Acid-Promoted Hydrolysis of m-Cl-Phenyl Phosphorotriamidate leading to its Highly Basic Nature by Kinetic Means

Introduction

Organic phosphoramidate have been widely utilized for synthetic^1,2 work, especially for the synthesis of pyrophosphates. These compouds may also function as fireproof materials³ (e.g. phosphoric aniline diamide); as polymers ^4,5 and co-polymers (Aromatic araliphatic compounds based on Phosphoric acid and Thiphosphoric acid amides). The latter are then suitable for making films, membranes and fibers etc. Organic phosphoramidates even have the potential for their function as the harmful insecticides,⁶ while others may act as very useful drugs for the treatment⁷ of AIDS and Cancer etc.

Experimental

The m-Cl-Phenyl Phosphorotriamidate had been synthesized by refluxing for ca.8 hrs. with morpholine as catalyst. The ratio of reactants such as m-Cl-Aniline,POCl₃ and Morpholine was 3:1:3 in a dry benzene medium. A creamish-solid was obtained after total refluxing period and this solid after treatment with CHCl₃, H₂O and acetone, a white substance with yellowish tinge was formed, having a sharp m.p.251-253^oC. Its purity was checked with tlc, and the single sharp spot was observed as desired. It was confirmed as the m-Cl-phenyl phosphorotriamidate on the basis of quantitative P content estimation.

Kinetic study of acid-catalysed hydrolysis(98±0.5)^oC of m-Cl-Phenyl phosphorotriamidate was made using Allen’s modified method. During the kinetic study the optical density was measured with help of Systronics-118: UV-Vis. spectrophotometer. Concentration of the compound was maintained as 8.0×10^-4 M throughout the study, except for concentration effect study.

Results and Discussion

m-Cl-Phenyl Phosphorotriamidate, a C-N-P bearing ester, has been synthesised in this chemical laboratory and examined for its hydrolysis in 12%AcOH-H₂O medium, in the acid range 0.01 to 7.0 M-HCl, at 98(±0.5)^oC.The estimated second-order rate coefficients have been presented in Table I, showing their general trend, in the entire acid region examined. Allen’s modified method⁸ has been used to quantitatively determine the extent of hydrolysis on the basis of phosphorus liberated as H₃PO₄ component. At 4.0 M-HCl and onwards, the observed rate coefficients rise continuously till 7.0 M-HCl under the common set of reaction conditions. The acid-rate profile (not shown) showed that there is a plateau in the acid range, 0.3 M to 3.0 M-HCl. After this, the rates show a steep rise without involving any rate maximum in this higher zone of acid concentrations. This pattern of rates reflects the kinetic behaviour of strongly basic compounds, the amides^9,10 in this molecule as well.

In order to determine the presence as well as the contribution of the reactive forms, the Neutral electrolyte effect study¹¹ had been made keeping the ionic strengths (µ) as 1.0, 2.0 and 3.0, using suitable compositions of both LiCl and conc. HCl. In Fig.1, three linear curves are seen to be formed, with different slopes (K_H⁺) but making a common intercept (K_N) on the Y-axis. Using the II^nd empirical term¹² of Debye Hückel equation correlation(і) is used to calculate the total rates for the contributory reactive species :

figure 1  Click here to View figure

 

Table 1 Click here to View table

 

Thus,           k_e  k_N   k_H⁺.C_H⁺  ……(і)

Also,        k_N = k_No × e^bN^µ    ………..(іі)

Equation (іі) is simplified, as Fig.1 shows that the Neutral species (I) makes a fixed contribution, so that:

k_N = k_No =1.50×10^-1 M^-1min^-1     ………….(ііі)

Further :          k_H⁺.C_H⁺ = k_Ho⁺.C_H⁺.e^b_H⁺.µ    ………(іv)

where, k_H⁺, C_H⁺ and k_Ho⁺ represents the acid-catalysed rates via the Conjugate acid species(II), the concentration of the H⁺ -ions and the rates via the Conjugate acid species(II) at zero ionic strength only.

Logarithmically, equation (іv) is represented as :

log k_H⁺.C_H⁺ = log k_Ho⁺. log C_H⁺ +.b’ _H⁺.µ    …………(v)

It may be seen that the Neutral species (I) makes a constant contribution in the acid region, particularly between 0.01 to 3.0 M-HCl (Table I). The acid-catalysed rate (k_H⁺) at zero ionic strength (1+ log k_Ho⁺ =0.63) is obtained (Fig.not shown), while b’_H⁺ =0.00. Using all these parameters in equation (v), the rates via Conjugate acid species(II) were determined at each acid molarity separately. Table I includes this data, and it may be noticed that there is a similarity between the calculated and the observed rate coefficients via the Neutral form(I) in 0.1-3.0 M-HCl region only. Between 4.0 M to 7.0 M-HCl, both the Neutral and the Conjugate acid (II) species are both found to contribute toward the overall rates of hydrolysis. However, the differences between k_e observed and k_e calculated values are due to the exceptional basic character shown by the m-Cl-phenyl phosphorotriamidate under observation. This particular feature makes it significant for the kinetic study in particular.

In higher acid media(1.0 M-HCl and above) Hammett¹¹ plot(slope=0.53) failed to give any concrete result. Normal Bunnett correlations¹³ (Figs. not included) giving w = +3.0 and w* = 1.90 are not satisfactory (see later) in this case. Bunnett and Ölsen plot¹³ drawn between (logk_e +H_o) versus [(log C_H⁺ + H_o)] gives a slope, Φ, as + 0.68. This favours the role of water both as a nucleophilic as well as a proton –transferring agent. The latest correlation¹⁴ till date in strong acid media, the Yates and McClelland plot(based on modified-Hammett plot : m= +0.285 and–log aH₂O data) gives slope, r =3.03. Both ‘r’ and ‘w’ giving identical (3.0) values strongly favour the participation of minimum three water molecules during the hydrolysis.

A simple but specific correlation (rates versus acid molarities) suggested by Bunnett for highly basic compounds was drawn (Fig. not included) giving a new slope, w¢ = 4.69. This value suggests that water acts as a second reactant, in the rate-determining step of the present hydrolysis. The slope of the special Bunnett plot thus leads to the role of around four to five water molecules, during the hydrolytic reaction. This value strongly supports the recently identified minimum sized-but stable hexahydrated-proton species¹⁵, [H⁺(H₂O)₆] to bring about protonation, in spite of having a very short span of life.

The Arrhenius parameters (Table II) were determined from rate data determined at three different (98, 90 & 80^oC) temperatures at 0.1 M-HCl in 12%AcOH-H₂O medium. The well-known Arrhenius equation was thus used leading to the suitable Arrhenius parameters. The high energy of activation¹¹, E_a and the high collision factor (A) support respectively, a uni- and a bi-molecular route of hydrolysis in this case. The entropy of activation (∆S^≠) being a +ve quantity (Table II) also supports the unimolecular mode of hydrolysis. Both ∆H^≠ and ∆G^≠ have been observed to be higher and positive favouring hydrolysis of the triamidate at the boiling water temperature i.e.at 98(±0.5)^oC.

Table 2 Click here to View table

 

Effect of change of medium from 12% to 79% AcOH-H₂O medium at
2.0 M-HCl shows an increase in rates from 1.74×10^-1 M^-1 min^-1 to 10.27×10^-1M^-1 min^-1 favouring a transition state with charges created in it, possible only via the Neutral species(I) of the phosphorotriamidate under observation. The decrease of e of the medium with rise in AcOH % age favours protonation of the substrate i.e. the phosphorotriamidate itself.

Scheme 1  Click here to View scheme

 

Scheme 2 Click here to View scheme

 

Concentration effect study at 3.0 M-HCl favours second-order for acid hydrolysis. The second reactant, H₂O, being in much large excess, the study suggests the overall hydrolysis belongs to the pseudo-first order type, however. They also indicate the compound to undergo direct scission. This mainly applies to the Conjugate acid species (II) of the phosphorotriamidate mainly.

Scheme 3  Click here to View scheme

 

Parent amine effect study at 1.0 M-HCl in 12%AcOH-H₂O medium only slightly affects the rates of hydrolysis, so that during the progress of hydrolysis when it is being liberated its role as a nucleophile is also not very significant. The effect of other nucleophilic reagents(Cl’, Br’, etc.) at 4.0M-HCl (12% AcOH-H₂O) at 98^oC, gave the following order of reactivity:

Nucleophilic reagents:             I’      <   Cl’       <   F’     <   Br’       <   H₂Ö

10¹ke M^-1 min^-1 :   0.52   1.10   1.80   1.98   3.55

All the above nucleophilic reagents (0.1 M) result in a decrease in the rates of hydrolysis and the iodide ions show the least reactivity towards the phosphorotriamidate.

Scheme 4 Click here to View scheme

 

The nature of the P-N bond fission was confirmed by applying an azo-dye¹⁶ test. During the progress of acid hydrolysis, the parent amine being released gave  a +ve test suggestsing P-N bond fission to occur. Other comparative kinetic and thermodynamic data (not included) for related C-N-P members also supported P-N bond fission only. The progress of hydrolysis of the phosphorotriamidate is based on its highest rates shown in the form of comparative kinetic data of the total series as under :

Monoamidate                  Diamidate             Triamidate

Compounds                1(m-Cl-Ph-NH-)    2(m-Cl-Ph-NH-)      3(m-Cl-Ph-NH-)

10² M^-1 min^-1                       20.43                     27.78                      35.50

Medium      20% AcOH-H₂O   10%AcOH-H₂O    12%AcOH-H₂O

The above comparison at 4.0 M-HCl shows that the triamidate does not hydrolyse via the formation of either the Mono- or the Di-amidate of the corresponding type. The hydrolysis thus, involves simultaneous scission of all the three subsd.-aryl units of the phosphorotriamidate, under observation.

Conclusion

Kinetic study performed during hydrolysis shows that m-Cl-Phenyl phosphorotriamidate undergoes hydrolysis via two reactive forms, Neutral Species (Bimolecular) and Conjugate acid (Uni- and Bi- molecular) with P-N bond fission, as shown below :

Mechanism (1): S_N2(P) : Bimolecular hydrolysis of m-Cl- phenyl phosphorotriamidate via the Neutral Species(I) in the entire (0.01 – 7.0 M-HCl) acid region with P-N bond fission:

Mechanism(2) : S_N1(P) : Unimolecular mechanism of hydrolysis via the Conjugate acid Species (II) between 4.0-7.0 M-HCl

(a)  Formation of Conjugate acid Species(II) by a fast pre- equilibrium proton transfer step

(b)  Simultaneous cleavage of all the three protonated units in the AcOH-H₂O (12%) medium :

Mechanism (3): S_N2 (P) : Bimolecular hydrolysis via the Conjugate acid Species (II) between 4.0-7.0 M, HCl :

(a)’ Formation of Conjugate acid species(II) of m-Cl-Phenyl Phosphorotriamidate: Same as given in 2(a) earlier

(b) ‘

Acknowledgement

The author, Harish Kumar Amb is thankful to Dr. Shashi Prabha, Retd. Professor & former Head, School of Studies in Chemistry, Jiwaji University, Gwalior for both guidance and providing all facilities.

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