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2-Hydroxy-4,6-dimethylpyridine-3-carbonitrile and 2-chloro-4,6-dimethylpyridine-3-carbonitrile compounds have been studied from a theoretical point of view in order to know their structural and vibrational properties in gas and aqueous solution phases by means of Density Functional Theory (DFT) calculations. The stable structures in both media were optimized by using the hybrid B3LYP/6-31G* method and the solvent effects in aqueous solution were studied by using the integral equation formalism of the polarizable continuum model (IEFPCM) employing the selfconsistent reaction field (SCRF) method. Detailed vibrational analyses for both compounds in the two phases were performed combining the DFT calculations with Pulay’s Scaled Quantum Mechanics Force Field (SQMFF) methodology. The different interactions for both compounds were analyzed by means of the bond orders, atomic charges, solvation energies, dipole moments, molecular electrostatic potentials and force constants parameters. The nature of the interactions was studied by using different descriptors.

As part of our investigations on compounds of great pharmacological interest [_{3}PO_{4} molecule. Also, from long time the cyano group structure in 3-cyanopyridinium tetrachloroferrate (III)-3-cya- nopyridine was determined by Daran et al. [^{*} method and the solvent effects in aqueous solution were studied by using the self-consistent reaction field (SCRF) calculations with the IEFPCM model [

Initially, the structures of the 2-hydroxy-4,6-dimethylpyridine-3-carbonitrile (2-OH) and 2-chloro-4,6-dime- thylpyridine-3-carbonitrile (2-Cl) derivatives were modeled with the GaussView program [^{*} method [_{1} symmetry was optimized which can be seen in

ported for other molecules in aqueous medium [

For both derivatives, the variations of molecular volumes expressed as a difference between the volumes in aqueous solution in relation to the volume in gas phase were calculated employing the Moldraw program [

^{*} level of theory. The theoretical values were compared with the experimental ones determined by Mefetah et al. for 2-anilino-4,6-dimethylpyridine-3-carbonitrile by using X-ray diffraction method by means of the root mean square deviation (RMSD) [

The results clearly show that this bond is strongly dependent of the groups linked to the pyridine ring and of the position of the C-CºN group. On the other hand, the C-C bond linked to the CºN bond in 4-cyanopyridine is

B3LYP/6-31G^{*}^{a} | ||||||
---|---|---|---|---|---|---|

Parameter | 2-Hydroxy-4,6-dimethylpyridine-3-carbonitrile | 2-Chloro-4,6-dimethylpyridine-3-carbonitrile | Exp.^{b} | |||

Gas phase | PCM | Gas phase | PCM | |||

Bond lengths (Å) | ||||||

C1-C2 | 1.412 | 1.411 | 1.410 | 1.405 | ||

C2-C3 | 1.407 | 1.409 | 1.411 | 1.413 | 1.383 | |

C3-C12 | 1.505 | 1.501 | 1.505 | 1.501 | 1.493 | |

C3-C4 | 1.397 | 1.395 | 1.395 | 1.394 | 1.384 | |

C4-C5 | 1.397 | 1.397 | 1.397 | 1.396 | 1.383 | |

C5-C8 | 1.505 | 1.501 | 1.504 | 1.499 | 1.501 | |

C1-N7 | 1.325 | 1.324 | 1.314 | 1.312 | 1.327 | |

C5-N7 | 1.345 | 1.350 | 1.347 | 1.353 | 1.346 | |

C2-C16 | 1.427 | 1.422 | 1.428 | 1.425 | 1.426 | |

C16-N17 | 1.164 | 1.167 | 1.163 | 1.166 | 1.145 | |

C1-O18/C1-Cl18 | 1.345 | 1.352 | 1.754 | 1.764 | ||

RMSD | 0.004 | 0.004 | 0.005 | 0.005 | ||

Bond angles (˚) | ||||||

C1-C2-C3 | 117.8 | 118.3 | 117.6 | 117.6 | ||

C2-C3-C4 | 117.5 | 117.1 | 117.3 | 117.0 | 121.8 | |

C2-C3-C12 | 120.7 | 121.0 | 120.8 | 121.0 | 121.5 | |

C4-C3-C12 | 121.6 | 121.8 | 121.7 | 121.9 | 120.0 | |

C4-C5-N7 | 121.9 | 122.1 | 121.6 | 121.5 | ||

C4-C5-C8 | 121.8 | 121.3 | 122.2 | 121.8 | 121.8 | |

C8-C5-N7 | 116.1 | 116.5 | 116.1 | 116.5 | 115.2 | |

C2-C1-O18/Cl18 | 118.3 | 117.6 | 119.0 | 118.8 | ||

N7-C1-O18/Cl18 | 117.6 | 118.4 | 116.4 | 116.1 | ||

C2-C16-N17 | 178.1 | 179.7 | 177.2 | 178.6 | 178.7 | |

C3-C2-C16 | 121.3 | 121.6 | 120.1 | 120.6 | 120.0 | |

C1-C2-C16 | 120.8 | 119.9 | 122.2 | 121.6 | ||

RMSD | 0.7 | 0.8 | 0.7 | 0.8 | ||

Dihedral angle (˚) | ||||||

C1-C2-C16-N17 | 179.9 | 179.9 | 180.0 | 180.0 | ||

C3-C2-C16-N17 | −0.0 | −0.0 | 0.0 | 0.0 | −94.0 | |

C3-C2-C1-O18 | 180.0 | −179.9 | 180.0 | 180.0 | ||

C5-N7-C1-O18 | −180.0 | −179.9 | 180.0 | 180.0 | ||

C1-C2-C3-C12 | 179.9 | 179.9 | 180.0 | 180.0 | ||

C1-N7-C5-C8 | −179.9 | 179.9 | 180.0 | 180.0 | −179.2 | |

C3-C4-C5-C8 | 179.9 | −180.0 | 180.0 | 180.0 | 179.1 | |

C5-C4-C3-C12 | −179.9 | −179.9 | 180.0 | 180.0 | 179.1 | |

RMSD | 92.7 | 157.2 | 92.8 | 92.8 | ||

^{a}This work; ^{b}From Ref [

1.439 Å [_{3} while in the (2-Cl) derivative are C1-Cl18 and C5-CH_{3}. Experimentally, the C-N distance in the symmetric molecule of 4-cyanopyridine [^{*} method. Note that in both media the dipole moments for the (2-Cl) derivative are higher than the other ones, as expected because the Cl atom is a voluminous atom. For this reasons, the calculated molecular volumes for the (2-Cl) derivative in both media by using the Moldraw program [^{*} method are higher than the other ones, as observed in

The uncorrected solvation energies (DG_{u}), calculated as relative energies (DE) and defined as the difference between the total energies in aqueous solutions and the values in gas phase for the (2-OH) and (2-Cl) derivatives using the 6-31G^{*} basis set, are presented in _{u}) and corrected (DG_{c}) solvation energies together with the total non electrostatic terms (DG_{ne}) due to the cavitation, dispersion and repulsion energies were calculated by using the PCM/SMD model [_{c} value is obtained, probably due to its higher variation of volume in solution (

The molecular electrostatic potential values for both derivatives calculated in the two media by using the B3LYP/6-31G^{*} method are given in

B3LYP/6-31G^{*}^{a} | |||||
---|---|---|---|---|---|

2-Hydroxy-4,6-dimethylpyridine-3-carbonitrile | 2-Chloro-4,6-dimethylpyridine-3-carbonitrile | ||||

Volume (Å^{3}) | |||||

Gas phase | PCM | DV | Gas phase | PCM | DV |

162.5 | 163.0 | 0.5 | 171.5 | 171.3 | −0.2 |

Solvation energies (kJ/mol) | |||||

DG_{u} | −32.26 | DG_{uncorr} | −23.61 | DG_{u} | −32.26 |

DG_{Totalne} | 19.02 | DG_{ne} | 16.01 | DG_{Totalne} | 19.02 |

DG_{c} | −13.24 | DG_{corrected} | −7.6 | DG_{c} | −13.24 |

DG_{c} = DG_{uncorrected}^{#} − DG_{Totalnon electrostatic}; ^{a}This work.

CH_{3} groups in the chlorinated derivative in the two media in relation to the other one. These results justify the higher blue coloration on the surface mapped of those groups in the chlorinated derivative, as observed in ^{*} method were calculated for both derivatives in the two media, as can be seen in _{3} groups, thus, the pyridine ring has in gas phase a higher stability in the chlorinated derivative than the other one. Note that the bond order values in both derivatives practically not change in aqueous solution and only a little decreasing is observed in the bond order corresponding to the Cl atom with the hydration. This fact, in (2-Cl) is probably related with the contraction volume observed in aqueous solution.

The stability of both derivatives were studied by means of second order perturbation energies E^{(2)} (donor à acceptor) whose values are given in _{p}_{®}_{p}_{*}, DET_{LP}_{®}_{s}_{*} and DET_{s}_{*}_{®}_{s}_{*} charges transfer, being the two latter interactions higher in the (2-OH) derivative than the other one while, the π-π interactions in the pyridine ring are higher in the chlorinated derivative. These results show that the calculated total stabilization energy favours to the (2-OH) derivative revealing thus a higher stability for this derivative in gas and aqueous solution phases. Here, it is very important to note that in the (2-OH) derivative the significant increase in the delocalization values in aqueous solution is related with the increase of the C-C and C-N double bonds of the pyridine ring as consequence of the hydration. This way, this analysis shows clearly that the DET_{π}_{-π} interactions in the pyridine ring are higher in the chlorinated derivative and in both media while, in general, the DE_{Total} are higher in the (2-OH) derivative than the other one.

Both derivatives were also studied employing the AIM analysis [^{2}r(r) were calculated for the ring critical points (RCPs) belonging to the pyridine rings and the values can be seen in

Many cyanopyridine derivatives have potentials antimicrobial and anticancer activities, for this reason, and to determine the exact nature of the interactions with electrophones and/or nucleophiles and, also to predict the behavior of both derivatives in gas and aqueous solution phases are very important the calculations of some descriptors. If both derivatives are used for the drugs design, the knowledge of these descriptors helps to understand the structural, dynamical, and functional properties of each derivative in both media. Thus, for both derivatives, the HOMO and LUMO orbitals, energy band gap, chemical potential (μ), electro negativity (χ), global hardness (η), global softness (S) and global electrophilicity index (ω) descriptors [^{*} level of theory can be seen in _{3} groups for the chlorinated derivative support the better capability to accept electrons while, the highest molecular electrostatic potentials observed on the N7 and N17 atoms of (2-OH) suggest that it derivative is better electrons donor than (2-Cl).

Experimental and calculated chemical shifts with the GIAO method using 6-311++G^{**} basis set for the ^{1}H and ^{13}C nuclei of both derivatives are compared in ^{13}C nuclei are lower than the corresponding experimental values. Note that the calculated chemical shifts for the H nuclei of (2-OH) show a significant variation (0.81 ppm) than the (2-Cl) derivative (0.22 ppm), in relation to the corresponding experimental values [^{13}C chemical shifts for both derivatives are slightly different between them, as expected due to the different (OH and Cl groups) present in each structure.

The recorded infrared spectra for both derivatives in solid phase compared with the corresponding theoretical in gas and aqueous solution phases can be seen respectively in ^{*} method for (2-OH) and (2-Cl) can be seen in ^{*} basis in gas (black color) and aqueous solution phases (red color) can be seen in ^{−1} region attributed to the H bonds, as observed in

OH modes. The broad and intense band in the IR spectrum of (2-OH) centred at 3350 cm^{−1} and predicted in aqueous solution at 3523 cm^{−1}, is assigned to the O-H stretching as observed in compounds containing this group [^{−1} while the corresponding out-of-plane deformation mode is associated to the band at 495 cm^{−1}.

CH_{3} modes. The IR bands between at 2980 and 2850 cm^{−1} are assigned to the CH_{3} antisymmetric and sym- metric stretching modes while the bands between 1465 and 1360 cm^{−1} are clearly assigned to the ant symmetric and symmetric CH_{3} deformation modes. The four expected rocking modes are assigned to the shoulder and

bands observed between 1095 and 1025 cm^{−1}. The twisting modes were not assigned because are predicted at 66 and 41 cm^{−1}.

C-CºN modes. Here, the IR band at 2220 cm^{−1} is assigned to the CºN stretching mode while the strong band at 720 cm^{−1} is assigned to the C2-C16 stretching mode, as observed in ^{−1} and, for this reason, they were not assigned.

Skeletal modes. The C-N stretching modes corresponding to the pyridine ring are predicted by the calcula-

tions in different regions. Hence, the IR bands at 1480 and 1140 cm^{−1} are associated respectively with those two C5-N7 and N7-C1 stretching modes while the strong band at 1375 cm^{−1}, is associated with the C-O stretching mode. Here, it is necessary to note that in aqueous solution there is a very important shifting in the wave numbers corresponding to those stretching modes, thus, the N7-C1 and C5-N7 stretching modes are predicted respectively at 1486 and 963 cm^{−1}, as observed in

CH_{3} modes. As in the (2-OH) derivative, the CH_{3} ant symmetric and symmetric stretching modes are assigned between 3010 and 2975 cm^{−1} while the ant symmetric and symmetric CH_{3} deformation modes bands are clearly assigned, as predicted by calculations, to the strong band at 1440 cm^{−1}. The four expected rocking modes are assigned to the bands between 1040 and 1000 cm^{−1}. In this derivative, the twisting modes were not assigned because both are predicted at 77 and 57 cm^{−1}. It is important to note that in this derivative the presence of the Cl atom in the structure shift the bands toward lower wave numbers, as observed in

C-CºN modes. Here, the CºN stretching mode is assigned to the IR band at 2225 cm^{−1} while the weak band at 700 cm^{−1} is assigned to the C2-C16 stretching mode, as predicted by calculations.

In this derivative, with the hydration only is observed a shifting in the wave numbers related to the C5-N7 stretching mode, as indicated in ^{−1} while the corresponding out-of-plane deformation mode is predicted at 241 cm^{−1} and, for this, it mode is not assigned.

Skeletal modes. In this derivative, the C-N stretching modes corresponding to the pyridine ring are predicted by the calculations in the same regions, thus, both modes were assigned to the band and shoulder respectively at 1260 and 1250 cm^{−1}. The C-Cl stretching mode is predicted by calculations at 448 cm^{−1} and assigned at 440 cm^{−1}. The bending and out-of-plane deformation modes corresponding to the C1-Cl18 group are predicted at 230 and 160 cm^{−1}, hence, these modes were not assigned. Finally, in accordance with similar molecules [

2-Hydroxy-4,6-dimethylpyridine-3-carbonitrile | 2-Chloro-4,6-dimethylpyridine-3-carbonitrile | ||||||||
---|---|---|---|---|---|---|---|---|---|

Exp | Gas phase^{a} | Aqueous solution^{a} | Exp | Gas phase^{a} | Aqueous solution^{a} | ||||

IR^{b} | SQM^{d } | Assignment | SQM^{e } | Assignment | IR^{c} | SQM^{d } | Assignment | SQM^{e } | Assignment |

3350 s | 3543 | nO18-H19 | 3523 | nO18-H19 | 3350 vw | ||||

3280 w | 3076 | nC4-H6 | 3085 | nC4-H6 | 3076 | nC4-H6 | 3097 | nC4-H6 | |

3140 m | 3016 | n_{ a}CH_{3}(C8) | 3050 | n_{ }_{a}CH_{3}(C12) | 3010 w | 3017 | n_{ a}CH_{3}(C12) | 3030 | n_{ a}CH_{3}(C12) |

3015 | n_{ a}CH_{3}(C12) | 3015 | n_{ a}CH_{3}(C8) | 3017 | n_{ a}CH_{3}(C8) | 3030 | n_{ a}CH_{3}(C8) | ||

2993 | n_{a}CH_{3}(C12) | 2991 | n_{a}CH_{3}(C8) | 2990 | n_{a}CH_{3}(C8) | ||||

2980 sh | 2987 | n_{a}CH_{3}(C8) | 2978 | n_{a}CH_{3}(C8) | 2975 w | 2986 | n_{a}CH_{3}(C12) | 2989 | n_{a}CH_{3}(C12) |

2950 s | 2984 | n_{a}CH_{3}(C12) | |||||||

2925 vs | 2932 | n_{s}CH_{3}(C8) | 2931 | n_{s}CH_{3}(C12) | 2920 w | 2934 | n_{s}CH_{3}(C8) | 2936 | n_{s}CH_{3}(C8) |

2850 s | 2931 | n_{s}CH_{3}(C12) | 2928 | n_{s}CH_{3}(C8) | 2850 w | 2932 | n_{s}CH_{3}(C12) | 2935 | n_{s}CH_{3}(C12) |

2220 s | 2250 | nC16-N17 | 2232 | nC16-N17 | 2225 m | 2254 | nC16-N17 | 2207 | nC16-N17 |

1699 | nC3-C12 | ||||||||

1660 vs | 1601 | nC3-C4 | 1595 | nC3-C4 | 1600 vs | 1586 | nC3-C4 | 1585 | nC3-C4 |

1625 s | 1536 | nC2-C3 | |||||||

1530 m | 1548 | nC2-C3 | 1486 | nN7-C1 | 1535 m | 1531 | nC2-C3 | 1519 | nC2-C3 |

1480 s | 1484 | nC5-N7 | 1455 | daCH_{3}(C8) | |||||

1465 sh | 1456 | daCH_{3}(C8) | 1446 | daCH_{3}(C12) | 1440 s | 1457 | daCH_{3}(C8) | 1442 | nC5-N7 |

1460 s | 1447 | daCH_{3 }(C12) | 1443 | daCH_{3}(C12) | 1449 | daCH_{3}(C12) | 1432 | daCH_{3}(C12) | |

1450 sh | 1443 | daCH_{3}(C12) | 1440 | daCH_{3}(C8) | 1444 | daCH_{3}(C12) | 1425 | daCH_{3}(C8) | |

1430 m | 1440 | daCH_{3}(C8) | 1433 | nC1-C2 | 1438 | daCH_{3}(C8) | 1424 | daCH_{3}(C12) | |

1375 s | 1409 | nC1-O18 | 1392 | nC5-C8 | 1415 sh | 1427 | nC1-C2 | 1422 | daCH_{3}(C8) |

1375 s | 1379 | dsCH_{3 }(C12) | 1370 | dsCH_{3}(C12) | 1380 s | 1379 | dsCH_{3}(C12) | 1370 | dsCH_{3}(C8) |

1360 sh | 1374 | dsCH_{3 }(C8) | 1351 | dsCH_{3}(C8) | 1360 m | 1375 | dsCH_{3 }(C8) | 1362 | dsCH_{3}(C12) |

1340 m | 1333 | nC4-C5 | 1292 | nC4-C5 | 1348 | nC4-C5 | 1346 | nC4-C5 | |

1225 s | 1285 | dO18-H19 | 1222 | nC2-C16 | 1260 s | 1274 | nN7-C1 | 1272 | nN7-C1 |

1250 sh | 1241 | nC5-N7 | 1245 | nC1-C2 | |||||

1215 m | 1219 | bC4-H6 | 1219 | bC4-H6 | 1220 w | 1215 | bC4-H6 | 1216 | bC4-H6 |

1175 sh | 1205 | nC1-C2 | 1160 m | ||||||

1140 s | 1123 | nN7-C1 | 1111 | dO18-H19 | 1140 s | 1130 | bR_{1} | 1131 | bR_{1} |

1095 w | 1063 | rCH_{3}(C12)_{ } | 1073 | nC1-O18 | 1052 | r’CH_{3}(C8) | |||

1060 sh | 1050 | r’CH_{3}(C12) | 1040 m | 1049 | r’CH_{3}(C12) | 1048 | r’CH_{3}(C12) | ||

1055 m | 1044 | r’CH_{3}(C8) | 1050 | r’CH_{3}(C8) r’CH_{3}(C12) | 1046 | r’CH_{3}(C8) | |||

1025 w | 1019 | rCH_{3}(C8) | 1022 | rCH_{3}(C8) | 1020 | 1025 | rCH_{3}(C12) | 1031 | rCH_{3}(C8) |

995 w | 1007 | gC4-H6 | 1000 | 1002 | rCH_{3}(C8) | 1008 | rCH_{3}(C12) | ||

960 w | 967 | bR_{1} | 963 | nC5-N7 | 950 w | 940 | nC5-C8 | 944 | nC5-C8 |

925 s | 934 | nC5-C8 | 911 | rCH_{3}(C12) | 910 w | 892 | gC4-H6 | ||

880 sh | 876 | gC4-H6 | |||||||

845 s | 851 | gC4-H6 | 795 | tR_{1} | 860 m | 859 | nC3-C12 | 847 | nC1-Cl18 |

775 s | 754 | gC1-O18 | 740 | tR_{1} | 740 w | 740 | tR_{1} | 736 | tR_{1} |

720 s | 691 | nC2-C16 | 672 | bR_{1} | 700 w | 692 | nC2-C16 | 696 | nC2-C16 |

634 | gC1-O18 | ||||||||

640 s | 626 | gC5-C8 | 621 | tR_{2} | 620 w | 620 | dC2C16N17 | ||

615 m | 618 | bC5-C8 | 614 | gC5-C8,tR_{1} | 615 w | 615 | bC2-C16 | 614 | gC5-C8 |

590 vw | 588 | nC3-C12 | 600 sh | 606 | gC5-C8 |

580 w | 581 | gC3-C12 | |||||||
---|---|---|---|---|---|---|---|---|---|

552 | gC3-C12 | 550 w | 559 | gC3-C12 | 560 | gC3-C12 | |||

540 w | 531 | bR_{2} | 531 | nC3-C12 | |||||

530 m | 523 | bR_{2} | 518 | bR_{2} | |||||

495 m | 502 | tOH | 492 | tOH | |||||

475 w | 466 | twC2-C16 | 456 | bC3-C12 | 480 w | 470 | twC2-C16 | 484 | twC2-C16 |

460 m | 447 | dC2C16N17 | 443 | bR_{3} | 440 w | 448 | nC1-Cl18 | 447 | bC5-C8 |

424 | bR_{3} | 428 | bC3-C12 | 430 | bR_{2} | ||||

401 | twC2-C16 | ||||||||

385 | bC5-C8 | 382 | bR_{3} | 379 | bR_{3} | ||||

303 | bC1-O18 | 297 | bC1-O18 | ||||||

277 | bC3-C12 | 275 | bC5-C8 | 279 | bC3-C12 | ||||

241 | gC2-C16 | 241 | gC2-C16 | 249 | gC2-C16 | ||||

236 | gC2-C16 | 230 | bC1-Cl18 | 230 | bC1-Cl18 | ||||

223 | tR_{3} | 228 | tR_{3} | ||||||

209 | tR_{3} | 210 | tR_{3} | ||||||

180 | tR_{1} | ||||||||

160 | gC1-Cl18 | 165 | gC1-Cl18 | ||||||

138 | bC2-C16 | 148 | bC2-C16 dC2C16N17 | 135 | dC2C16N17 | 138 | bC2-C16 | ||

122 | gC5-C8 | ||||||||

95 | twCH_{3}(C12) | ||||||||

82 | tR_{2}_{ } | 78 | twCH_{3}(C12) | 77 | twCH_{3}(C12) | 83 | twCH_{3}(C8) | ||

66 | twCH_{3}(C8) | 74 | twCH_{3}(C8) | 73 | tR_{2} | 73 | tR_{2} | ||

41 | twCH_{3}(C12) | 57 | twCH_{3}(C8) |

n, stretching; d, scissoring; wag and g, wagging or out of plane deformation; r, rocking; t, torsion, twist, twisting; a, antisymmetric; s, symmetric; R, ring; ^{a}This work, ^{b}From Ref [^{c}From Ref [^{d}From scaled quantum mechanics force field B3LYP/6-31G^{*}, ^{e}From scaled quantum mechanics force field PCM/B3LYP/6-31G^{*}.

The force constants were calculated from the corresponding scaled force fields by using the Molvib program [

The theoretical molecular structures of the 2-hydroxy-4,6-dimethylpyridine-3-carbonitrile and 2-chloro-4,6-di- methylpyridine-3-carbonitrile derivatives were determined in gas phase and in aqueous solution by using the B3LYP/6-31G^{*} method employing the IEFPCM model. The complete assignments of the vibrational modes for both derivatives and the corresponding SQM force fields were obtained by using the B3LYP/6-31G^{*} method. The predicted Raman spectra for the 2-hydroxy-4,6-dimethylpyridine-3-carbonitrile and 2-chloro-4,6-dime- thylpyridine-3-carbonitrile derivatives have been reported by using the B3LYP/6-31G^{*} method. Differences in

B3LYP/6-31G^{*}^{a} | ||||
---|---|---|---|---|

Force constant | 2-Hydroxy-4,6-dimethylpyridine-3-carbonitrile | 2-Chloro-4,6-dimethylpyridine-3-carbonitrile | ||

Gas phase | PCM | Gas phase | PCM | |

f(nO-H) | 7.03 | 7.01 | ||

f(nCºN) | 17.77 | 17.91 | 17.82 | 17.06 |

f(nC-N) | 7.25 | 13.56 | 7.22 | 7.10 |

f(nC-C)_{A6} | 6.34 | 11.07 | 6.33 | 6.36 |

f(nC-C)_{CH3} | 4.40 | 5.38 | 4.40 | 4.49 |

f(nC-C)_{C}_{º}_{N} | 5.46 | 6.22 | 5.42 | 5.48 |

f(nC-O) | 6.45 | 14.29 | ||

f(nC-Cl) | 3.20 | 3.00 | ||

f(δCH_{3}) | 0.54 | 0.69 | 0.54 | 0.53 |

f(δC-O-H) | 0.79 | 2.30 | ||

f(δC-CºN) | 0.34 | 0.48 | 0.33 | 0.36 |

n, stretching; δ angle deformation. Units in mdyn Å^{−1} for stretching and mdyn Å rad ^{−2} for angle deformations; ^{a}This work.

the studied properties for both derivatives in both media were justified by the molecular electrostatic potentials, atomic charges, bond orders, solvation energies, dipole moments, deslocalization energies and AIM analysis. A higher stability in aqueous solution for the 2-hydroxy-4,6-dimethylpyridine-3-carbonitrile derivative was found, which is supported in part by the NBO analysis, by a higher hydration of this derivative in solution due to its higher solvation energy and, by the higher force constant values. The analysis of the descriptors suggests that the OH group in the 2-hydroxy-4,6-dimethylpyridine-3-carbonitrile derivative reduces the HOMO-LUMO gap deactivating the ring while the calculated chemical hardness, chemical potential and global electrophilicity index values suggest a higher stability for the 2-chloro-4,6-dimethylpyridine-3-carbonitrile derivative and a better capability to accept electrons, as suggested by the AIM analysis. Here, the differences observed between the NBO and AIM results are probably due to that in the total energy only were considered those contributions with values higher than 20 kJ/mol. ^{1}H-NMR spectra observed for both derivatives were successfully compared with the calculated chemical shifts at the B3LYP/6-311++G^{**} level of theory. The high value observed in the hydrogen chemical shift corresponding to the H atom of the OH group of 2-hydroxy-4,6-dimethylpyridine-3-carbonitrile, in relation to the calculated value, confirms the presence of the hydrogen bonds in solution for this derivative.

This work was founded with grants from CIUNT (Consejo de Investigaciones, Universidad Nacional de Tucumán). The authors thank Prof. Tom Sundius for his permission to use MOLVIB.

B3LYP/6-31G^{*} | ||
---|---|---|

Compound | E (Hartrees) | m (D) |

Gas phase | ||

2-Hydroxy-4,6-dimethylpyridine-3-carbonitrile | −494.3993 | 5.12 |

2-Chloro-4,6-dimethylpyridine-3-carbonitrile | −878.7631 | 5.53 |

Aqueous solution | ||

2-Hydroxy-4,6-dimethylpyridine-3-carbonitrile | −494.4116 | 7.07 |

2-Chloro-4,6-dimethylpyridine-3-carbonitrile | −878.7721 | 7.95 |

B3LYP/6-31G^{*} | |||||
---|---|---|---|---|---|

2-Hydroxy-4,6-dimethylpyridine-3-carbonitrile | 2-Chloro-4,6-dimethylpyridine-3-carbonitrile | ||||

Atoms | Gas phase | PCM | Atoms | Gas phase | PCM |

1 C | −14.619 | −14.619 | 1 C | −14.617 | −14.617 |

2 C | −14.690 | −14.691 | 2 C | −14.671 | −14.672 |

3 C | −14.688 | −14.688 | 3 C | −14.676 | −14.675 |

4 C | −14.723 | −14.723 | 4 C | −14.708 | −14.708 |

5 C | −14.673 | −14.673 | 5 C | −14.662 | −14.662 |

6 H | −1.085 | −1.085 | 6 H | −1.073 | −1.072 |

7 N | −18.349 | −18.348 | 7 N | −18.336 | −18.335 |

8 C | −14.726 | −14.726 | 8 C | −14.721 | −14.720 |

9 H | −1.098 | −1.098 | 9 H | −1.093 | −1.092 |

10 H | −1.098 | −1.098 | 10 H | −1.093 | −1.092 |

11 H | −1.101 | −1.101 | 11 H | −1.095 | −1.095 |

12 C | −14.720 | −14.720 | 12 C | −14.711 | −14.711 |

13 H | −1.094 | −1.094 | 13 H | −1.085 | −1.084 |

14 H | −1.098 | −1.098 | 14 H | −1.085 | −1.084 |

15 H | −1.094 | −1.094 | 15 H | −1.089 | −1.088 |

16 C | −14.716 | −14.717 | 16 C | −14.704 | −14.704 |

17 N | −18.377 | −18.377 | 17 N | −18.364 | −18.364 |

18 O | −22.261 | −22.262 | 18 Cl | −64.367 | −64.368 |

19 H | −0.948 | −0.948 |

B3LYP/6-31G^{*} | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|

2-Hydroxy-4.6-dimethylpyridine-3-carbonitrile | 2-Chloro-4.6-dimethylpyridine-3-carbonitrile | |||||||||

Atoms | Gas phase | PCM | Atoms | Gas phase | PCM | |||||

MK’ charges | NPA | MK’ charges | NPA | MK’ charges | NPA | MK’ charges | NPA | |||

1 C | 0.796 | 0.604 | 0.789 | 0.604 | 1 C | 0.371 | 0.247 | 0.381 | 0.252 | |

2 C | −0.600 | −0.258 | −0.590 | −0.258 | 2 C | −0.278 | −0.225 | −0.300 | −0.227 | |

3 C | 0.557 | 0.070 | 0.552 | 0.070 | 3 C | 0.470 | 0.067 | 0.484 | 0.069 | |

4 C | −0.714 | −0.301 | −0.708 | −0.300 | 4 C | −0.639 | −0.273 | −0.660 | −0.274 | |

5 C | 0.765 | 0.259 | 0.759 | 0.258 | 5 C | 0.739 | 0.255 | 0.777 | 0.255 | |

6 H | 0.222 | 0.244 | 0.220 | 0.243 | 6 H | 0.217 | 0.247 | 0.218 | 0.247 | |

7 N | −0.775 | −0.538 | −0.769 | −0.534 | 7 N | −0.591 | −0.462 | −0.602 | −0.460 | |

8 C | −0.545 | −0.703 | −0.541 | −0.703 | 8 C | −0.585 | −0.705 | −0.624 | −0.705 | |

9 H | 0.158 | 0.256 | 0.157 | 0.256 | 9 H | 0.170 | 0.261 | 0.178 | 0.261 |
---|---|---|---|---|---|---|---|---|---|

10 H | 0.158 | 0.256 | 0.157 | 0.256 | 10 H | 0.170 | 0.261 | 0.178 | 0.261 |

11 H | 0.130 | 0.238 | 0.129 | 0.237 | 11 H | 0.141 | 0.238 | 0.150 | 0.238 |

12 C | −0.419 | −0.701 | −0.415 | −0.701 | 12 C | −0.454 | −0.702 | −0.452 | −0.702 |

13 H | 0.129 | 0.262 | 0.127 | 0.262 | 13 H | 0.148 | 0.264 | 0.146 | 0.264 |

14 H | 0.120 | 0.244 | 0.120 | 0.244 | 14 H | 0.148 | 0.264 | 0.146 | 0.264 |

15 H | 0.129 | 0.262 | 0.127 | 0.262 | 15 H | 0.129 | 0.247 | 0.131 | 0.247 |

16 C | 0.514 | 0.277 | 0.506 | 0.276 | 16 C | 0.336 | 0.269 | 0.348 | 0.268 |

17 N | −0.478 | −0.304 | −0.476 | −0.303 | 17 N | −0.415 | −0.284 | −0.418 | −0.282 |

18 O | −0.571 | −0.672 | −0.571 | −0.675 | 18 Cl | −0.078 | 0.030 | −0.083 | 0.023 |

19 H | 0.427 | 0.503 | 0.427 | 0.504 |

B3LYP/6-31G^{*} | |||||
---|---|---|---|---|---|

2-Hydroxy-4,6-dimethylpyridine-3-carbonitrile | 2-Chloro-4,6-dimethylpyridine-3-carbonitrile | ||||

Atoms | Gas phase | PCM | Atoms | Gas phase | PCM |

1 C | 3.898 | 3.899 | 1 C | 4.014 | 4.014 |

2 C | 3.965 | 3.965 | 2 C | 3.976 | 3.975 |

3 C | 3.990 | 3.990 | 3 C | 3.991 | 3.990 |

4 C | 3.935 | 3.935 | 4 C | 3.937 | 3.937 |

5 C | 3.974 | 3.975 | 5 C | 3.976 | 3.976 |

6 H | 0.942 | 0.942 | 6 H | 0.940 | 0.941 |

7 N | 3.073 | 3.073 | 7 N | 3.112 | 3.113 |

8 C | 3.835 | 3.835 | 8 C | 3.832 | 3.832 |

9 H | 0.936 | 0.936 | 9 H | 0.934 | 0.933 |

10 H | 0.936 | 0.936 | 10 H | 0.934 | 0.933 |

11 H | 0.945 | 0.945 | 11 H | 0.944 | 0.944 |

12 C | 3.822 | 3.822 | 12 C | 3.819 | 3.819 |

13 H | 0.933 | 0.933 | 13 H | 0.931 | 0.931 |

14 H | 0.942 | 0.941 | 14 H | 0.931 | 0.931 |

15 H | 0.933 | 0.933 | 15 H | 0.940 | 0.940 |

16 C | 4.005 | 4.006 | 16 C | 4.006 | 4.006 |

17 N | 3.026 | 3.026 | 17 N | 3.031 | 3.031 |

18 O | 1.975 | 1.969 | 18 Cl | 1.259 | 1.251 |

19 H | 0.749 | 0.748 |

B3LYP/6-31G^{*} | |||||
---|---|---|---|---|---|

2-Hydroxy-4,6-dimethylpyridine-3-carbonitrile | 2-Chloro-4,6-dimethylpyridine-3-carbonitrile | ||||

Delocalization | Gas phase | PCM | Delocalization | Gas phase | PCM |

s (2)C1-N7 ® s^{*}C4-C5 | 120.13 | 117.79 | s (2)C1-N7 ® s^{*}C2-C3 | 42.55 | 43.18 |

0 | 0 | s (2)C1-N7 ® s^{*}C4-C5 | 102.24 | 99.9 | |

s (2)C2-C3 ® s^{*}C1-N7 | 140.57 | 140.24 | s (2)C2-C3 ® s^{*}C1-N7 | 131.88 | 134.55 |

s (2)C2-C3 ® s^{*}C4-C5 | 52.46 | 53.38 | s (2)C2-C3 ® s^{*}C4-C5 | 57.14 | 57.56 |

s (2)C2-C3 ® s^{*}C16-N17 | 84.56 | 86.11 | s (2)C2-C3 ® s^{*}C16-N17 | 79.08 | 80.09 |

s (2)C4-C5 ® s^{*}C1-N7 | 52.08 | 51.08 | s (2)C4-C5 ® s^{*}C1-N7 | 67.13 | 64.5 |

s (2)C4-C5 ® s^{*}C2-C3 | 123.64 | 123.31 | s (2)C4-C5 ® s^{*}C2-C3 | 120.34 | 120.17 |

s (1)C16-N17 ® s^{*}C2-C16 | 25.62 | 25.87 | s (1)C16-N17 ® s^{*}C2-C16 | 26.08 | 26.25 |

s (2)C16-N17 ® s^{*}C1-C2 | 14.29 | 14.46 | s (2)C16-N17 ® s^{*}C1-C2 | 14.21 | 14.34 |
---|---|---|---|---|---|

s (3)C16-N17 ® s^{*}C2-C3 | 30.72 | 31.64 | s (3)C16-N17 ® s^{*}C2-C3 | 32.23 | 32.94 |

s (1)O18-H19 ® s^{*}C1-C2 | 25.12 | 23.37 | 0 | 0 | |

DET_{p}_{®}_{ }_{p}_{*} | 669.19 | 667.25 | DET_{p}_{®}_{ }_{p}_{*} | 672.88 | 673.48 |

LP(1)N7 ® s^{*}C1-C2 | 49.78 | 49.28 | LP(1)N7 ® s^{*}C1-C2 | 47.52 | 47.48 |

LP(1)N7 ® s^{*}C2-C16 | 53.17 | 53.63 | LP(1)N7 ® s^{*}C2-C16 | 54.09 | 54.55 |

LP(2)O18 ® s^{*}C1-N7 | 166.78 | 165.56 | LP(3)Cl18 ® s^{*}C1-N7 | 68.34 | 65.83 |

DET_{LP}_{®}_{ }_{s}_{*} | 269.73 | 268.47 | DET_{LP}_{®}_{ }_{s}_{*} | 169.95 | 167.86 |

s*(2)C1-N7 ® s^{*}C2-C3 | 644.76 | 673.02 | s^{*}(2)C1-N7 ® s^{*}C2-C3 | 541.81 | 591.26 |

s*(2)C1-N7 ® s^{*}C4-C5 | 420.42 | 426.61 | s^{*}(2)C1-N7 ® s^{*}C4-C5 | 378.67 | 384.18 |

s*(2)C2-C3 ® s^{*}C16-N17 | 82.72 | 85.15 | s^{*}(2)C2-C3 ® s^{*}C16-N17 | 79.75 | 81.43 |

DET_{s}_{*}_{®}_{ }_{s}_{*} | 1147.9 | 1184.78 | DET_{s}_{*}_{®}_{ }_{s}_{*} | 1000.23 | 1056.87 |

DE_{Total} | 2086.82 | 2120.5 | DE_{Total} | 1843.06 | 1898.21 |

B3LYP/6-31G^{*} | ||||
---|---|---|---|---|

Parameter (a.u.) | 2-Hydroxy-4,6-dimethylpyridine-3-carbonitrile | 2-Chloro-4,6-dimethylpyridine-3-carbonitrile | ||

Gas phase | PCM | Gas phase | PCM | |

r(r_{c}) | 0.0217 | 0.0217 | 0.0220 | 0.0220 |

Ñ^{2}r(r_{c}) | 0.1694 | 0.1694 | 0.1717 | 0.1719 |

l_{1} | −0.0171 | −0.0171 | −0.0176 | −0.0176 |

l_{2} | 0.0876 | 0.0876 | 0.0883 | 0.0874 |

l_{3} | 0.0988 | 0.0988 | 0.1009 | 0.1021 |

|l_{1}|/l_{3} | 0.1730 | 0.1730 | 0.1744 | 0.1724 |

B3LYP/6-31G^{*} | |||||
---|---|---|---|---|---|

2-Hydroxy-4,6-dimethylpyridine-3-carbonitrile | 2-Chloro-4,6-dimethylpyridine-3-carbonitrile | ||||

Orbitals | Gas phase | PCM | Orbitals | Gas phase | PCM |

HOMO (39) (eV) | −6.7102 | −6.7025 | HOMO (43) (eV) | −7.2680 | −7.2762 |

LUMO (40) (eV) | −1.5401 | −1.5571 | LUMO (44) (eV) | −1.8776 | −1.9073 |

GAP (eV) | −5.1701 | −5.1454 | GAP (eV) | −5.3904 | −5.3689 |

Descriptors | 2-Hydroxy-4,6-dimethylpyridine-3-carbonitrile | 2-Chloro-4,6-dimethylpyridine-3-carbonitrile | ||
---|---|---|---|---|

Gas phase | PCM | Gas phase | PCM | |

c = ?[E(LUMO) ? E(HOMO)]/2 (eV) | −2.5850 | −2.5727 | −2.6952 | −2.6844 |

m = [E(LUMO) + E(HOMO)]/2 (eV) | −4.1251 | −4.1251 | −4.5728 | −4.5917 |

h = [E(LUMO) ? E(HOMO)]/2 (eV) | 2.5850 | 2.5727 | 2.6952 | 2.6844 |

S = 1/2h (eV) | 0.1934 | 0.1943 | 0.1855 | 0.1862 |

w = m^{2}/2h (eV) | 3.2914 | 3.3071 | 3.8792 | 3.9271 |

Atoms | 2-Hydroxy-4,6-dimethylpyridine-3-carbonitrile | 2-Chloro-4,6-dimethylpyridine-3-carbonitrile | ||
---|---|---|---|---|

Calc.^{a} | Exp^{b} | Calc.^{a} | Exp^{b} | |

H6 | 6.588 | 6.100 s, H, pyridyl | 6.324 | 7.000 s, H, pyridyl |

H9 | 2.511 | 2.300 s, 3H, CH3-C?C | 2.240 | 2.400 s, 3H, CH3-C?C |

H10 | 2.511 | 2.300 s, 3H, CH3-C?C | 2.240 | 2.400 s, 3H, CH3-C?C |

H11 | 2.030 | 2.300 s, 3H, CH3-C?C | 1.519 | 2.400 s, 3H, CH3-C?C |

H13 | 2.511 | 2.400 s, 3H, CH3-C?N | 2.240 | 2.500 s, 3H, CH3-C?N |
---|---|---|---|---|

H14 | 1.926 | 2.400 s, 3H, CH3-C?N | 2.240 | 2.500 s, 3H, CH3-C?N |

H15 | 2.511 | 2.400 s, 3H, CH3-C?N | 1.519 | 2.500 s, 3H, CH3-C?N |

H19 | 5.750 | 12.200 s, H, OH | ||

RMSD | 0.81 | 0.22 |

^{a}GIAO/B3LYP/6-311++G^{**} Ref. to TMS; ^{b}Experimental dissolved in CDCl_{3} [

Atoms | 2-Hydroxy-4,6-dimethylpyridine-3-carbonitrile | 2-Chloro-4,6-dimethylpyridine-3-carbonitrile |
---|---|---|

Calculated.^{a} | Calculated.^{a} | |

C1 | 188.021 | 147.974 |

C2 | 113.798 | 97.364 |

C3 | 181.849 | 141.92 |

C4 | 138.881 | 109.563 |

C5 | 185.507 | 148.577 |

C8 | 43.145 | 17.296 |

C12 | 39.429 | 14.417 |

C16 | 136.111 | 96.088 |

^{a}GIAO/B3LYP/6-311++G^{**} Ref. to TMS.