Investigation of the acidity constants and Hammett relations of some

A-9

Journal of Molecular Structure (Theochem) 538 (2001) 107±116

www.elsevier.nl/locate/theochem

Investigation of the acidity constants and Hammett relations of some oxazolo[4,5-b]pyridin derivatives using semiempirical AM1 quantum chemical calculation method È gÆretir*, E. Ac,Âõkkalp, T. GuÈray C. O Osmangazi University, Faculty of Arts and Sciences, Chemistry Department, 26040 Eskisehir, Turkey Received 23 June 2000; accepted 17 July 2000

Abstract The thermodynamic properties of some oxazolo[4,5-b]pyridin derivatives were calculated by semiempirical AM1 quantum chemical calculation method and any possible parallelism with the reported experimental data were searched. Some acceptable correlations between the calculated and experimental properties were detected. The theoretically calculated acidity constants were used to calculate the substituent effects and the obtained data were compared with the literature data. The observed con®dence levels of correlation were satisfactory. q 2001 Elsevier Science B.V. All rights reserved. Keywords: Oxazolopyridin; Acidity; Basicity; Proton af®nity; Semiempirical calculation; Hammett relation

1. Introduction

Hammett equation to Molecular Orbital Calculations.

The experimental determination of the acidity constants of those investigated oxazolo[4,5-b]pyridine derivatives were carried out by our group and the results were reported elsewhere [1] in which it was claimed that the ®rst protonation takes place on the nitrogen of the six-membered ring (i.e. pyridine ring) relying on ab inito calculations (Fig. 1). In the present work we extended our studies to discover the effect of substituent which is located at 2C of this molecule by applying the modi®ed Hammett equation (1) to these semiempirically calculated energies searching the applicability of the

pKa substituted molecule 2 pKa unsubstituted molecule s substituent ´rprotonation reaction

Since the addition of a substituent at any position of a molecule causes perturbation in energy of the system and bearing in mind that 1 pKa (thermodynamic) unit is equivalent to 1.34 kcal/mol in terms of energy it is possible to expect a correlation, as shown in Eq. (2), between experimentally obtained pKa values and the calculated energy changes, which taken as the proton af®nity of the systems in the protonation process. DG DH 2 TDS 2RTDln Ka

* Corresponding author. Tel.: 190-222-220433, ext. 350; fax: 190-222-239-35-78. È gÆretir). E-mail address: [email protected] (C. O

1

2

The semiempirical molecular orbital calculations were carried out in both gas e 1 and aqueous phase e 78:4 to obtain the related data.

0166-1280/01/$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. PII: S 0166-128 0(00)00653-9

108

È gÆretir et al. / Journal of Molecular Structure (Theochem) 538 (2001) 107±116 C. O

Therefore the proton af®nities can be calculated by using Eq. (4). dDHBH1 DHB 1 DHAH1 2 DHBH1 1 DHA 4 Fig. 1. Oxazolo[4,5-b]pyridine molecule. R H, C6H5, p-NH2 ± C6H4, p-OCH3 ±C6H4, p-OC2H5 ±C6H4, p-C2H5 ±C6H4, p-Cl±C6H4, p-C(CH3)3 ±C6H4, p-CH3 ±C6H4, p-Br±C6H4, p-NO2 ±C6H4.

The basicity of a given base B, is the standard free energy change for reaction (I).

2. Computational methods

dDGB DGBH1 1 DGA 2 DGB 1 DGAH1 5

Theoretical calculations were carried out at the restricted Hartree±Fock level (RHF) using AM1 [2] semiempirical SCF-MO methods in mopac 7.0 program [3] implemented on an Intel Pentium Pro 133 MHz computer, using a relative permittivity of 78.4 corresponding to water, with up to 60 surface segments per atom for the COSMO model [4] being used to construct a solvent accessible surface area based on van der Waals radii. All structures were optimized to a gradient norm of ,0.1 in the gas phase and 0.1±1.0 in the aqueous phase, using the eigenvector method following (EF). The absolute entropies of all structures were calculated from a complete vibrational analysis. Entropies were corrected to free energies using calculated entropies. Initial estimates of all the structures were obtained by a molecular mechanics program (CS Chem Of®ce Pro for Windows) [5], followed by full optimization of all geometrical variables (bond lengths, bond angles and dihedral angles), without any symmetry constraint, using the semiempirical AM1 quantum chemical methods in the mopac 7.0 program. 3. Result and discussion 3.1. Acidity and basicity The acidity of a given base can be calculated using Eq. (3) where DG is a standard free energy [6]

dDGBH1 DGB 1 DGAH1 2 DGBH1 1 DGA 3 The proton af®nity of given base B is de®ned as the heat of formation change for reaction (I). B : 1AH1 O BH1 1 A

I

A general scheme for the protonation of the studied oxazolo[4,5-b]pyridine derivatives were summarized in Scheme 1. Whatever the followed pattern is, eventually a common dication was reached at the end of the protonation process. To elucidate the protonation pattern for the studied compounds the electronic charges on the nitrogen atoms in both rings and proton af®nities had to be calculated. The calculated electronic charges, thermodynamic data and proton af®nities by AM1 method in the gas and liquid the phases were given in Tables 1±4, respectively. As it can be seen from Table 1 both in gas and liquid phases the nitrogen atoms in oxazole ring has bigger charges than that of the pyridine nitrogen. This situation led us to think that the ®rst protonation should take place at oxazole ring. This approach however neglects the other effects such as steric effects of the substituent which is located at 2C of the molecule. This effect however, is taken into account in the calculations of proton af®nities and the PA values were obtained for the formation of the monocation for the pyridine ring protonation (i.e. x ! a pattern) are bigger than that of the oxazole protonation (i.e. x ! b pattern) PA values (Table 4). Therefore we can claim that the ®rst protonation in oxazolo[4,5-b]pyridine derivatives takes place preferably at pyridine nitrogen as reported before [1] but with the exception of the molecule 3 in which there is an amino group as a substituent and this group is more available for the protonation than that of pyridine or oxazole ring nitrogen (i.e. PA for amino protonation was found to be around 15 in liquid phase and is larger than the others). For the second protonation (i.e. formation of the dication) however the PA values for the oxazole ring protonation (i.e. b ! c pattern) were found to


Scheme 1.

109


110

Table 1 The AM1 calculated electronic charges on the nitrogen atoms in gas and liquid phases Compound

1 2 3 4 5 6 7 8 9 10 11

R

H± C6H5 ± p-NH2 ±C6H4 ± p-OCH3 ±C6H4 ± p-OC2H5 ±C6H4 ± p-C2H5 ±C6H4 ± p-Cl±C6H4 ± p-C(CH3)3 ±C6H4 ± p-CH3 ±C6H4 ± p-Br±C6H4 ± p-NO2 ±C6H4 ±

Electronic charges Pyridine ring nitrogen

Oxazole ring nitrogen

Gas phase

Liquid phase

Gas phase

Liquid phase

20.0651 20.0698 20.0738 20.0713 20.0716 20.0707 20.0683 20.0707 20.0705 20.0676 20.0628

20.2079 20.2098 20.2116 20.2098 20.2099 20.2058 20.2050 20.2072 20.2107 20.2074 20.2007

20.1039 20.1100 20.1234 20.1160 20.1168 20.1124 20.1061 20.1124 20.1121 20.1034 20.0894

20.2802 20.2391 20.2586 20.2455 20.2490 20.2414 20.2325 20.2416 20.2415 20.2279 20.2143

be greater than that of pyridine protonation (i.e. a ! c pattern). These data also let us to conclude that the oxazole protonated species might rearrange as follows:

In this way the ring has retained, it's aromaticity and make the oxazole ring available for the protonation. So we can say that with the exception of molecule 3 we never get dication at all and PA values of

In this way the aromaticity is retained and the pyridine nitrogen becomes more available for protonation and presumably the calculated PA values belongs to pyridine ring protonation not to the oxazole ring. Similarly the protonated pyridine receives the electrons and rearranges as follows:

pyridine protonation are always bigger than that of oxazole ring. 3.2. Hammett relations Hammett equation is one of the earlier Linear Free


111

Table 2 The gas phase AM1 calculated thermodynamic data of the studies molecules e 1 R Compound DHf (kcal/mol) DS (cal/mol K) DGf (kcal/mol) a Mole fraction b KT H

DGf(WA) (kcal/mol) c DDG (kcal/mol) d

1 2a 2b

47.15 200.890 205.194

0.077 0.077 0.078

24.204 177.646 181.950

± 1.000 0.000

6.99 £ 10 24 ± ±

177.646 ± ±

158.638 ± ±

C6H5 ± 1 2a 2b

74.247 221.501 221.965

0.103 0.103 0.103

43.553 190.807 191.271

± 0.686 0.314

0.457 ± ±

190.953 ± ±

164.503 ± ±

p-NH2C6H4 ± 1 2a 2b 2c

71.344 212.681 210.701 232.518

0.109 0.108 0.109 0.114

38.362 180.497 178.219 198.546

± 0.021 0.979 0.000

2.134 £ 10 22 ± ± ±

178.249 ± ± ±

172.516 ± ± ±

p-CH3OC6H4 ± 1 35.771 2a 180.780 2b 180.349

0.116 0.115 0.116

1.203 146.212 145.781

± 0.326 0.674

2.071 ± ±

145.922 ± ±

167.185 ± ±

p-C2H5OC6H4 ± 1 29.966 2a 174.617 2b 173.953

0.125 0.124 0.125

27.284 137.665 136.703

± 0.165 0.835

5.077 ± ±

136.862 ± ±

167.757 ± ±

p-C2H5C6H4 ± 1 2a 2b

61.030 206.972 206.738

0.121 0.120 0.120

24.972 171.212 170.978

± 0.402 0.598

1.485 ± ±

171.072 ± ±

165.803 ± ±

p-ClC6H4 ± 1 2a 2b

67.567 216.332 217.232

0.110 0.110 0.110

34.787 183.552 184.452

± 0.821 0.179

0.219 ± ±

183.713 ± ±

162.977 ± ±

p-C(CH3)3C6H4 ± 1 55.556 2a 201.342 2b 200.981

0.130 0.130 0.130

16.816 162.367 162.240

± 0.352 0.648

1.840 ± ±

162.367 ± ±

166.352 ± ±

p-CH3C6H4 ± 1 2a 2b

66.386 212.565 212.490

0.113 0.114 0.114

32.712 178.593 178.518

± 0.468 0.532

1.135 ± ±

178.553 ± ±

166.062 ± ±

p-BrC6H4 ± 1 2a 2b

79.782 229.126 130.209

0.113 0.113 0.113

46.108 195.452 196.535

± 0.861 0.139

0.161 ± ±

195.603 ± ±

162.408 ± ±

p-NO2C6H4 ± 1 2a 2b

79.816 234.669 237.901

0.118 0.118 0.119

44.652 199.505 202.439

± 0.993 0.007

7.046 £ 10 23 ± ±

199.526 ± ±

157.030 ± ±

a b c d

DGf DHf 2 TDS: N1a 1=1 1 KT N1b KT =1 1 KT : DGfWA N1a DGf1a 1 N1b DGf1b 1 ¼ DDG DGB 1 DGH1 2 DGBH1 ; DHf H1 322:035 kcal=mol; DSH1 33:05 cal=mol K; DGf H1 311:903 kcal=mol:


112

Table 3 The liquid phase AM1 calculated thermodynamic data of the studies molecules e 78:4 R Compound DHf (kcal/mol) DS (cal/(mol K)) DGf (kcal/mol) a Mole fraction b KT H

DGf(WA) (kcal/mol) c DDG (kcal/mol) d

1 2a 2b

30.146 135.438 137.704

77.999 77.580 76.071

6.902 112.194 114.758

± 0.987 0.013

0.013 ± ±

112.227 ± ±

7.161 ± ±

C6H5 ± 1 2a 2b

59.700 164.138 168.914

104.017 105.662 102.020

28.708 132.550 138.518

± 1.000 0.000

4.19 £ 10 25 132.418 ± ± ± ±

8.776 ± ±

p-NH2C6H4 ± 1 2a 2b 2c

50.824 155.980 156.348 148.980

109.664 111.047 111.131 111.197

18.044 122.902 123.270 115.902

± 0.000 0.000 1.000

0.537 ± ± ±

p-CH3OC6H4 ± 1 18.793 2a 121.057 2b 126.030

117.031 117.657 117.945

216.073 85.893 90.866

± 1.000 0.000

p-C2H5OC6H4 ± 1 14.334 2a 117.021 2b 120.969

128.036 126.596 126.085

223.810 79.175 83.421

p-C2H5C6H4 ± 1 2a 2b

46.894 150.403 154.995

123.097 122.636 121.850

p-ClC6H4 ± 1 2a 2b

53.023 157.269 162.065

115.786 ± ± ±

14.744 ± ± ±

2.25 £ 10 24 ± ±

85.807 ± ±

9.949 ± ±

± 1.000 0.000

7.68 £ 10 24 ± ±

79.096 ± ±

9.580 ± ±

10.240 113.749 118.639

± 1.000 0.000

2.59 £ 10 24 113.635 ± ± ± ±

9.091 ± ±

110.501 111.144 111.444

19.945 124.191 128.987

± 1.000 0.000

7.94 £ 10 29 124.067 ± ± ± ±

8.364 ± ±

p-C(CH3)3C6H4 ± 1 41.003 2a 146.238 2b 149.693

130.161 131.504 129.095

2.263 106.902 111.251

± 1.000 0.000

6.45 £ 10 24 106.795 ± ± ± ±

7.954 ± ±

p-CH3C6H4 ± 1 2a 2b

51.725 156.420 160.768

113.083 113.075 112.306

18.051 122.746 127.392

± 1.000 0.000

3.91 £ 10 24 122.623 ± ± ± ±

7.914 ± ±

p-BrC6H4 ± 1 2a 2b

64.458 169.235 173.952

114.662 114.327 113.616

30.188 135.263 139.980

± 1.000 0.000

1.08 £ 10 28 135.128 ± ± ± ±

7.546 ± ±

p-NO2C6H4 ± 1 2a 2b

56.154 161.976 167.810

117.207 118.011 117.972

21.288 126.812 132.646

± 1.000 0.000

5.28 £ 10 25 126.685 ± ± ± ±

7.089 ± ±

a b c d

DGf DHf 2 TDS: N1a 1=1 1 KT N1b KT =1 1 KT : DGfWA N1a DGf1a 1 N1b DGf1b 1 ¼ DDGBH1 DGB 1 DGH3 O1 2 DGBH1 1 DGH2 O:

È gÆretir et al. / Journal of Molecular Structure (Theochem) 538 (2001) 107±116 C. O Table 4 The liquid and gas phase AM1 calculated proton af®nities (PA) (PAgas 367:2 1 DHf B 2 DHf BH1 ; PAliquid DHf B 1DHf H3 O1 2 DHf BH1 1 DHf H2 O) acidity constants pKa and experimental pKa (taken from Ref. [1]) values of the studied molecules PA (gas)

PA (liq.)

pKa (calc.)

pKa (exp.)

RH 1.83

2.419

27.57

Table 4 (continued) PA (gas)

PA (liq.)

1 ! 2b 2a ! 3c

209.115 118.420

0.929 23.154

2b ! 3c

121.652

2.689

2a 0 ! 3a

224.553

20.498

2b 0 ! 3b

214.678

10.323

pKa (calc.)

pKa (exp.)

22.717

29.08

1 ! 2a

213.460

7.493

1 ! 2b

209.156

5.227

2a ! 3c

107.446

3.872

1 ! 2a

219.946

8.347

6.434

1.88

2b ! 3c 2a 0 ! 3a

111.750 274.374

6.138 19.889

2b 0 ! 3b

1 ! 2b 2a ! 3c

219.482 128.254

4.171 20.174

20.541

27.44

216.377

9.237

2b ! 3c

128.718

4.602

R p-NH2 C6 H4 ± 1 ! 2c 206.026

5.246

113

15.029

10.809

4.85

2c ! 3a

169.836

8.001

6.327

0.48

2c ! 3b

156.832

2.488

3a ! 4c

252.723

2189.791

3b ! 4c

257.836

2176.787

3a 0 ! 4a

176.969

19.417

3b 0 ! 4b

169.568

9.516

222.549

10.980

1 ! 2b

223.213

6.150

2a ! 3c

137.335

20.185

2b ! 3c 2a 0 ! 3a

136.671 234.385

3.763 22.108

2b 0 ! 3b

223.563

13.671

2a 0 ! 3a

232.968

21.874

2b 0 ! 3b

217.461

10.185

R p-CH3 OC6 H4 ± 1 ! 2a 1 ! 2b

R p-C2 H5 OC6 H4 ± 1 ! 2a

R C6 H5 ±

7.024

3.03

20.763

24.18

221.191 219.482

10.521 4.171

7.294

3.97

2a ! 3c

135.905

21.083

20.987

24.06

2b ! 3c

135.474

4.890

2a 0 ! 3a

184.255

21.950

2b 0 ! 3b

223.095

8.615 6.665

2.65

20.466

25.16

5.831

2.38

0.037

25.38

5.532

2.19

21.485

24.60

R p-C2 H5 C6 H4 ± 1 ! 2a

221.258

9.276

1 ! 2b

221.492

4.684

2a ! 3c

132.109

20.375

2b ! 3c

131.875

4.217

2a 0 ! 3a

233.884

22.090

2b 0 ! 3b

225.482

13.163

R p-ClC6 H4 ± 1 ! 2a 218.435

8.539

1 ! 2b

217.232

3.743

2a ! 3c

128.296

21.069

2b ! 3c

129.196

3.727

2a 0 ! 3a

230.462

20.091

2a ! 3c

132.964

0.607

10.741

2b ! 3c

132.603

4.062

2a 0 ! 3a 2b 0 ! 3b

234.029 223.239.

21.995 13.120

0

2b ! 3b

218.759

6.132

2.49

22.958

25.33

R p-CCH3 3 C6 H4 ±

R p-CH3 C6 H4 ± 1 ! 2a

221.021

8.090

1 ! 2b

221.096

3.742

2a ! 3c

131.707

0.386

2b ! 3c

131.632

4.734

2a 0 ! 3a 2b 0 ! 3b

233.678 222.815

21.663 9.292

5.802

2.21

0.031

25.67

R p-NO2 C6 H4 ± 1 ! 2a

212.347

6.963

5.197

1.35

1 ! 2a

221.414

7.550

1 ! 2b

221.775

4.095

R p-BrC6 H4 ± 1 ! 2a

217.856

8.008

1 ! 2b

216.773

3.291

2a ! 3c

127.272

21.165

2b ! 3c 2a 0 ! 3a

128.355 228.499

3.552 19.945

2b 0 ! 3b

219.946

10.566

114


Fig. 2. The plot of the liquid phase AM1 calculated ®rst protonation constants, pKa (calc.), and experimentally obtained acidity constants, pKa (exp.), for oxazolo[4,5-b]pyrindin derivatives.

Fig. 3. The plot of the liquid phase AM1 calculated second protonation constants, pKa (calc.), and experimentally obtained acidity constants, pKa (exp.), for oxazolo[4,5-b]pyrindin derivatives.

Fig. 4. The plot of the gas phase AM1 calculated proton af®nities, PA, and experimentally obtained acidity contents pKa (exp.) for oxazolo[4,5b]pyridin derivatives.


115

Fig. 5. The plot of the liquid phase AM1 calculated proton af®nities, PA, and experimentally obtained acidity contents pKa (exp.) for oxazolo[4,5-b]pyridin derivatives. Table 5 The liquid phase (AM1) calculated s (calc.) and s (exp.) values of oxazolo[4,5-b]pyridin derivatives Compound

R

s (calc.)

s (exp.)

H± C6H5 ± p-NH2 ±C6H4 ± p-OCH3 ±C6H4 ± p-OC2H5 ±C6H4 ± p-C2H5 ±C6H4 ± p-Cl±C6H4 ± p-C(CH3)3 ±C6H4 ± p-CH3 ±C6H4 ± p-Br±C6H4 ± p-NO2 ±C6H4 ±

1 2 3 4 5 6 7 8 9 10 11

± 20.248 21.159 20.417 20.370 20.296 20.185 20.122 20.116 20.060 0.010

± 20.01 20.63 20.45 20.25 20.17 20.14 20.11 20.08 20.07 0.12

Energy Relationship Equation and can be applied to heterocyclic compound safely [7]. In this work we have attempted to test the validity of this equation in computational work. Firstly, we have tried to observe a parallelism between the experimentally obtained acidity constants (i.e. pKa values) and liquid phase AM1 computed pKa values. It seems that an acceptable correlation for the ®rst protonation with a correlation coef®cient of 0.8377 is present (Fig. 2). Whereas, for the second protonation we have obtained a scattogram (Fig. 3). Similarly acceptable correlation between the experimentally obtained PA values and pKa values in both gas and liquid phases are observed (i.e. R2 0:71188 and R2 0:8743; respectively)

Fig. 6. The plot of the liquid phase AM1 calculated substituent constants, s (calc.), and experimentally obtained substituent constants, s (exp.) for oxazolo[4,5-b]pyridin derivatives.

116


(Figs. 4 and 5). These correlations has been re¯ected in the application of Hammett Equation to calculate the substituent constants (i.e. s values show in Table 5, Fig. 6) with a con®dence level of R 2 0:8008: A slope of unity (i.e. 1.351) is indicative of a nice correlation also. 4. Conclusion It seems that AM1 semiempirical quantum chemical calculation method can safely be applied in the prediction of the acidity and substituent constants of the heterocyclic systems in both and gas phases.

References È gÆretir, H. Berber, N. KanõÂs,kan, Turkish J. Chem. 17 (1993) [1] C. O 33±34. [2] M.J.S. Dewar, et al., J. Am. Chem. Soc. 107 (1985) 3902±3909. [3] J.J.P. Stewart, MOPAC 7.0 QCPE, University of Indiana, Bloomington, IN., USA. [4] A. Klamt, G. SchuÈuÈrmann, J. Chem. Soc. Perkin Trans. 2 (1993) 799. [5] CS ChemOf®ce Pro for Microsoft Windows, Cambridge Scienti®c Computing Inc., 875 Massachusetts Avenue, Suite 61, Cambridge MA, 02139, USA. [6] M. Speranza, Adv. Heterocycl. Chem. 40 (1985) 25. [7] C.D. Johnson, The Hammett Equation, Cambridge University Press, Cambridge, 1973.