Indian Journal of Chemistry Vol. 38B, August 1999, pp.953 - 958

Effects of mixed CH3CN-H20 solvents on the rate of intramolecular general base-catalysed aminolysis of ionized phenyl salicylate

Mohammad Niyaz Khan*, Zainudin Arifin, Mohammad Amin M Hanifiah, Mohammad Noh Lasidek & Alex George

Department of Chemistry, Universiti Malaya, 50603 Kaula Lumpur, Malaysia.

Received 21 March 1997; accepted (revised) 8 December 1998

Nucleophilic second-order rate constants, kn ms, for the reaction of n-butylamine, piperidine and pyrrolidine with ionized pheyl salicylate, PS-, show a nonlinear decrease with increase in the content of CH3CN in mixed aqueous solvents at :5 60% (V/V)CH3CN. The values of kn

lns remain almost unchanged with change in the content ofCH3CN at > 60 % (v/v) CH3CN. Effects of mixed CH3CN-H20 solvents on pKa of leaving group, phenol. and protonated amine nucleophile are concluded to be the major factors affecting kn ms values.

Exceptionally high catalytic efficiency of an enzyme may partly be attributed to its ability of converting an intermolecular reaction into an approximately intramolecular reaction. The enzyme-catalysed, membrane- and micellar-mediated reactions are believed to occur in a micro reaction environment where solvent polarity and water activity are significantly lower compared with pure water solvent. Although a huge amount of work has been carried out on the effect of solvents on neutral, acid- and base­cata lyzed solvolyses of various types of substrates, the effects of mixed aqueous-organic solvents on rates of aminolysis of esters and other related substrates appear to bcrare. 1 Only recently, the effects of CJ-l3CN-l-hO solvents on the rates of reactions of p-nitrophenyl acetate with morphoiine, piperazine, and piperidine have becn reported.2

Studies on the effects of mixed aqueous-organic solvents on the rates of inter- and intramolecular reactions might be considered of some importance in understanding the complexity of many biological and nonbiological reactions including micellar-mediated related reaction.3 The effects of mixed aqueous-organic solvents on intramolecular general base (IGB)­catalysed hydrolysis of ionized phenyl salicylate, PS-, and methyl salicylate have been studied by a few workers .4•

5

Recently, the effect of temperature, salt, and mixed CHJCN-H20 solvents on IGB-catalysed methanolysis of PS' have been reported.6 The present study was

initiated with an aim to discover the effects of mixed CH3CN-H20 solvents on the rates of reactions PS­with a few amines and on pKa of these amines. T he results and their probable explanation(s) are described in this paper. Materials and Methods Materials. Reagent grade n-butylamine, piperidine, and pyrrolidine were obtained from Flub and Aldrich. All other chemicals used were also of reagent grade commercial products. Distilled water was used throughout. The stock solutions of phenyl salicylate were prepared in acetonitrile. Kinetic measurements. Nonionized N-substituted salicylamide, salicylic acid, salicylate ion, phenol and phenolate ion do not absorb to a detectable extent at 350 nm.7 The molar absorption coefficient of PS ' is larger than those of ionized N-a lkyl and N,N-dialkyl substituted salicylamides by more than 4_fold.7

,8 Thus, the rates of aminolysis of PS- were eas ily studied spectrophotometrically by monitoring the disappea­rance of PS- as a function of time at 350 nm and

35°C. The details of the kinetic procedure and data analysis are described elsewhere.8

Determination of pKa in mixed CH3CN-H10 solvents. The ionization constants (KJ of the conjugate aeids of n-butylamine, piperidine and pyrrolidine were determined at 35 °C and in mixed Cl-I3CH-I-l20 solvents by potentiometric titration technique, The pH values of the solutions were determined using a Witeg model of W500 digital pI-!

954 INDIAN J. CHEM. SEC. B, AUGUST 1999

meter. The accuracy of pH measurements was 0.01 pH

± 1 digit. The pH values .-:f CH3CN-H20 solvent mixtures were correCted using the equation of Douheret9 (Eq. 1),

pH' = pH(R) - 8 ... (1) where pl-I* and pH(R) represent the corrected reading and pH-meter reading, respectively. The values of 8 at different contents of CH3CN in mixed aqueous solvents were determined by Douheret.9

The corrected pH values were used to calculate pK. from (Eq. 2), .

pK. = pH(R) - 8 + log{ [BH+]/[B]} ... (2)

where BW is the conjugate acid of base, B, and [ ] represents molar concentration. The calculated values of pKa for It-butylamine, piperidine, and pyrrolidine are summarized in Table I.

Table I - pK. values of amines at different concentrations of CHJCN in water.

CHJCN % (v/v) n-Butylamine-H+ Piperidine-W

2 10.74 11.37 to 10.82 11.32 20 10.71 11.24 30 10.66 11.17 40 10.59 11.07 50 10.47 10.98 60 10.39 10.99 70 10.80 11.36

Pyrrolidine-W

11 .58 11.59 11.57 11.49 11.40 11.34 11 .28 11.70

Product analysis: The detailed procedure as described elsewhere8 was used to confirm formation of N­substituted salicylamide, phenol and salicylic acid in the reactions of phenyl salicylate with It-butylamine, piperidine, and pyrrolidine in mixed CH3CN-H20 solvents containing 0.005 or 0.01 or 0.02 mol dm-3

NaOH .

Results

The effects of mixed CH3CN-H20 solvents on the rate of aminolysis of PS' were studied by carrying out several kinetic runs at different total amine concentrations, [Amh, in mixed aqueous solvents containing a constant concentration of CH3CN and NaOH. The temperature was kept constant at 35 °C. Pseudo first-order rate constants, Kobs, obeyed (Eq. 3),

k obs = ko + kn"lS [Amh ... (3)

where ko is the fU'st-order rate constant for hydrolysis of PS-. The rate constants, ko and kn

lllS, were calculated

from Eq. (3) using linear least squares technique. The values of ko and kn IllS as summarized in Table II were obtained at different contents of CH3CN in mixed

aqueous solvents for It-butylamine, piperidine and pyrrolidine. The fitting of observed data to Eq. (3) is evident from the standard deviations associated with ko and kn

nlS (Table II).

The values of ko calculated from Eq. (3) are not very reliable especially for the highly reactive amines such as piperidine and pyrrolidine. Perhaps the more reliable values of ko may be obtained from the kinet ic runs carried out under similar experimental conditions in the absence of amine. Such values of ko are available from literature at 30 °CID. These ko values were used to ca lculate ko at 35°C Cfable II) using Eyring equation. The values of kn ms were also calculated from Eq.(3) considering ko as the known parameter. These results are also summarized in Table II.

Discussion

The nonionized phenyl salicylate, PSH, does not absorb to a detectable level while PS- absorbs strongly at 350 nm? The values of initial absorbance (i.e. absorbance at reaction time, t = 0) of the reaction mixtures for the kinetic rllns carried out under the present experimental conditions were found to be unchanged with the change in contents of CI-hCH in mixed aqueous solvents . This shows the presence of 100 % ionized form, PS-, of phenyl salicylate.

Concentrations of the protonated amines were considered to be negligible under the experimental conditions of the present study. This conclusion is based on the fact that the increase in LNaOH] from 0.005 or 0.01 to 0.02 mol dm-3 did not appear to have any effect on kn IllS for piperidinolysis of PS- at 2 60% (v/v) Cl-hCN (Table II). However, simple calculation and observed kn IllS values at 0.005 and 0.02 mol dm,3 NaOH indicate the presence of nearly 6-10% proto­nated piperidine at 0.005 mol dm-3 NaOI-I and 2% (v/v) CH3CN. Since n-butylamine is a weaker base than piperidine, simple calculation reveals the presence of < 1 % protonated n-butylamine at 2% (v/v) CI-I3CN. The increase in the content of CI-I3CN decreases pKa of n-butylamine, piperidine and pyrrolidine until CH3CN content becomes 50 - 60% (v/v). The pK, values of these amines become equal or slightly larger than the corresponding pKa at 20% (v/v) CH3CN. The pKa of l-hO is expected to increase with increase in the content of CH3CN in mixed aqueous solvents. Thus, the presence of protonated amine is expected .10 decrease with increase in the content of CH3CN. Slightly lower value of kn

lllS at 0.02 mol dm-3 NaOH

KHAN et al.: BASE-CATALYSED AMINOLYSIS OF IONIZED PHENYL SALICYLATE 955

than at 0.005 mol dm-3 NaOH for piperidinolysis of ps- in mixed aqueous solvent containing 70% (v/v) CH3CN may be attributed to negative salt effectlJ.

The increase in the content of CI-hCN from 2 to 70% (v/v) in mixed aqueous solvents decreases kn ITlS by 9.0-, 7.4-, and 6.8- fold for n-butylamine, piperidine and pyrrolidine, respectively. The rate constants kn nl5,

turned out to be almost independent of CH3CN content at ~ 70% (v/v) CH3CN for all the three amines. In a recent related study on methanolysis of PS-, the increase in the content of CH3CN from 2 to 20% (v/v)

decreased the second-order rate constants, kMeOH, only by 1.16-fold while kMeOH increased by 1.30-fold with the increase in CH3CN content from 20 to 60% (V/V)6. The effect of mixed ethanol-water solvents on kn

lTlS for the reactions of primary and secondary amines with PS- revealed that the increase in ethanol content from 0 to 70% (v/v) decreased kn

lTlS by 15.9-, 11.0-.8.9-, 10.6-, and 6.2-fold for methylamine, ethylamine, n-propyl­amine, piperidine, and pyrrolidine12

, respectively. The reactions of primary and secondary a mines

with PS- involve intramolecular general base (1GB)

Table II - First- and second-order rate constants, ko and Kn ms, calculated from Eq. (3) for hydrolysis and aminolysis of PS·a

Amine CH)CN 104ko 103knms [Amh range No. of

(% , v.v) s -I dm3 mol-I S- I mol dm-3 runs

n-Butylamineb 2 8.45 ± 0.55c 70.5 ± I.1c 0.0015 - 0.10 9

(8.14)d) 70.3 ± 3.6

10 7.60 ± 0.76 51.2 ± 1.2 0.02 - 0.10 5

(6.43) 53.9 ± 2.4

20 5.00 ± 0.41 31.8 ± 0.6 0.D2 - 0.10 5

(5 .19) 31.4 ± 0.6

30 5.00 ± 0.36 21.1 ± 0.5 0.02 - 0.10 5

(4.39) 21.5 ± 1.1

50 3.39 ± 0.45 11.7 ± 0.7 0.02 - 0.10 5

(3.32) 11.9 ± 0.7

70 3.41 ± 0.09 7.83±0.14 0.01 - 0.10 6

(3.09) 8.80 ± 0.81

80 3.13 ± 0.09 7.80±0.15 0.01-0.10 6

(2.97) 8.38 ± 0.73

90 2.85 ± 0.23 8.15 ± 0.37 0.01-0.10 6

(2.83) 8.60 ± 1.54

Piperidine e 2b 7.60 ± 1.24 303 ±5 0.003 - 0.05 II

i 5.40 ± 0.65 341 ± 2 0.02 - 0.06 5

(8.14) 297± 5

(8.14) 333 ± 4f

10 6.58 ± 2.14 238± 5 0.02 - 0.06 5

IOf 3.56 ± 2.47 259± 6 0.02 - 0.06 5

(6.43) 239 ±4

(6.43) 251 ± 6f

20 7.82 ± 1.32 144±3 0.02 - 0.06 5 20f 5.32±2.ll 157 ± 5 0 .02 - 0.06 5

(5.19) 152 ± 3

(5 .19) 158 ± 3f

30 5.98 ± 1.36 95.5 ± 3.2 0.02 - 0.06 5

30f 5.34 ± 0.37 97.3 ± 0.9 0.02 - 0.06 5 (4.39) l00± 3

(4.39) 100 ± If

40 4 .84 ± 0.24 65.9 ± 0.6 0.02 - 0.06 5 40f 5.76 ± 0.33 63.5 ± 0.8 0.02 - 0.06 5

- COllln

956 INDIAN J. CHEM. SEC. B, AUGUST 1999

Table Il - First- and second-order rate constants, ko and Kn ms, calculated from Eg. (3) for hydrolysis and aminolysis of PS-a( - Con/d. )

Amine CH3CN 104ko (%, v.v) S-I

(3.73)

(3.73)

50 3.86

50f 4.06±O.34

(3.32)

60 3.10 ± 0.10

60f 4.02 ± 0.25

(3 .18)

(3 .18)

70b 3.60± 0.35

70f 3.04 ± 0.31

(3.09)

(3.09)

80b 3.92 ± 1.12

(2.97)

Pyrrolidinef 2 13.7 ± 5.0

(8.14)

10 5.06± 5.37

(6.43)

20 7.03 ± 1.07

(5.19)

30 4.25 ± 0.84

(4.39)

40 3.99 ± 2.31

(3.73)

50 4.58 ± 0.65

(3 .32)

60 4.40±0.71

(3 .18)

70 3.79 ± 0.54

(3.09)

80 5.01 ± 0.46

(2.97)

'Conditions: [Phenyl salicylatelo = 2 x 10-4 mol dm-3, 35°C, A = 350 nm.

b[NaOH] = 0.005 mol dm-3•

cError limits are standard deviations.

dparenthesized values are obtained from ref. 10 as described in the text.

·Unless otherwise noted [NaOHl = 0.01 mol dm-3•

f[NaOH] = 0.02 mol dm-3

103knms [Amh range No. of dm3 mor l S-I mol dm-3 runs

69.2 ± 2.0

69.3 ± 2.4f

52.8 ± 1.0 0.02·· 0.06 5

52.4 ± 0.8 0.02 .. 0.06 5

54.4 ± 1.0

46.4 ± 0.2 0.02 - 0.06 5

43.0± 0.6 0.02 - 0.06 5

46.2 ± 0.1

45.4 ± 1.0f

40.7 ± 0.9 0.006 - 0.06 6

37.6 ± 0.8 0.02 - 0.05 4

43.2 ± 2.0

37.5 ± 0.6f

37.2 ± 2.9 0.006 - 0.06 6

42.0±4.0

790 ±15 0.01 - 0.05 5

813 ±1.3

622 ± 16 0.01 - 0.05 5

619 ± 15

414± 3 0.01 - 0.05 5

422± 5

277± 3 0.01 ± 0.05 5

277± 3

198 ± 7 0.01 - 0.05 5

199 ± 5

151 ± 2 0.01 ± 0.05 5

157 ±4

129 ± 2 0.01 - 0.05 5

134 ± 4

177 ± 2 0.01 - 0.05 5

120± 2

116±1

126± 5

KHAN ef al. : BASE-CATALYSED AMlNOLYSIS OF IONIZED PHENYL SALICYLATE 957

catalysis through an intramolecular intimate ion-pair

intermediate (T) formation 13. Thus, the nucleophilic

reaction of a primary or a secondary amine with PS­

involves a neutral and an anionic charged molecule as

the reactants. According to the simple electrostatic theory, the rate of an elementary reaction involving a

neutral and a charged molecule as the reactants should increase with the decrease in dielectric constant of the

reaction mediuml4• The observed decrease kn ms with

increase in the content of CH3CN in mixed aqueous solvents indicates that the simple electrostatic theory

can not be applied in the present reaction system. The

reason for this behavior may be attributed to: (i) the location of the anionic charge in the reactant, PS-, which is far from the actual reaction site, and (ii) the

overall reaction probably involves more than one

elementary step. A reasonable mechanism for aminolysis of PS- in mixed aqueous-organic solvent

has been discussed elsewhere l2•

The pKa value of n-butylamine, piperidine, and

pyrrolidine decreased by nearly 0.3 - 0.4 pk units with increase in the content of CH3CN from 2 to 60% (v/v)

while pKa values for these amines increased by nearly

0.4 pK unit at 70% (v/v) CH3CN compared to those at 60% (v/v) CH3CN. The mixed aqueous-organic

solvents are expected to have little effect on the ionization constants of isoelectric ionization reactions (i.e. reaction of the type: BH+ H B + H+) if the

reactants, BH+, and products, B, are not highly

hydrophobic. The decrease in pKa of several protonated amines Aml-l+, with increase in the organic

content in mixed aqueous solvents has been reported12,15,16 while a large increase in pKa of AmJ-l+

is reported at > 90% CH3CN I7,18. These observations

indicate that the increase in CH3CN content from 2 to 60% (v/v) slightly decreases the nucleophilicity while

at ~ 70% (v/v) the nucleophilicity of an amine nucleophile is slightly increased [compared to that at 60% (v/v) CH3CN].

The ioniza tion of phenol is not an isoelectric

ionization reaction, and hence the pKa of phenol is expected to be affected significantly by an increase in C)-hCN content in mixed aqueous solvents. The study on the effects of mixed aqueous-methanol solvents on

pKa of phenol showed an increase in pKa from 9.99 to 14.36 with the increase in methanol content from 0 to 100% (w/w/,

The most probable factors which affect the kn ms_%

(v/v) CH3CN profLIes (el Table II) may be described as follows:

(i) The decrease in polarity due to increase in CH3CN content from 2 to 60% (v/v) in mixed aqueous solvent decreased the pKa of amines which in turn decrease the nucleophilicity of the amine nucleophiles. This effect is bound to decrease kn ms with increase in the content of CH3CN from 2 to 60%, v/v and to increase kn

ms at CH3CN content ~ 70% (v/v).

(ii) An expected significantly large decreasing effect of increasing CH3CN content on the pKa of phenol (phenolate ion is the leaving group in the aminolysis of PS-) is expected to decrease kn

ll1s values. The rate constants, k" [ = ko ms at 2% (v/v) CH3CN] for the reactions of several primary amines with PS' and ionized methyl salicylate revealed significant dependence upon pKa of the leaving groups8,20.

(iii) The nucleophilic reactant (amine, Am) molecules are solvated predominantly by water molecules at low CH3CN content. However, the solvation shell of Am molecule is expected to involve more CH3CN molecules at high CH3CN, content, Since the solvation energy of Am in water is presumably higher than in CH3CN, the increase in CH3CN content should increase kn ms.

(iv) The decrease kn ms with partial loss of the efficiency of 1GB catalysis due to ion-pair (IP) formation at significantly low dielectr ic constant of the mixed aqueous reaction medium containing a predominantly aprotic solvent (such as CH3CN) can not be completely ruled out.

o II

I -..;:::: ,+ (X

c, OAl

h N­Q'H/I

T

Acknowledgement

o II

~C-OAl

l(A- + O·Na

IP

We would like to thank the Universiti Malaya (F408/96) and IRPA (09-2-03-0003) for financial support.

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958 INDIAN J. CHEM. SEC. B, AUGUST 1999

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