Journal of Structural Chemistry. Vol. 45, No. 1, pp. 64-73, 2004 Original Russian Text Copyright © 2004 by E. B. Burgina, V. P. Baltakhinov, E. V. Boldyreva, and T. P. Shakhtschneider
IR SPECTRA OF PARACETAMOL AND PHENACETIN. 1. THEORETICAL AND EXPERIMENTAL STUDIES E. B. Burgina,1 V. P. Baltakhinov,3 E. V. Boldyreva,2 and T. P. Shakhtschneider2
UDC 539.2+543.42
IR spectra of paracetamol and phenacetin have been measured for powder crystals of these compounds and for their solutions in chloroform and dimethylsulfoxide. Ab initio calculations of their equilibrium geometry and vibrational spectra were carried out for spectrum interpretation. Differences between the experimental IR spectra of solutions and crystalline samples have been analyzed. Variations of molecular structure from the isolated state to molecular crystal were estimated based on the difference between the optimized molecular parameters of free molecules and the experimental bond lengths and angles evaluated for the crystal forms of the title compounds. The role of hydrogen bonds in the structure of molecular crystals of paracetamol and phenacetin is investigated, and spectral ranges with maximal intermolecular interactions are determined. Key words: pharmaceuticals, ab initio calculation, molecular crystals, hydrogen bond, intermolecular interaction.
Paracetamol (para-acetaminophenol) and phenacetin (para-acetophenitidine) are widespread pharmaceuticals with analgesic and anti-fever activities. As is known, the biological activity and the pharmaceutical properties of drugs are strongly dependent on their structure. The structural formulas and some physicochemical properties of these compounds have been known for decades. Detailed investigations of their crystal forms, however, were started in recent years [1-13]. For paracetamol, three polymorphic modifications were described [2, 3, 5, 6]. Low-temperature [5, 8-11] and high-pressure [12, 13] diffraction experiments indicate that an important role in crystal structure formation for paracetamol modifications is played by the OH…O and NH…O intermolecular hydrogen bonds [2-13]. Molecular spectroscopy methods, in particular, experimental IR spectroscopy, have long been successfully employed for structure investigations of complex molecular compounds. These techniques are especially effective when used in combination with direct methods of structural analysis in hydrogen bond investigations. At present, few works reporting the IR spectra of paracetamol are available. Thus IR spectra have been published for three of its crystal modifications, and an assignment of the most intense bands has been suggested [6]. The first and, to the best of our knowledge, the single spectroscopic work with full quantum-chemical calculation of the structure and vibrational spectrum of paracetamol appeared in 1998 [14]. The vibrational spectrum calculated with a good (HF/6-31G) basis set and with appropriate scaling of frequencies was successfully correlated with the experimental IR spectrum of a deuterochloroform solution of paracetamol. Full spectrum assignment was made based on the calculation using the shapes of normal vibrations
1
G. K. Boreskov Institute of Catalysis, Siberian Branch, Russian Academy of Sciences, Novosibirsk;
[email protected]. 2Institute of Solid State Chemistry and Mechanochemistry, Siberian Branch, Russian Academy of Sciences, Novosibirsk. 3MDEBT Research and Educational Center, Novosibirsk State University. Translated from Zhurnal Strukturnoi Khimii, Vol. 45, No. 1, pp. 67-76, January-February, 2004. Original article submitted December 2, 2002. 64
0022-4766/04/4501-0064 © 2004 Springer Science+Business Media, Inc.
in accordance with the potential energy distribution over internal coordinates. We do not know of any publications analyzing the vibrational spectrum of phenacetin. The aim of the present work is theoretical and experimental spectroscopic investigation of free molecules and molecular crystals of paracetamol and phenacetin to gain insight into the structure and role of hydrogen bonds in their molecular crystals.
EXPERIMENTAL Paracetamol and phenacetin (commercial samples, Kursk Drug Plant) were purified by recrystallization from an ethanol solution. The orthorhombic modification of paracetamol was obtained from a melt according to the procedure described in [15]. IR spectra were recorded on a Bomem MB-102 Fourier spectrometer (resolution 4 cm–1) for KBr pellets (2 mg sample with 500 mg KBr) and solutions (at first, the spectrum of the solvent was recorded and then the spectrum of the solution was measured in the same cell with subsequent subtraction of the spectrum of the solvent). The solvents used include chloroform, deuterochloroform, and dimethylsulfoxide. Saturated solutions of paracetamol and phenacetin were prepared, then their IR spectra were recorded and processed, and the solutions were successively diluted until the spectrum of the solute completely vanished. Attempts were made to monitor the intermolecular interactions in solutions according to changes in the spectra. As paracetamol has much lower solubility in chloroform and deuterochloroform compared to phenacetin, for spectrum measurements in solution we used a NaCl cell 1.0 mm thick for paracetamol and a KBr cell 0.3 mm thick for phenacetin. In each case, the spectrum of the solvent in a cell of appropriate thickness was subtracted. For spectrum measurements in the near IR range (4000 cm–1 -10000 cm–1), an Interspec 2010 Fourier spectrometer was used. Diffuse scattering spectra of paracetamol and phenacetin powders were recorded, which were subsequently converted into absorption spectra. Ab initio calculation of equilibrium geometry and normal vibration frequencies for paracetamol and phenacetin molecules was carried out using the Gaussian-94/DFT program.
RESULTS AND DISCUSSION Ab initio quantum-chemical calculation of the structure and vibrational spectra of paracetamol and phenacetin molecules was carried out in a density functional theory (DFT) approximation using hybrid (B3LYP) potentials [16]. The DFT method provides the best agreement with experiment for vibrational frequencies and is considered to be the most suitable technique for spectrum calculations of moderately large molecules [17]. The standard 6-31G* basis set was used. For geometry optimization for paracetamol, the Cartesian atomic coordinates obtained from structure determination of the monoclinic modification were specified as initial data [3]. The optimized geometry of paracetamol with the OH group replaced by the ethyl fragment was given as the initial structure for geometry optimization of phenacetin. Frequency assignment for normal vibrations was fulfilled by analyzing atomic displacements in Cartesian coordinates, by calculating the potential energy distribution over internal coordinates (bond lengths and angles, dihedral angles, and coordinates of bond departure from the molecular plane), and by calculating the potential and kinetic energy distribution over the molecular fragments –CH3, –C=O, –NH, –C6H4, and –O–H (for paracetamol) or –CH2CH3 (for phenacetin), or over larger fragments: phenyl, amide, and –O–H or –CH2CH3. Optimization gave planar conformations (with the phenyl and amide fragments lying in the same plane) for both molecules (Fig. 1). The calculated normal vibration frequencies and their assignment are given in Table 1. Theoretical spectra of paracetamol and phenacetin. The X–H high-frequency vibrations above 2900 cm–1 (Table 1) are completely localized on the corresponding molecular fragments of paracetamol and phenacetin, namely, on –OH, –NH, –C4H6, –CH3, and –CH2CH3. Judging from the splitting of the stretching frequencies of the amide methyl fragment, the sym-
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TABLE 1. Normal Vibration Frequencies and Their Assignment Ȟ, theor
form
1
2
3661 3517 3167 3134 3108 3093
QOH QNH QPhH QPhH QPhH QPhH
3092
Q CH3
3090
3000
66
Paracetamol Ȟ, CDCl3
Q CH3 Q CH3
Ȟ, mon
Ȟ, orth
Ȟ, theor
3
4
5
6
3600 3438
3161 3327
3205 3327
3026
3032
Ȟ, CDCl3
Ȟ, cryst
7
8
9
3515 3164 3147 3145 3097 3096
QNH QPhH QPhH QPhH QPhH Q CH 2
3436
3283
3069
3072
3093
Q CH3 amid
3092
Q CH3 + Q CH 2
3091
Q CH3 amid
3005
Q CH 2 + Q CH3
2983
2981
3001
Q CH3 amid
2930
2927
2956
Q CH3
2900
2920
Q CH3
2882
2884
1777 1677 1634 1552 1531 1482
QC=O + GCNH QPh QPh + GCNH GCNH + QPh GCNH + QPh G CH 2 + G CH3
1679 1599 1556 1538 1510 1478
1659,1646 1605 1556 1538 1509 1482
1463
QPh + G CH3
1447
1447
1457
QPh + G CH3
1413
1412
1451
G CH3 amid
1424
1442
G CH 2 + G CH3
1375
1422
G CH3 amid
1412
QPh + G CH3
1394
1393
1391
QPh + G CH3
1370
1369
1356
G CH3 amid
1351
G CH 2 + G CH3
1323
G CH3 + QCN
3041
2964
2927
2926
2940
1779 1682 1642 1559 1529
QC=O + GCNH QPh QPh + GCNH GCNH + QPh GCNH + QPh
1683 1624 1605 1560 1513
1653 1610
1667,1655 1622,1610
1565 1516,1506
1559 1513
1466
G CH3 + QPh
1448
1442
1454
1450
G CH3 + QPh
1438
1428
GCOH + QPh
1423
1423
G CH3
1367
1355
G CH3
1335
QCO + GCNH
1291
GPhH + QCN
1259 1237 1171 1155
GPhH + QCC GPhH + QCC GPhH + GCOH GPhH
1327
1260
1170
1371
1327
Phenacetin form
1326
1260
1280 1243
1279 1262
GPhH + QCN G CH 2 + G CH3
1227
1220
1172
1169
1259 1239 1154 1152 1137 1103
3044
1324 1300
1306 1266
1240
1245 1223
GPhH + QCC GPhH + QCC GPhH G CH 2 + G CH3
1173
1174 1152
QCO + GPh GPhH + G CH3
1116
1116
TABLE 1 (Continued) 1 1095
2 GPhH + G CH3
1015 1006 984 969 952
GCOH + GPhH GPhH + QCC GPhH + QCN GPhH + QCN ȤPhH
872 855 830 799
GPh + QCC ȤPhH ȤPhH GPh + Gamid
765 699 645 621 613 545 511 490 415 412 390
3 1102
4 1107
5 1106
6 1099
7 GPhH + QCO
1015
1015
1015 1006 984 968 939
GPhH + QCC GPhH + QCC GPhH + QCN GPhH + QCN GPhH + G CH3
937 890 864 830 803 793 783 705 643 630 617 545 535 516 441 415 390 382
ȤPhH ȤPhH GPh + Gamid ȤPhH ȤPhH GPh + Gamid ȤPhH ȤCNH + ȤPhH GPh + Gamid GPh + Gamid ȤPh + Ȥamid b(Ph-amid) Gin-plane b(Ph-amid) Gin-plane b(Ph-amid) Gin-plane b(Ph-amid)
1023 968 924
966
856 837 810,795
861 837 797
ȤPhH ȤCNH + ȤPhH GPh + Gamid ȤPh + Ȥamid ȤPh + Ȥamid b(Ph-amid) b(Ph-amid)
730 715,668 650 624 604
727 710 670 625 608
520
513
b(Ph-amid) Gin-plane b(Ph-amid) b(Ph-amid)
504 413
508
392
388
8
1020 1013
9 1107 1048 1020 1013 968 951 923
838 826 785 744
542 520
646 631 605 546 523 456 417 398
Note: Q are stretching vibrations; G, deformation vibrations; F, out-of-plane vibrations (deviation of atoms from the plane of the molecule); b, vibrations corresponding to alteration of the dihedral angle between the planes.
Fig. 1. Ab initio DFT structures of paracetamol (a) and phenacetin (b) molecules.
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metry of the fragment corresponds to C3v symmetry of the free methyl group in both molecules. The nearly free rotation of the methyl group noted [9] for the monoclinic modification of crystalline paracetamol is evidently also due to the minor changes in the parameters of the methyl fragment in the molecular crystal compared to the free methyl group. The vibrations of the methyl fragment of the ethyl group of phenacetin are partially mixed with the vibrations of the –CH2 fragment. The 1779 cm–1 (1777 cm–1 in phenacetin) vibrations are localized on the amide fragment. According to the potential energy distribution over the internal coordinates (more than 57% of which is on the C=O bond), these vibrations may be assigned to the band that is interpreted in experimental spectroscopy as the first band of the amide group. The potential energy of these vibrations also has contributions from the variation of the NCH bond angle and of the bond lengths and angles of the amide methyl group. The frequencies in the range 1682 cm–1 -1530 cm–1 are due to the stretching vibrations of the phenyl ring; the highest frequency is completely localized on the phenyl ring in both molecules, and the other frequencies are mixed with the vibrations of the amide fragment. The largest contribution to the potential energy of these mixed vibrations is from the variation of the NCH bond angle in the plane of the molecule. For lower frequencies from this range, the contributions from the amide and phenyl fragments are approximately the same. Based on the potential energy distribution over the internal coordinates, these vibrations are in a certain sense attributable to the band that is interpreted in experimental spectroscopy as the second band of the amide group. It should be noted, however, that none of the vibrations in this range is localized on the amide fragment. In the range 1500 cm–1 -1300 cm–1, the C–C stretching vibrations of the phenyl group are mixed with the deformation vibrations of the amide methyl fragment; in phenacetin, they are also mixed with the deformation vibrations of the ethyl group. The potential energy of the low frequencies of this range has a contribution from the variation of the CO and CN bonds, but this contribution is too low (20%) to assign any of these frequencies to the stretching vibrations. The vibrations in the range 1291 cm–1 -950 cm–1 are in-plane deformation vibrations of the C–H bonds of the phenyl ring, which are mixed [except the 1155 (1154) cm–1 frequencies] with the stretching and deformation vibrations of the amide fragment (and also with the deformation vibrations of the ethyl group in the case of phenacetin). Starting from 952 cm–1 for paracetamol and 937 cm–1 for phenacetin, one can observe the out-of-plane deformation vibrations of the phenyl C–H bonds; these are mixed with the deformation vibrations of the C–C bonds accompanied by the departure of the carbon atoms from the plane of the phenyl ring. Some of these are completely localized on the phenyl fragment, while the others are mixed with the deformation and out-of-plane vibrations of the amide group. The frequencies below 600 cm–1 correspond to the in-plane and out-of-plane (alteration of the dihedral angles between the planes of the phenyl and amide groups) vibrations of molecules and are not localized on any fragments. Thus our calculations enabled us to assign the calculated frequencies within the framework of the group frequency concept, which is conveniently used for interpreting the experimental data. Experimental spectra of paracetamol and phenacetin. In nonpolar solvents (chloroform and deuterochloroform), the spectra of paracetamol and phenacetin are not changed by dilution, indicating that no solute–solvent and solute–solute interactions take place in solution. Figures 2 and 3 show the spectra of the CDCl3 solutions of paracetamol and phenacetin; Table 1 lists the frequencies. The calculated frequencies of free paracetamol and phenacetin molecules are similar to the frequencies in the experimental spectra of diluted chloroform and deuterochloroform solutions of these compounds. Therefore, one can conclude that the calculated molecular parameters (bond lengths and angles, dihedral angles, and force constants) are similar to the corresponding parameters of free molecules. Our DFT calculation is slightly better in reproducing the experimental frequencies of paracetamol than the calculation of [14]. The maximal divergence of the unscaled frequencies is 435 cm–1 in [14] and 96 cm–1 in our calculation. It seemed useful to give our assignment of the calculated normal vibration frequencies for paracetamol (Table 1), although it does not differ fundamentally from [14].
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Fig. 2. IR spectra of paracetamol and phenacetin in the region of XH vibrations: 1) CDCl3 solution of paracetamol; 2) CDCl3 solution of phenacetin; 3) monoclinic modification of paracetamol; 4) orthorhombic modification of paracetamol; 5) crystalline phenacetin.
Fig. 3. IR spectra of paracetamol and phenacetin in the range 2000 cm–1 400 cm–1: 1) CDCl3 solution of paracetamol; 2) CDCl3 solution of phenacetin; 3) monoclinic modification of paracetamol; 4) orthorhombic modification of paracetamol; 5) crystalline phenacetin. For the spectra of solutions, the assignment of the experimental 3600 cm–1 and 3438 cm–1 absorption bands (ABs) to the OH and NH stretching vibrations in paracetamol and of the 3436 cm–1 band to the NH stretching vibrations in phenacetin does not raise any doubt. The weak ABs above 3000 cm–1 are also unambiguously assigned to the C–H stretching vibrations of the phenyl ring, and the stronger bands above 2800 cm–1 are attributed to the stretching vibrations of the methyl and ethyl groups (Fig. 2, 1, 2; Table 1).
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Fig. 4. Near IR spectra of monoclinic paracetamol (1) and crystalline phenacetin (2). In the case of the crystal modifications of the compounds (Fig. 2, 3-5), this range is much more difficult to interpret. The spectra of crystalline powders differ significantly from the spectra of solutions. First, the intermolecular interactions are most conspicuous in this spectral region because of the displacement and broadening of the absorption bands caused by hydrogen bonding. Second, interpreting the spectral region above 2500 cm–1 is complicated by the presence of overtones and composite frequencies. In view of the Fermi resonance, the intensity of these bands may be anomalously high. The presence of anharmonic frequencies in great numbers in the spectra of paracetamol and phenacetin is also confirmed by the experimental spectra of the crystalline powders in the near IR region (Fig. 4). According to our calculation, the intense 1683 cm–1 band of a paracetamol solution and the 1679 cm–1 band of a phenacetin solution (nonpolar solvents in both cases) correspond to the first band of the amide group, more than 57% of their potential energy reflecting the state of the C=O bond. In the spectra of the two crystal modifications of paracetamol and crystalline phenacetin, the frequency of this vibration is 20 cm–1 -30 cm–1 lower than that in the spectra of the molecular forms. For the monoclinic modification of paracetamol, this is a single vibration band (1654 cm–1); for the orthorhombic modification, there are two bands (1667 cm–1 and 1656 cm–1). In the spectrum of crystalline phenacetin, this is the 1659 cm–1 band with a shoulder at 1646 cm–1. In the range 1625 cm–1 -1000 cm–1, the spectra of the solutions and crystal forms of paracetamol (Fig. 3, 1, 3, 4) and phenacetin (Fig. 3, 2, 5) differ mainly in the relative intensity and in the number of absorption bands, while the position of the fundamental bands changes insignificantly and the experimental spectra are rather close to the theoretical spectra (Table 1). Below 1000 cm–1, the spectra of solutions could not be obtained for any of the two compounds because of solvent absorption and the narrow spectral ranges of solvent transparency, leading to unreliable spectrum subtraction. Therefore in the range 1000 cm–1 -400 cm–1, Fig. 3 shows only the spectra of the crystal forms of the compounds. The assignment of the relevant absorption bands in the spectra of the crystalline samples based on the assignments in the theoretical spectra seems to be quite correct because of good agreement between the theoretical and experimental frequencies (Table 1). Spectral features indicative of intermolecular interactions. The molecular crystals of paracetamol and phenacetin are suitable model systems for investigating intermolecular interactions. The paracetamol molecule includes two potential donor (N–H and O–H) and two acceptor (C=O and H–O) groups, while the phenacetin molecule has one donor (N–H) and one acceptor (C=O) groups, which can be involved in hydrogen bonding in molecular crystals. The OH group is both proton donor and acceptor (–NH…OH…O=C–), while the NH group is a proton donor alone. The difference between the optimized parameters of the free paracetamol and phenacetin molecules (Fig. 1) and the experimental bond lengths and angles of their crystal forms is associated with the presence of hydrogen bond systems in the crystals of these compounds [2-13, 20]. The paracetamol molecule is planar in the free state, but not in molecular crystals, where the angle between the planes of the amide and phenyl fragments is about 22q. This may be due to the fact that both OH
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and NH groups form hydrogen bonds of varying strength [14, 18]. In the phenacetin molecule, there are no OH groups, NH being the only group involved in hydrogen bonding. This molecule is planar in the free state and in molecular crystal [20]. According to neutron diffraction data obtained in precision experiments [11], intermolecular hydrogen bonding leads to lengthening of OH and NH bonds in the crystal forms of paracetamol (Fig. 1). The difference between the spectra of crystalline powders and those of diluted solutions of paracetamol and phenacetin, which is especially conspicuous in the region of the X–H stretching vibrations, is a spectral indication to the presence of a system of hydrogen bonds in paracetamol and phenacetin crystals. Based on the data of [2-13] about the presence of a system of hydrogen bonds (–NH…OH…O=C–) in molecular crystals of paracetamol and using the results of spectral studies at elevated hydrostatic pressures and reduced temperatures [18, 19], we suggest the following assignment of experimental frequencies in the spectra of the crystal modifications of paracetamol and phenacetin. The narrow 3324 cm–1 and 3327 cm–1 bands in the monoclinic and orthorhombic modifications of paracetamol, respectively, and the 3283 cm–1 band in the spectrum of phenacetin are assigned with confidence to the QNH stretching vibrations. The broader bands with maxima at 3161 cm–1 and 3205 cm–1 in the monoclinic and orthorhombic modifications of paracetamol are attributed to the QOH mode. The large shifts of these frequencies compared to the spectra of solutions, as well as the complex shape of the absorption contours, point to the presence of a system of strong hydrogen bonds (NH…O and OH…O) in the molecular crystals of both modifications of paracetamol and NH…O in the molecular crystals of phenacetin. This agrees with the results of diffraction studies [2-5, 7-13] including studies at reduced temperatures and elevated pressures. The lowering of the QXH frequency due to hydrogen bonding compared to the spectrum of the free molecule is a direct measure of hydrogen bond strength. Therefore, one can assume that in the monoclinic modification of paracetamol, the –O–H…O hydrogen bonds ('QOH = 440 cm–1) are slightly stronger than those in the orthorhombic modification ('QOH = 400 cm–1). This agrees with the conclusions based on the diffraction analysis of the geometrical parameters of hydrogen bonds [13, 18]. Similarly, from the shifts of the QNH frequencies ('QNH = 110 cm–1) one can assume that in both crystal modifications of paracetamol, the –N–H…O hydrogen bonds are approximately equal in stability and are less stable than the N–H…O hydrogen bonds in phenacetin crystals ('QNH = 153 cm–1). As intermolecular hydrogen bonding in the latter is only possible to NH groups, one would expect that the NH stretching vibration frequency will decrease more drastically compared to the spectrum of the free molecule. Indeed, in the crystal forms of paracetamol, the QNH frequency has a 44 cm–1 smaller shift than in phenacetin crystals relative to the position of this frequency in the molecular state that is free from hydrogen bonds. The C=O bond length was calculated to be 1.226 Å (Fig. 1) for the optimized structure of free paracetamol and phenacetin molecules, 1.235 Å for monoclinic paracetamol, and 1.241 Å for crystalline phenacetin. The larger C=O bond length and the correspondingly decreased QC=O frequency unambiguously indicate that hydrogen bonding leads to a redistribution of electron density. In the spectra of both crystalline modifications of paracetamol and crystalline phenacetin, the frequencies in the range 1660 cm–1 -1640 cm–1, reflecting the state of the C=O bond (denoted for simplicity QC=O), are 20 cm–1 -30 cm–1 lower than in the spectra of the molecular form. This is another indication to strong intermolecular interactions involving the C=O bond in crystals. We traced the effect of intermolecular interactions on the QC=O frequency in the spectra of DMSO solutions of paracetamol and phenacetin. The QC=O frequency was slightly shifted in both paracetamol and phenacetin solutions depending on the solution concentration; it was roughly the same — around 1670 cm–1, which is lower than in the molecular form and higher than in crystal forms. Probably, the formation of hydrogen bonds between the S=O group of DMSO and the NH and OH groups of paracetamol, as well as the NH group of phenacetin, also leads to an electron density redistribution on the C=O bond, which is manifested as the decreased QC=O frequency.
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The larger shift of QC=O in the monoclinic form of paracetamol versus the orthorhombic form relative to the same frequency in a molecule that is free from hydrogen bonds also points to stronger hydrogen bonds in the monoclinic modification of paracetamol. The spectral features responsible for hydrogen bonding in the crystals of the two polymorphic modifications of paracetamol and phenacetin recorded at low temperatures and elevated pressures will be discussed in our next communication [19].
CONCLUSIONS Ab initio quantum-chemical calculations of the geometry and vibrational spectra of para-acetaminophenol (paracetamol) and para-acetylphenitidine (phenacetin) have been carried out. Based on the similarity between the frequencies in the calculated spectra of free paracetamol and phenacetin molecules and the frequencies in the experimental spectra of solutions of these compounds in nonpolar solvents, it is concluded that the calculated molecular parameters (bond lengths and bond and dihedral angles) agree with the corresponding parameters of free molecules. The calculated distributions of the potential and kinetic energies over fragments of the two molecules (–CH3, –C=O, –NH, C6H4, CO, and OH for paracetamol and CH2CH3 for phenacetin) permitted us to determine the spectral ranges in the experimental spectra corresponding to the vibrations of these fragments. The spectra of the solutions differ significantly from the spectra of the crystalline powders, especially in the range 2800 cm -3600 cm–1 corresponding to the OH, NH, and CH stretching vibrations of paracetamol and NH and CH stretching –1
vibrations of phenacetin. This spectral region contains overtones. In the range 400 cm–1 -10000 cm–1 for crystalline powders, a spectrum of anharmonic frequencies has been recorded. The effect of hydrogen bonds on the frequencies has been investigated. It has been shown that the intermolecular hydrogen bonds formed by the OH…O and NH…O groups of paracetamol and NH…O=C of phenacetin play an essential role in molecular crystals of these compounds. Comparison of the calculated structural parameters of free molecules of paracetamol and phenacetin and comparison of these values with bond lengths and bond and dihedral angles in crystal forms have made it possible to evaluate structural changes due to intermolecular interactions. This work was supported by CRDF and RF Ministry of Education grant REC-008, by DLR grant RUS-131-98, and by RF Ministry of Education (Integration Program) grants 274, Ch0069, and E-00-5.0-81.
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