yielded the alcohol and inorganic phosphate without significant accumulation of monoester.

Buffers:

The hydrolysis of phosphodiesters of methanol and neopentanol (0.01 M) was conducted in HCl (1–0.1 M), in 0.1 M buffers containing potassium formate, acetate, phosphate, borate, or carbonate, and in KOH (0.1–1 M). These buffers were chosen because the heats of ionization of the conjugate acids, like those of phosphoric acid esters, are 4 kcalmol, and their pH values are correspondingly insensitive to changing temperature.

Transformation products:

yes

No.:

#1

No.:

#2

Details on hydrolysis and appearance of transformation product(s):

Rate constants were obtained for Bis(2,2-dimethylpropyl) hydrogen phosphate (Np2P) (0.01 M) hydrolysis at 250°C in anion-forming buffers (0.1 M potassium formate, acetate, phosphate, borate, and carbonate) whose pH had been determined at 25°C and also in solutions containing HCl (0.1–1.0
M) and KOH (0.1–1.0 M). For Np2P, C–O cleavage by nucleophilic substitution is sterically precluded and cannot occur through elimination. Hence, only P–O cleavage occurs, as was demonstrated by mass spectrometric analysis of the products of hydrolysis in H218O. Very similar rate constants were obtained for hydrolysis over the range from pH 6.5 to 13. Extrapolation of those results indicates that, at 25°C, the apparent first-order rate constant is 7 x 10^-16 s^-1 for hydrolysis of the Np2P anion.In strongly alkaline solution, hydroxide ion catalysis became apparent at KOH concentrations > 0.1 M. The results of an Arrhenius plot of rate constants obtained in 1 M KOH were extrapolated to give k25 = 1.4 x 10^-15 s^-1 for this reaction.
). The rate of Np2P hydrolysis also increased at pH values < 6 ,consistent with water attack on uncharged Np2P. Solubility limitations precluded determination of rate constants for Np2P hydrolysis at low pH values where the ester is mostly protonated, except at high temperatures near 250°C. For that reason, the thermodynamics of activation could not be determined for the reaction of the neutral species.

Key result

Temp.:

25 °C

Hydrolysis rate constant:

0 s-1

DT50:

> 1 000 yr

Type:

(pseudo-)first order (= half-life)

Remarks on result:

hydrolytically stable based on preliminary test

Remarks:

pH = 6.5 - 13

The similarity between the extrapolated value of k25 = 7 x  10^-16 s^-1 for Np2P and the approximate upper limit

on the rate constant for P–O cleavage of dimethyl phosphate (1 x 10^-15 s^-1 at 25°C) that was indicated by earlier experiments on dimethyl phosphate uggests that P–O cleavage is not sterically impeded in Np2P. It seems reasonable to infer that the extrapolated rate constant of k25 =7 x 10^-16 s^-1, equivalent to a half-time of 31,000,000 years at 25°C, can be considered typical of apparent water attack on the phosphorus atom of simple dialkyl phosphate anions. Because the activation parameters for the hydroxide-catalyzed and spontaneous reactions are very similar, the form of the pH rate profile at high pH will not change at lower temperature.

Hydroxide attack at the diester anion appears to become a significant contributor to hydrolysis only at very high pH.

Validity criteria fulfilled:

not applicable

Conclusions:

Abiotic hydrolitic cleavage is not a relevant degradative pathway for alkyl diesters of phosphoric acid at neutral to moderately high pH values. Abiotic hydrolitic cleavage can be considered a relevant degradative pathway for alkyl diesters of phosphoric acid at low pH values < 6.5 and high temperature conditions (not relevant under environmental conditions).

Executive summary:

Abiotic hydrolitic cleavage is not a relevant degradative pathway for alkyl diesters of phosphoric acid at neutral to moderately high pH values. Abiotic hydrolitic cleavage can be considered a relevant degradative pathway for alkyl diesters of phosphoric acid at low pH values < 6.5 and high temperature conditions (not relevant under environmental conditions).

Reference 5

Endpoint:

hydrolysis

Type of information:

other: publication

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

abstract

Qualifier:

no guideline followed

GLP compliance:

no

Analytical monitoring:

not specified

Key result

pH:

7

Temp.:

298 K

Hydrolysis rate constant:

0 s-1

DT50:

1.22 yr

Remarks on result:

other:

Remarks:

Kn: 1.8Exp-8, Kb 1.3Exp-4, Kh: 1.8 Exp-8

Validity criteria fulfilled:

not applicable

Conclusions:

W. Mabey and T. Mill published a critical review of hydrolysis of organic compounds in water under environmental conditions. At 298 K and pH 7 the hydrolysis half-life of Trimethyl phosphate was determined to be 1.22 years. For Dimethyl phosphte the rate constant is 10-20fold higher and for monomethyl phosphate the rate constant is ca. 70fold higher. Based on the findings of Miller et al. abiotic hydrolysis is not considered a relevant degradation pathway for mono-, di- and triphosphroic acid esters at neutral pH.

Executive summary:

Miller et al. published a ritical Review of Hydrolysis of Organic Compounds in Water Under Environmental Conditions. At 298 K and pH 7 the hydrolysis half-life of Trimethyl phosphate was determined to be 1.22 years. For Dimethyl phosphte the rate constant is 10-20 fold higher and for monomethyl phosphate the rate constant is ca. 70 fold higher. Based on the findings of Miller et al. abiotic hydrolysis is not considered a relevant degradation pathway for mono-, di- and triphosphroc acid esters at neutral pH.

Description of key information

Abiotic hydrolyis based on known reaction mechanism of the test item results in easily degradable or inorganic components and is therefore considered of minor importance when assessing the environmental impact of the test item in the registered tonnage. Besides information on phosphoric acid esters available in literature indicate that abiotic hydrolysis is only a relevant degradation pathway at elevated temperature (> 50 °C) and not under environmental conditions. Long half-life periods at basic and neutral pH values for abiotic hydrolysis have been reported for phosphoric acid esters in literature. Abiotic hydrolyis is not considered a relevant pathway of test item removal from the environment (see attached summaries of selected literature on hydrolysis of phosphoric acid esters).