Kinetics and mechanism of the nucleophilic ring opening of ... - NOPR

Indian Journal of Chemistry Vol. 46A, June 2007, pp. 916-922

Kinetics and mechanism of the nucleophilic ring opening of oxazolinone in mixed aqueous solvents Amel M Ismail Chemistry Department, Faculty of Science, Alexandria University, P.O.426 Ibrahimia, Alexandria 21321, Egypt Email: amelmostafa @yahoo.com Received 1 September 2006; revised 25 March 2007 Solvent effect on the kinetics of ring opening of oxazolinone has been investigated in neutral and alkaline medium in dioxan-water mixtures up to 50% v/v in the temperature range of 40-60°C. The thermodynamic activation parameters have been calculated and discussed in terms of solvation effect. The isokinetic temperature in both media (310, 303 and 298 K for neutral, alkaline hydrolysis by NaOH and Na2CO3 respectively) indicates that the reaction is entropy controlled and that solute-solvent interactions play an important role. The correlation of logk2 against either Grunwald-Wientien Y values or log[H2O] was found to be linear, while the correlation between logk2 and the reciprocal of the dielectric constant was nonlinear. The estimated value of the slope m in Grunwald relationship gives a value less than unity indicating SAN/SN2 mechanism. Mechanism for the oxazolinone ring opening has been proposed.

Oxazolinones are a noval class1 of antimicrobial agents that target a wide spectrum of gram positive and anaerobic bacteria2-4. These compounds by inhibiting protein synthesis and have no effect on replication or transcription. Oxazolinones are considered as activated internal esters of N-acyl amino acids and as such are susceptible to nucleophilic ring opening reactions. Ring opening5 of oxazolin-5(4H) ones by lipases yielding the esters have been selected as a model for biotransformation. Oxazolinones are also widely used for the preparation of a large number of organic compounds which posses a wide spectrum of biological activities6-8. These molecules are suitable for study by absorption spectroscopy because of their intense extinction coefficient in the visible region and the large difference in absorption maxima of the oxazolinones compared to the ring -opened products. The starting azlactones, 2-aryl-or (alkyl-) 4-arylmethylene-2oxazolin-5-one were prepared using Erlenmeyer azlactone synthesis9-11, give the thermodynamically stable Z isomer (Ib). H

X

H

O

N

O

C

O

C

X

O

N

Previously studies12 of the hydrolysis of unsaturated oxazolinones in either acidic or alkaline medium gives the corresponding 2-acylamino acrylic acid (II). H

(I)

H2O /H+

C C6H5

hydrolysis

(Ia) X=aryl or alkyl

C6H5

(Ib)

COOH NHCOC6H5

(II)

The effect of solvent on the hydrolysis rate of unsaturated oxazolinone (I) has not received enough attention. Thus, systematic kinetic studies on neutral and alkaline hydrolysis of oxazolinone have been carried out up to 50% v/v dioxan-water mixtures. These solvent mixtures provide a useful range of dielectric constant and medium effect properties. The hydrolysis of oxazolinone (I) is usually considered to be a typical case of ester hydrolysis. However, Olson and others12,13 have shown that the hydrolysis of ester in basic and strongly acid solutions results in the expected acyl-oxygen fission (see a below), while, in the neutral or slightly acidic solution, the only observable reaction is a pH independent hydrolysis, affording the splitting of alkyl-oxygen bond (see b below). H C

C6H5

C

C6H5

O a)

C

C

O

N C

b)

ISMAIL: KINETICS OF NUCLEOPHILIC RING OPENING OF OXAZOLINONE

Materials and Methods Oxazolinone was prepared as reported earlier14. Na2CO3 (BDH) and NaOH (BDH carbonate-free) were standardized against potassium hydrogen phathalate. The stock solution of NaOH (5×10-2mol dm-3) was kept in a waxed automatic micro burette. Dioxan (BDH, analar) was further purified as recommended15. The solvent-water binary mixture was prepared using doubly distilled water. The spectra of oxazolinone in dioxan and dioxanwater mixed solvents was recorded on a computerized Jasco V-350 UV-vis spectrophotometer. The λmax for the reactant and product were 364 and 282 nm respectively. The maximum observed at λmax 364 nm for the disappearance of reactant in all media indicates that the mixed solvent does not cause any shift in the position of this absorption band. Kinetic studies

The reaction of oxazolinone in neutral and in alkaline medium with both sodium hydroxide and sodium carbonate was followed spectrophotometrically at 40, 45, 50, 55 and 60ºC in dioxan-water mixtures (15-50% v/v) using Jasco PSC temperature control for all the studied reactions at λmax 364 nm. The two solutions (substrate and mixed solvent in the case of neutral, and substrate and mixed solvent with base in the case of alkaline medium) were separately allowed to attain the desired temperature (± 0.05°C) in a thermostated bath before being mixed. The two solutions were quickly and thoroughly mixed; the initial concentrations were 4×10-5and 8×10-5 mol dm-3 for oxazolinone and the base, respectively. Zero time was recorded and the rate was followed spectrophotometrically in 1 cm cell. The reaction was followed at λmax = 364 nm with the progress of time through the hypochromic shift.

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The second rate constants were calculated by leastsquares analysis of a plot of (a-b)-1 ln [b(a-x ) /a(b-x)] versus time, where a = initial concentration of oxazolinone, b = initial concentration of the base (NaOH or Na2CO3), and x is the concentration of the product. Extinction coefficients were obtained from Beer’s law plots. Reactions were followed up to 80% for 15, 20 and 30% v/v dioxan and 50% completion reaction for 40 and 50% v/v of dioxan. The rate constants for neutral were obeyed the first order rate equation by plotting log (At -A∞) versus time. Results and Discussion Nucleophilic ring opening reactions of oxazolinone have been studied in dioxan-water mixtures (15-50% v/v) of organic solvent component at the temperatures 40, 45, 50, 55 and 60ºC. The obtained results fit the pseudo first order rate equation for neutral medium, while second order rate equation is obeyed for basic hydrolysis. The pseudo-first order rate constant, kw, for the neutral and the second order rate constant, k2, for the alkaline medium are listed in Tables 1 and 2 respectively. The iso-composition activation energies, Ec, which are quoted at fixed volume % of organic solvent, was computed for each solvent composition from the linear least square-method and fitted to Arrhenius plots. From the linear Eyring plots of ln k/T versus 1/T, the activation parameters were evaluated for each solvent composition .The values of ΔH#, ΔS# and ΔG# with their standard deviations were calculated at 25ºC for each mole fraction of cosolvent using a computer program, (Tables 1 and 2). It is seen from these tables that the reaction rate decreases as the co-solvent increases. The decrease of the reaction rates with the progressive addition of organic solvent can be explained in terms of three factors; (a) the decrease in the water concentration,

Table 1 — First order rate constant (kw × 105 s−1) for the solvolysis of oxazolinone in neutral medium at different temperatures and thermodynamic parameters at 25ºC dioxan-water mixtures Temp. (ºC)

0.035

40 45 50 55 60

19.33 20.89 23.83 28.84 32.50

kw × 105 s−1 at xa2 0.050

20.1± 2.9 ΔH# (kJ mol−1) 252.7 ± 9.1 −Δ S# (J mol−1K−1) 95.3 ± 5.6 ΔG# (kJ mol−1) (a) Mole fraction of dioxan

0.083

0.124

10.80 11.61 12.60 13.89 14.16

6.16 7.41 8.16 8.71 9.33

3.00 3.47 4.16 4.68 5.33

10.6 ± 0.1 287.4± 0.2 96.3 ± 0.1

15.5 ± 3.4 276.1 ± 10.5 97.9 ± 6.5

22.5 ± 1.6 260.0 ± 5.0 100.0 ± 3.1

INDIAN J CHEM, SEC A, JUNE 2007

918

Table 2 — Second order rate constant k2 (l mol−1 s–1) for base catalyzed reaction of oxazolinone by Na2CO3 and NaOH at different temperatures and the corresponding thermodynamic parameters at 25ºC in dioxan-water mixtures Temp. (ºC) Na2CO3 40 45 50 55 60

0.033

k2 (L mol−1s−1) at xa2 0.050 0.083

0.124

0.177

---6.03 7.42 8.45 10.06

3.83 5.36 6.49 7.94 9.13

1.89 2.46 3.06 3.72 4.96

0.98 1.10 1.19 1.28 1.49

0.50 0.59 0.79 0.94 1.10

--5.01 6.17 6.92 8.67

3.38 4.88 5.93 6.46 7.94

1.22 1.64 2.19 2.86 3.55

0.63 0.72 0.79 0.84 0.97

0.22 0.27 0.37 0.41 0.51

26.9 ± 1.6 145.9 ± 5.0 70.4 ± 5.0

34.6 ± 3.1 123.2 ± 9.6 71.32 ± 5.9

38.2 ± 1.6 118.1 ± 4.8 73.38 ± 3

14.7 ± 1.4 198.6 ± 4.3 73.89 ± 2.7

33.0 ± 2.1 145.8 ± 6.5 76.5 ± 4.0

28.5 ± 2.7 142.3 ± 8.2 70.97± 5.1

32.2 ± 4.45 131.9 ± 13.8 71.5 ± 8.6

44.3 ± 1.1 102.2 ± 3.5 74.7 ± 2.2

15.2 ± 1.3 200.6 ± 4.0 74.99 ± 2.9

33.9 ± 1.5 149.8 ± 4.7 78.56 ± 2.9

NaOH 40 45 50 55 60 Na2CO3 ΔH# (kJ mol−1) −ΔS# (J mol−1K−1) ΔG# (kJ mol−1) NaOH ΔH# (kJ mol−1) −ΔS# (J mol−1K−1) ΔG# (kJ mol−1) a

Mole fraction of dioxan

(b) the decrease in the fraction of the free water molecules due to the fact that addition of co-solvent causes the water tetrahedral structure to be gradually broken down by interposition of organic solvent molecules, and hydrogen bonding between water molecules to be replaced by the stronger hydrogen bonding between water and organic solvent molecules, and, (c) the increase of hydroxide ion affinity of the medium by gradual addition of solvent due to the increase in its preferential solvation. Thus, the net result is the decrease of the hydrolysis rate in a given binary mixture.

Fig. 1 — Variation of log rate constant with water concentration at 45ºC. [1, Neutral; 2, NaOH; 3, Na2CO3].

The variation of the reaction rate constants with water concentration was investigated for each type of hydrolysis reaction at 45ºC. Plots of log k2 against log [H2O], were linear with slope ≈ 5 mol L-1 (Fig. 1), indicating that five water molecules are involved in the formation of the activated complex. The plot of log k against the reciprocal of the relative permittivity D-1 (Fig. 2) at 50ºC, interpolated from the data of Akrelof16 revealed a non-linear relationship. The electrostatic treatment of reaction rate, on the basis of point charge in a dielectric

Fig. 2 — Variation of log rate constant with 1/D at 50˚C. [1, Neutral; 2, NaOH; 3, Na2CO3].


continuum suggested that the plots of log k against D-1 should be linear17. The failure of the simple electrostatic interpretation, leads to the conclusion that the non-electrostatic part of solvent effect overcomes the electrostatic part17. In such cases, the differential solvation of the initial and transition states is the controlling factor for changes in the rate constant with the solvent composition. This is shown from the extension of the equation of Landskroaner17, which allows for the changes in solvent structure with varying solvent composition. Thus, deviation from linearity reflects the greater solvation of the activated complex motion of solvent molecules surrounding the

919

Fig. 3 — Variation of log rate constant with Grunwald Wienstien Y value at 45ºC in dioxan- water mixtures. [1, Neutral; 2, NaOH; 3, Na2CO3].

# H

H C

C

C6H5

C

N

O

2H2O / kw R.D.S

O

C

C C6H5

C

-δ N

O O

+δ

C

C

C6H5

C6H5

H

O H O

+δ H

H

-H3O+ fast # H

H C

C

C6H5

C

OH

N

H

C

C

C

O

H3O+

C6H5

C

-N

O C

O

OH

C6H5

C6H5

H

O C

C6H5

C

C OH

HN C C6H5

O

O

Scheme 1


920

activated species. This is quite in agreement with the negative ∆ S# values obtained. However, the rate of hydrolysis increases slowly as the water content of the solvent mixture increases, indicating that the rate is slightly accelerated by the solvent with higher ionizing power Y (ref. 18). This suggests that the bond formation in the transition state is of a relative importance and that the rate determining step is the bond formation step, as seen in the reaction of SN2 substrate. Plots of log k with the Grunwald-Winstien Y values, values interpolated from the published data19 are linear with small slopes m = 0.57 (r = 0.97), m = 0.67 (r = 0.99), m = 0.59 (r = 0.98) for neutral medium and for alkaline medium (NaOH and Na2CO3) respectively), (Fig. 3), implying that the reaction in the binary aqueous mixtures20 proceeds by addition-elimination SAN or associative SN2 channel SAN/SN2. ΔG#, ΔH# and ΔS# (Tables 1 and 2) ΔG# values show a small increase with increase in the mole fraction, giving a good indication of the compensation between ΔH# and ΔS#, while the non-linear variation of ΔS# is a criterion of specific solvation. Furthermore, the highly negative ΔS# value supports the formation of a highly restricted transition state. The strong electrostriction developed in the activated state restricts the freedom of motion of solvent molecules in the neighborhood of the activated species and causes loss of entropy. It is seen from

Table 2 that both ΔH# and ΔS# have maximum at x2 =0.083 and minimum at x2 = 0.122, which are similar to those reported previously in the same binary aqueous mixtures21. The observation of this extrema can be visualized in light of change of water structure22 in the presence of the organic solvent. This type of variation is associated with solvent shell reorganization of the substrate in the initial and transition states, which contributes appreciably to the overall activation enthalpy, and entropy of the reaction22. The plots of ΔH# versus ΔS# for each type of the hydrolysis reaction in several solvent composition at 25ºC, give straight line where the slope (β) = 310, 303 and 298 K for neutral medium and alkaline hydrolysis for NaOH and Na2CO3 respectively. These values represent the isokinetic temperatures, which indicate that the rate of the reaction is entropy controlled with the solute-solvent interaction playing an important role. Mechanism

In neutral medium, the mechanism consists of nucleophilic attack of water molecule, which is activated by other water molecules as a base on the azo group. This affords a highly rigid activated complex in the rate determining step which stabilizes by resonance with the substrate moiety, followed by fast azo-oxygon bond breaking, forming the acylamino acid (Scheme 1). #

H H C

C

C

R.D.S

O

N

C6H5

OH-

O

C

-δ C

C

O

−δ

C6H5

O

N

OH

C

k2

C6H5

C6H5

fast H

O C

C

#

C

H OH

C6H5

HN

O-

O C

ii)H3O +

C

C

i) v.fast C6H5

OH O

N C

C6H5 C6H5

Acylamino acid Scheme 2


Based on the above mechanism, the rate law for the solvolysis reaction may be given as: Rate = kw [H2O] 2 [substrate] Thus, the observed first order rate constant is expressed as: kw = kobs / [H2O]2 where kw is the solvolysis rate constant. In the basic medium the OH- ion attacks the carbonyl carbon of oxazolinone forming a charged tetrahedral activated complex in rate determining step followed by the fast step (acyl-oxygen bond fission), affording the final acylamino acid product (Scheme 2). The rate equation for alkaline hydrolysis fits with the following second order rate kinetics: ν =k2 [OH-] [substrate] For studying the salt effect of CO3-2 ion on the solvolysis and alkaline hydrolysis of the ring-opening of oxazolinone, a series of runs were made in the presence of different concentrations of sodium carbonate solution at 40ºC for 30% dioxan-water mixture. The kinetic data are collected in (Table 3).

The plot of the reaction constants versus sodium carbonate concentrations is linear (slope = 10.654×103 L2 mol-2 s-1; r = 0.987), showing an acceleration in the hydrolysis rate of oxazolinone on successive addition of sodium carbonate solution in the reaction medium. This may be attributed to the existence of carbonate ion in solution as a hydrated ion, where there is change in the shape of the O–H stretching band of water23. Moreover, sodium carbonate is a structure breaker for water and thus, more free water will be available in the presence of sodium carbonate, which may accelerate the reaction24 (Scheme 3). Therefore, in general the observed first order constant for the solvolysis reaction in the neutral Table 3 — Reaction rate constants kw (s−1) and k2 (L mol−1s−1) for the ring opening of oxazolinone in 30% dioxan-water at 40ºC in presence of different concentration of sodium carbonate [CO3−2] (mol dm−3)

kw (s−1)

k2 (L mol−1s−1)

0.0 8×10−5 1.6×10−4 3.2×10−4 4.8×10−4

0.616×10−4 1.512×10−4 2.842×10−4 6.104×10−4 8.872×10−4

1.22 1.89 2.853 4.949 6.104

# H

[CO3HOH]

-2

1+CO3 +H2O

C

C

C

O

C6H5 N

k(CO3--) R.D.S

O

HO-

C

HCO3-

C6H5

# H

C6H5

C

C

C

C

O

O-

H

O OH

HN

C

i) fast

921

C

C

C6H5

OH N

+

ii) H3O

O C

C6H5

C6H5

Scheme 3

+HCO3-

922


media is the sum of the rate constants for the two parallel simultaneous reactions: kobs = kw +k (CO3--) [CO3--] For the alkaline hydrolyses kobs is given by the following equation: kobs = k2 [OH-] +k (CO3--) [CO3--2] References 1 Hiroyuki A, Lizhu K, Susan M P, Toni J P, Elizabeth W A, Robert C G, Richard C T, Deam L S & Ganoza M C, Antimicrob Agents Chemother, 46 (2002) 1080. 2 BricknerJ S, Hutchinson M R, Barbuchyn M R, Manninen P R, Ulaniwicz A, Garmon S, Grega K, Hendges S, Toops D, Wford C & Zurenko G E, J Med Chem, 39 (1996) 673. 3 Daly J S, Eliopoulos G M, Willey S, Moellering C, Antimicrob Agents Chemother, 32 (1988) 1341. 4 Ford C W, Hamel J C, Wilson D M, Moerman J K, Stepert D, Yancey R J, Hutchinson D K, Barbachyn M R & Brickner S J, Antimicrob Agents Chemother, 40 (1996) 1508. 5 Nigel T A, Duncan J H G, Asutosh T Y, Jennifer A L & Vgeny N V, Protein Eng, 14 (2001) 269. 6 Bourotte M, Schmit M, Wund A F, Pigault C, Haiech J & Bourguignon J J, Tetrahedron Lett, 45 (2004) 6343.

7 Shukla J S & Fadagan M, Indian J Pharm Sci, 51 (1989) 5. 8 Ladva K, Dava V & Vtpal H, J Inst Chem (India), 62 (1992) 80. 9 Nicholes E S & Phelps D J, J Chem Eng, 25 (1980) 89. 10 Phelps D J, Godreau V P & Nicholes E S, J Chem Soc Perkins II, (1981) 140. 11 Soslac C & Phaneendrasai K, Tetrahedron Lett, 47 (2006) 5763. 12 Amin F M F, Arkivoc,VII (2006) 309. 13 Olson A R & Hyde, J Am Chem Soc, 60 (1941) 2687. 14 Kidwai M & Kumar R, Org Prep Proced Int, 30 (1998) 451. 15 Vogel A I, A Text Book of Practical Organic Chemistry, 5th Edn, (Longmans, London) 1989. 16 Akerlof G & Short O A, J Am Chem Soc, 58 (1963) 1241. 17 Reichardt G, Solvent Effects in Organic Chemistry, 3rd Edn, (Weinhein, New York) 2003 and references therein. 18 Grunwald E & S Winstein, J Amer Chem Soc, 70 (1948) 846. 19 Burgess J, J Chem Soc, Dalton, (1972) 487. 20 Koo I S, Yang K, Young S K, Lee C K & Lee I, Bull Korean Chem Soc, 21 (2000) 10. 21 Ismail A M, Harfoush A A & Abdel-Rahman H H, Egypt J Chem, 45 (2002) 105. 22 Casassas E, Fonrodona G & Juan A, Inorg Chim Acta, 187 (1991) 187. 23 Nickolov Zh S, Ozcan O & Miller J D, J Coll Surf, 224 (2003) 231. 24 Singh N B & Abha Km, J Am Ceramic Soc, 66 (1983) 308.