Dihydropyrimidines of type 1 exhibit a diverse range of biological activities, e.g. antihypertensive activity¹. For instance, they act as calcium channel modulators. Some representatives of them (e.g. 2, SQ 32926, and 3, SQ 32547) have become superior in potency and duration of antihypertensive activity to classical dihydropyridine drugs and compete with the second generation analogs such as amlodipine 4 and nicardipine 5^1,2. These dihydropyrimidines possess a stereogenic centre at C4 and are interesting for the existing structure-activity relationship. The molecular interactions at the receptor level are determined by the conformation as well as the configuration of these compounds. The calcium channel modulation occurs in conformers with s-cis directed C=O bond of ester group with respect to the C5=C6 double bond. This side is recognized by receptor. The absolute configuration at C4 is responsible for the “molecular switch” between antagonist and agonist activity³. In the receptor-bound conformation the unsymmetrically substituted aryl moiety occupies a pseudoaxial position perpendicular to and bisecting the puckered boat-like dihydropyrimidine ring. Moreover, a synperiplanar orientation of aryl substituent with respect to C4-H4 is required for the activity.

This study deals with theoretical prediction of vibrational spectra in gaseous state and in CHCl₃ solution of compounds 6a, 6b at density functional B3LYP/6-31G* level. The Onsager reaction field model⁴ has been employed to simulate the effect of solvent and in addition, models with specific interactions were examined. The primary attention was paid to stretching vibrations of both C=O bonds and N-H bonds. The results are compared with experimental IR spectra. The conformers within both of series 6a and 6b arising from the orientation of CF₃ substituent and CH₃ group in ethoxy fragment were considered. The nomenclature syn or anti distinguishes the relative orientation of these groups with respect to the C4-H4 bond. The influence of conformation as well as position of CF₃ group in phenyl ring were investigated.

The calculated unscaled wavenumbers of CO stretching vibration in carbamate fragment n_car(CO), ester group n_es(CO) as well as NH stretching vibrations n_s(N1H) and n_as(N3H) are presented in Table 1. Experimentally, in CHCl₃ as a solvent the CO stretching band wih the lower wavenumber is assigned to CO of the carbamate fragment and the higher one to the ester CO. The n_es(CO) covers the range 1700 cm^-1 -1713 cm^-1 whereas n_car(CO) is in interval 1645 cm^-1 –1650 cm^-1. In contrast to this experimental assignment, B3LYP/6-31G* calculations predict n_car(CO)>n_es(CO) in the gaseous state. Possible reasons for these discrepancies between theoretically and experimentally determined order of CO vibrations are

• Effect of solvation (bulk solvent effects as approximated by the Onsager reaction field model )
  This model treats the electrostatic field effect of solvent and assumes solute in a spherical cavity of radius a₀.
• Specific solvent-solute interactions, which can not be simulated by Onsager reaction field model. (e.g., hydrogen bonds between the CO group of solute and the partially acidic hydrogen atom of CHCl₃ molecules)
  
• Formation of dimers through intermolecular hydrogen bonds. Such interactions could reduce the stretching vibration of carbamate CO group and thus change the order of CO vibrations.

Three possible dimers 7a, 7b and 7c can be considered.

In IR spectra of analogous compounds (with unsubstituted phenyl ring) the methylation of N1 atom leads to increase of n_car(CO) from 1644,8 cm^-1 to 1676,4 cm^-1, which indicates that assumption of dimers in solution is realistic and hydrogen of N1 is involved in the hydrogen bonding. This encouraged us to use dimer 7a, but in order to reduced the computational cost the calculations were performed for the dimer 7d (Figure 1) without the aryl rings and methyl groups and with methoxy groups instead of ethoxy.

Moreover, measurements on the related compound 8 in different solvents revealed the sequence of stretching vibrations n(C2O)>n(C7O) consistent with that obtained by these calculations⁵.

The presence of butyl substituent at nitrogen atom prevents the formation of the dimers through hydrogen bonds. The hydrogen bonds between solute and CHCl₃ group are also implausible since the wavenumber of C2=O stretching mode in CHCl₃ solution (1704 cm^-1) is only 6 cm^-1 lower than in CCl₄ (1710 cm^-1) solution. This shift can satisfactorily be attributed to the lower dielectric constant of CCl₄. If C3 were replaced by nitrogen atom, the n(C2O) could be expected at even higher value. This can be deduced from the comparison of IR spectra of urea (n(CO)=1734 cm^-1) with acetamide (n(CO)=1728 cm^-1) measured in Ar-matrix⁶ . The calculation on dimer 7d provides the order of CO stretching vibrations in agreement with experiment. The theoretical n_car(CO) is 1785 cm^-1 for symmetric A_g mode and 1788 cm^-1 for asymmetric A_u mode and the n_es(CO) is 1797 cm^-1 and 1802 cm^-1 for symmetric A_g and asymmetric A_u mode, respectively. Besides treating the solvent as a contimuum, specific solvent-solute interactions were taken into consideration too. At the B3LYP/6-31G* level the associate of one representative solute with two molecules of CHCl₃ (hydrogen bonds between hydrogen of CHCl₃ and the oxygen of carbamate CO group (O…H)_carbamate and between the hydrogen of the second CHCl₃ molecule and the oxygen of ethoxy group (O…H)_ethoxy) was calculated. We supposed that the (O…H)_carbamate could be responsible for the reduction of n_car(CO) and (O…H)_ethoxy could enhance the n_es(CO) to such an extent, that the order of these vibrations would be consistent with the experimentally determined one. The calculations on the complex in which all three oxygen atoms are forming hydrogen bonds with three CHCl₃ molecules (Figure 2), were performed at B3LYP/3-21G level on a model structure without aryl substituent. Although the hydrogen bond (O…H)_carbamate was the strongest (CH stretching vibration of CHCl₃ n(CH)=3048,6 cm^-1) whereas (O…H)_ethoxy was the weakest (n(CH)=3158,9 cm^-1), it was not sufficient to alter the sequence n_car(CO)>n_es(CO).

The calculations in CHCl₃ provide lower values for both the n_car(CO) and n_es(CO) than those obtained for the gaseous state. The s-trans conformers possess lower n_es(CO) when compared to s-cis. The n_s(N1H) and n_as(N3H) are systematically higher in series of 2-CF₃ positional isomers than in series of 3-CF₃ positional isomers. The stretching vibrations of N-H are coupled to each other. The lower vibrations n_as(N3H) in asymmetric mode are predominantly of N3-H character, while the higher vibrations n_s(N1H) in symmetric mode are mainly of N1-H character. In Table 1 the significant vibrational coupling is marked and is typical for conformers with syn directed CF₃ group in 2 position of phenyl. In the case of such a coupling the values of n_as(N3H) and n_s(N1H) become closer to each other. The relative energies with respect to the most stable conformer within both series are listed in Table 2 together with selected torsion angles. The effect of syn or anti orientation of CF₃ group on relative energies is more pronounced in the set of conformers with CF₃ in 2 position, where syn conformers are more stable. In set of conformers with CF₃ in 3 position the s-cis or s-trans orientation decides the stability of conformers with s-cis orientation being more favourable.

We have presented the result from density functional B3LYP/6-31G* study of type s-cis-6a and s-trans-6b. The IR spectra are predicted for gas and for solution in CHCl₃ using the Onsager reaction field model. The calculations on gaseous monomer as well as on monomer in CHCl₃ solution give the opposite order of CO stretching vibrations than assigned experimentally. In order to resolve this discrepancy models for specific solvent-solute interactions as well as formation of dimers were applied. The associate formed between solute and solvents molecules through hydrogen bonds left the order unaffected, whereas in the dimer the hydrogen bonding altered the sequence consistent with experimental assignment. All possible conformers were assumed and relative stability of them was determined.

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