Investigation of the acidity constants and Hammett relations ofsome oxazolo[4,5-b]pyridin derivatives using semiempirical AM1

quantum chemical calculation method

C. OÈ gÆretir*, E. Ac,õÂkkalp, T. GuÈray

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

The experimental determination of the acidity

constants of those investigated oxazolo[4,5-b]pyri-

dine 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 calcu-

lated energies searching the applicability of the

Hammett equation to Molecular Orbital Calculations.

pKa �substituted molecule� 2 pKa �unsubstituted molecule�

� s�substituent�´r�protonation reaction� �1�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 (thermody-

namic) 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 proto-

nation process.

DG � DH 2 TDS � 2RTDln Ka �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.

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

0166-1280/01/$ - see front matter q 2001 Elsevier Science B.V. All rights reserved.

PII: S0166-1280(00)00653-9

www.elsevier.nl/locate/theochem

* Corresponding author. Tel.: 190-222-220433, ext. 350; fax:

190-222-239-35-78.

E-mail address: cogretir@ogu.edu.tr (C. OÈ gÆretir).

2. Computational methods

Theoretical calculations were carried out at the

restricted Hartree±Fock level (RHF) using AM1 [2]

semiempirical SCF-MO methods in mopac 7.0program [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]

dDG�BH1� � �DG�B� 1 DG�AH1��2 �DG�BH1� 1 DG�A���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�

Therefore the proton af®nities can be calculated by

using Eq. (4).

dDH�BH1� � �DH�B� 1 DH�AH1��2 �DH�BH1� 1 DH�A���4�

The basicity of a given base B, is the standard free

energy change for reaction (I).

dDG�B� � �DG�BH1� 1 DG�A��2 �DG�B� 1 DG�AH1���5�

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 proto-

nation 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 prefer-

ably 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 pyri-

dine or oxazole ring nitrogen (i.e. PA for amino proto-

nation 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

C. OÈ gÆretir et al. / Journal of Molecular Structure (Theochem) 538 (2001) 107±116108

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.

C.

O Èg Æretir

eta

l./

Jou

rna

lo

fM

olecu

lar

Stru

cture

(Theo

chem

)538

(2001)

107

±116

109

Scheme 1.

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 aromaticity is retained and the pyri-

dine 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 elec-

trons and rearranges as follows:

In this way the ring has retained, it's aromaticity

and make the oxazole ring available for the protona-

tion. So we can say that with the exception of mole-

cule 3 we never get dication at all and PA values of

pyridine protonation are always bigger than that of

oxazole ring.

3.2. Hammett relations

Hammett equation is one of the earlier Linear Free

C. OÈ gÆretir et al. / Journal of Molecular Structure (Theochem) 538 (2001) 107±116110

Table 1

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

Compound R Electronic charges

Pyridine ring nitrogen Oxazole ring nitrogen

Gas phase Liquid phase Gas phase Liquid phase

1 H± 20.0651 20.2079 20.1039 20.2802

2 C6H5± 20.0698 20.2098 20.1100 20.2391

3 p-NH2±C6H4± 20.0738 20.2116 20.1234 20.2586

4 p-OCH3±C6H4± 20.0713 20.2098 20.1160 20.2455

5 p-OC2H5±C6H4± 20.0716 20.2099 20.1168 20.2490

6 p-C2H5±C6H4± 20.0707 20.2058 20.1124 20.2414

7 p-Cl±C6H4± 20.0683 20.2050 20.1061 20.2325

8 p-C(CH3)3±C6H4± 20.0707 20.2072 20.1124 20.2416

9 p-CH3±C6H4± 20.0705 20.2107 20.1121 20.2415

10 p-Br±C6H4± 20.0676 20.2074 20.1034 20.2279

11 p-NO2±C6H4± 20.0628 20.2007 20.0894 20.2143

C. OÈ gÆretir et al. / Journal of Molecular Structure (Theochem) 538 (2001) 107±116 111

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

H1 47.15 0.077 24.204 ± 6.99 £ 1024 177.646 158.6382a 200.890 0.077 177.646 1.000 ± ± ±2b 205.194 0.078 181.950 0.000 ± ± ±

C6H5±1 74.247 0.103 43.553 ± 0.457 190.953 164.5032a 221.501 0.103 190.807 0.686 ± ± ±2b 221.965 0.103 191.271 0.314 ± ± ±

p-NH2C6H4±1 71.344 0.109 38.362 ± 2.134 £ 1022 178.249 172.5162a 212.681 0.108 180.497 0.021 ± ± ±2b 210.701 0.109 178.219 0.979 ± ± ±2c 232.518 0.114 198.546 0.000 ± ± ±

p-CH3OC6H4±1 35.771 0.116 1.203 ± 2.071 145.922 167.1852a 180.780 0.115 146.212 0.326 ± ± ±2b 180.349 0.116 145.781 0.674 ± ± ±

p-C2H5OC6H4±1 29.966 0.125 27.284 ± 5.077 136.862 167.7572a 174.617 0.124 137.665 0.165 ± ± ±2b 173.953 0.125 136.703 0.835 ± ± ±

p-C2H5C6H4±1 61.030 0.121 24.972 ± 1.485 171.072 165.8032a 206.972 0.120 171.212 0.402 ± ± ±2b 206.738 0.120 170.978 0.598 ± ± ±

p-ClC6H4±1 67.567 0.110 34.787 ± 0.219 183.713 162.9772a 216.332 0.110 183.552 0.821 ± ± ±2b 217.232 0.110 184.452 0.179 ± ± ±

p-C(CH3)3C6H4±1 55.556 0.130 16.816 ± 1.840 162.367 166.3522a 201.342 0.130 162.367 0.352 ± ± ±2b 200.981 0.130 162.240 0.648 ± ± ±

p-CH3C6H4±1 66.386 0.113 32.712 ± 1.135 178.553 166.0622a 212.565 0.114 178.593 0.468 ± ± ±2b 212.490 0.114 178.518 0.532 ± ± ±

p-BrC6H4±1 79.782 0.113 46.108 ± 0.161 195.603 162.4082a 229.126 0.113 195.452 0.861 ± ± ±2b 130.209 0.113 196.535 0.139 ± ± ±

p-NO2C6H4±1 79.816 0.118 44.652 ± 7.046 £ 1023 199.526 157.0302a 234.669 0.118 199.505 0.993 ± ± ±2b 237.901 0.119 202.439 0.007 ± ± ±

a DGf � DHf 2 TDS:b N1a � 1=�1 1 KT� N1b � KT=�1 1 KT�:c DGf�WA� � �N1a��DGf�1a��1 �N1b��DGf�1b��1 ¼d DDG � �DG�B�1 DG�H1��2 DG�BH1�; DHf�H1� � 322:035 kcal=mol; DS�H1� � 33:05 cal=�mol K�; DGf �H1� � 311:903 kcal=mol:

C. OÈ gÆretir et al. / Journal of Molecular Structure (Theochem) 538 (2001) 107±116112

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

H1 30.146 77.999 6.902 ± 0.013 112.227 7.1612a 135.438 77.580 112.194 0.987 ± ± ±2b 137.704 76.071 114.758 0.013 ± ± ±

C6H5±1 59.700 104.017 28.708 ± 4.19 £ 1025 132.418 8.7762a 164.138 105.662 132.550 1.000 ± ± ±2b 168.914 102.020 138.518 0.000 ± ± ±

p-NH2C6H4±1 50.824 109.664 18.044 ± 0.537 115.786 14.7442a 155.980 111.047 122.902 0.000 ± ± ±2b 156.348 111.131 123.270 0.000 ± ± ±2c 148.980 111.197 115.902 1.000 ± ± ±

p-CH3OC6H4±1 18.793 117.031 216.073 ± 2.25 £ 1024 85.807 9.9492a 121.057 117.657 85.893 1.000 ± ± ±2b 126.030 117.945 90.866 0.000 ± ± ±

p-C2H5OC6H4±1 14.334 128.036 223.810 ± 7.68 £ 1024 79.096 9.5802a 117.021 126.596 79.175 1.000 ± ± ±2b 120.969 126.085 83.421 0.000 ± ± ±

p-C2H5C6H4±1 46.894 123.097 10.240 ± 2.59 £ 1024 113.635 9.0912a 150.403 122.636 113.749 1.000 ± ± ±2b 154.995 121.850 118.639 0.000 ± ± ±

p-ClC6H4±1 53.023 110.501 19.945 ± 7.94 £ 1029 124.067 8.3642a 157.269 111.144 124.191 1.000 ± ± ±2b 162.065 111.444 128.987 0.000 ± ± ±

p-C(CH3)3C6H4±1 41.003 130.161 2.263 ± 6.45 £ 1024 106.795 7.9542a 146.238 131.504 106.902 1.000 ± ± ±2b 149.693 129.095 111.251 0.000 ± ± ±

p-CH3C6H4±1 51.725 113.083 18.051 ± 3.91 £ 1024 122.623 7.9142a 156.420 113.075 122.746 1.000 ± ± ±2b 160.768 112.306 127.392 0.000 ± ± ±

p-BrC6H4±1 64.458 114.662 30.188 ± 1.08 £ 1028 135.128 7.5462a 169.235 114.327 135.263 1.000 ± ± ±2b 173.952 113.616 139.980 0.000 ± ± ±

p-NO2C6H4±1 56.154 117.207 21.288 ± 5.28 £ 1025 126.685 7.0892a 161.976 118.011 126.812 1.000 ± ± ±2b 167.810 117.972 132.646 0.000 ± ± ±

a DGf � DHf 2 TDS:b N1a � 1=�1 1 KT� N1b � KT=�1 1 KT�:c DGf�WA� � �N1a��DGf�1a��1 �N1b��DGf�1b��1 ¼d DDG�BH1� � �DG�B�1 DG�H3O1��2 �DG�BH1�1 DG�H2O��:

C. OÈ gÆretir et al. / Journal of Molecular Structure (Theochem) 538 (2001) 107±116 113

Table 4

The liquid and gas phase AM1 calculated proton af®nities (PA)

(PA�gas� � �367:2 1 DHf�B��2 DHf �BH1�; PA�liquid� � �DHf �B�1DHf �H3O1��2 �DHf �BH1�1 DHf �H2O��) acidity constants pKa

and experimental pKa (taken from Ref. [1]) values of the studied

molecules

PA (gas) PA (liq.) pKa (calc.) pKa (exp.)

R � H

1! 2a 213.460 7.493 5.246 1.83

1! 2b 209.156 5.227

2a! 3c 107.446 3.872 2.419 27.57

2b! 3c 111.750 6.138

2a 0 ! 3a 274.374 19.889

2b 0 ! 3b 216.377 9.237

R � p-NH2C6H4±

1! 2c 206.026 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

R � p-C2H5OC6H4±

1! 2a 222.549 10.980 7.024 3.03

1! 2b 223.213 6.150

2a! 3c 137.335 20.185 20.763 24.18

2b! 3c 136.671 3.763

2a 0 ! 3a 234.385 22.108

2b 0 ! 3b 223.563 13.671

R � p-ClC6H4±

1! 2a 218.435 8.539 6.132 2.49

1! 2b 217.232 3.743

2a! 3c 128.296 21.069 22.958 25.33

2b! 3c 129.196 3.727

2a 0 ! 3a 230.462 20.091

2b 0 ! 3b 218.759 10.741

R � p-CH3C6H4±

1! 2a 221.021 8.090 5.802 2.21

1! 2b 221.096 3.742

2a! 3c 131.707 0.386 0.031 25.67

2b! 3c 131.632 4.734

2a 0 ! 3a 233.678 21.663

2b 0 ! 3b 222.815 9.292

R � p-NO2C6H4±

1! 2a 212.347 6.963 5.197 1.35

Table 4 (continued)

PA (gas) PA (liq.) pKa (calc.) pKa (exp.)

1! 2b 209.115 0.929

2a! 3c 118.420 23.154 22.717 29.08

2b! 3c 121.652 2.689

2a 0 ! 3a 224.553 20.498

2b 0 ! 3b 214.678 10.323

R � C6H5±

1! 2a 219.946 8.347 6.434 1.88

1! 2b 219.482 4.171

2a! 3c 128.254 20.174 20.541 27.44

2b! 3c 128.718 4.602

2a 0 ! 3a 232.968 21.874

2b 0 ! 3b 217.461 10.185

R � p-CH3OC6H4±

1! 2a 221.191 10.521 7.294 3.97

1! 2b 219.482 4.171

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

R � p-C2H5C6H4±

1! 2a 221.258 9.276 6.665 2.65

1! 2b 221.492 4.684

2a! 3c 132.109 20.375 20.466 25.16

2b! 3c 131.875 4.217

2a 0 ! 3a 233.884 22.090

2b 0 ! 3b 225.482 13.163

R � p-C�CH3�3C6H4±

1! 2a 221.414 7.550 5.831 2.38

1! 2b 221.775 4.095

2a! 3c 132.964 0.607 0.037 25.38

2b! 3c 132.603 4.062

2a 0 ! 3a 234.029 21.995

2b 0 ! 3b 223.239. 13.120

R � p-BrC6H4±

1! 2a 217.856 8.008 5.532 2.19

1! 2b 216.773 3.291

2a! 3c 127.272 21.165 21.485 24.60

2b! 3c 128.355 3.552

2a 0 ! 3a 228.499 19.945

2b 0 ! 3b 219.946 10.566

C. OÈ gÆretir et al. / Journal of Molecular Structure (Theochem) 538 (2001) 107±116114

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[4,5-

b]pyridin derivatives.

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)

C. OÈ gÆretir et al. / Journal of Molecular Structure (Theochem) 538 (2001) 107±116 115

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.

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.

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± 1 ± ±

C6H5± 2 20.248 20.01

p-NH2±C6H4± 3 21.159 20.63

p-OCH3±C6H4± 4 20.417 20.45

p-OC2H5±C6H4± 5 20.370 20.25

p-C2H5±C6H4± 6 20.296 20.17

p-Cl±C6H4± 7 20.185 20.14

p-C(CH3)3±C6H4± 8 20.122 20.11

p-CH3±C6H4± 9 20.116 20.08

p-Br±C6H4± 10 20.060 20.07

p-NO2±C6H4± 11 0.010 0.12

(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 corre-

lation also.

4. Conclusion

It seems that AM1 semiempirical quantum chemi-

cal calculation method can safely be applied in the

prediction of the acidity and substituent constants of

the heterocyclic systems in both and gas phases.

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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, Bloo-

mington, IN., USA.

[4] A. Klamt, G. SchuÈuÈrmann, J. Chem. Soc. Perkin Trans. 2

(1993) 799.

[5] CS ChemOf®ce Pro for Microsoft Windows, Cambridge Scien-

ti®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.

C. OÈ gÆretir et al. / Journal of Molecular Structure (Theochem) 538 (2001) 107±116116