摘要:

J. CHEM. SOC. PERKIN TRANS.2 1990 Prototropic Tautomerism in N,N-Dimethyl-"-(I -nitro-9-acridyl)propane-l,3-diamine and its Nitro Isomers. Application of MNDO and PPP Methods for the Examinationof Structure and Electronic Absorption Spectra Anna Tempczyk Janusz Rak and Jerzy B+aFejowski * Institute of Chemistry University of Gdarisk 80-952 Gdarisk Poland N,N-Dimethyl-N'-(1 -nitro-9-acridyl)propane-l,3-diamine (LedakrinB or nitracrine) which exhibits distinctive anticancer activity and its three nitro isomers can potentially exist in two or three tautomeric forms (amino imino aci). This is due to the possibility of migration of the hydrogen atom which is bound to the nitrogen atom attached to carbon C-9 to the acridine ring nitrogen or to the nitro group. The structures of several possible tautomers were determined by geometry optimization using the MNDO method.The latter procedure enabled also the evaluation of (i) the heats of formation (ii) the dipole moments and (iii) the ionization potentials to be undertaken. From these structures the frequencies of electronic transitions and the oscillator strengths for individual tautomeric forms were calculated using an adaptation of the PPP method. The evaluated UV absorption spectra were compared with experimental data. It was revealed that the observed absorption in the long-wavelength region is characteristic for a given molecule. Moreover in the case of a given isomer the absorption can be readily explained by the results of theoretical calculations presented here assuming that the molecule may occur in various accessible tautomeric forms.The biological activity of acridine derivatives has been known aqueous solution.23 The main aim of the present study is to since the end of the last century.2 Many different biological reveal which structures can be expected for nitracrine and its activities of acridines have been disclosed e.g. antibacterial three nitro isomers in different accessible tautomeric forms in antivirial antimalarial and analeptic activities (see e.g. refs. gaseous and inert liquid phases and further how these 3-6). Special attention has been devoted to this group of structures influence physicochemical properties of individual compounds however since their anticancer activity was docu- tautomers and their electronic absorption spectra.Lastly we mented.7-12 N,N-Dimethyl-N'-(l-nitro-9-acridyl)propane-1,3-wanted to know which forms are probable in liquid solutions diamine which is known under the name nitracrine (WHO) or and how features of the medium may influence existing in Poland Ledakrim (e.g. refs. 9-12 and references cited equilibria. The results of this study may shed more light on the therein) exhibits among other effects such anticancer activity. features of specific biological activity of the drug and on the The mechanism of the antitumour action of nitracrine has been structure-activity relationships. the subject of extensive investigation^.^^'^*' 3-16 In addition To achieve these goals we combined UV absorption other papers have been devoted to the examination of the measurements with theoretical calculations using semiempirical chemical and physical properties of both nitracrine and its MNDO and PPP methods.Application of the MNDO method isomers.' '*I7 These studies were undertaken in order to shed resulted from the fact that it correctly reproduced tautomeric more light on the nature of the biological activity of this group equilibria in several other system^.^^,'^of compounds to find connections between their structure and their biological activity and to extend our knowledge regarding the behaviour of the compounds in the liquid phase and perhaps in bodily tissues. Our two earlier reports were concerned with Materials and Methods the latter problem.'8*19 In the present work we have turned our Chemicals.-N,N-Dimeth yl-N '-(1-nitro-9-acridyl)propane-attention to the tautomeric phenomena in nitracrine and its 1,3-diamine and its isomers were synthesized as dihydro-three nitro isomers in solution.chlorides and purified by the method reported in the liter- The prototropic tautomerism of these derivatives is known at~re.'~.~~The compounds were kindly supplied by Professor J. from crystallographic investigations.' 1*20-22 Th ese studies re- Konopa and his research group from the Technical University vealed that a molecule of nitracrine in the solid phase exists in of Gdansk. The free bases were obtained by the alkalization of the non-planar imino tautomeric form which is characterized by aqueous solutions of original compounds with K2C03 and the fact that the central ring system is folded at an angle along extraction with toluene.The extracts were subsequently dried the C(9) .N( 10) axis. Moreover the nitro group in position 1 over anhydrous MgSO filtered and evaporated under reduced is tilted with a torsion angle of ca. 60' to atoms in the acridine pressure. The purity of both hydrochlorides and free bases was ring.20 On the other hand the 2-nitro isomer exists as a planar examined by TLC.28 amino tautomer with coplanarity between the acridine nucleus Solvents i.e. hexane methanol and toluene all from and the nitro group.2 ' These distinctive structural differences Mallinckrodt and ethanol (P.O.Ch. Poland) of spectroscopic between nitroacridin-9-amines have been considered to be the grade were used as received.main factor determining the unique anticancer activity of nitracrine.8*20-22It is also worth mentioning that differences in Apparatus.-Spectral measurements in the UV and visible the behaviour of nitracrine and its isomers upon hydrolysis have regions were carried out on SPECORD M40and VSU-2P (Carlbeen attributed to the existence of tautomeric equilibria in Zeiss Jena) spectrophotometers. Calculations.-The geometry optimizations were performed by the standard MNDO method with the DFP optimization pr~cedure.~’For these optimizations it is necessary to know the starting geometry of the compounds studied. Such geometry can be chosen from the crystallographic data.Unfortunately so far only crystal structures for the 1-nitro isomer (which crystallizes in the imino tautomeric form) and the 2-nitro isomer (which crystallizes in the amino form) are Using these data we chose starting structures of amino forms of all four isomers by keeping the solid-state geometry of the acridine nucleus of the 2-nitro isomer and changing the position of the nitro group. Analogously the starting structures of all imino tautomers were chosen by adopting the crystallographic data for the 1-nitro isomer. Because of the lack of crystallographic data for aci tautomeric forms we assumed starting structures of appropriate 2-nitro and 4-nitro isomers by chemical intuition. As seen in substructure (1) the acridine skeleton in the aci form J.CHEM. SOC. PERKIN TRANS. 2 1990 C(14)-C(9)-C( 11)-N( 18). The latter is quite characteristic of the imino form. Therefore the starting structure of the acridine nucleus in the aci form was assumed to be a combination of the structural elements of both amino and imino forms. This skeleton was combined with structural elements of the uci- nitro group which were obtained from the optimization of nitromethane in the aci form by use of the MNDO method. Because of the limited capability of our computer (all calculations were performed on an IBM PC/AT) we kept unchanged during the optimizations the internal co-ordinates of all the hydrogen atoms except those in the close neighbourhood of the polar groups. Further in amino and aci tautomeric forms we assumed the geometry of the acridine nucleus to be planar.Lastly we substituted a methyl group for R (see Scheme). The above mentioned simplifications undoubtedly influenced some- what the physicochemical characteristics obtained on the basis of the MNDO method (Table 1) but should not affect the is similar to that for the amino form except for the fragment subsequently derived spectral characteristics. For the structures obtained by optimization with the MNDO method several 18 characteristics were also computed on applying the INDO pr~cedure.~’These characteristics are shown in Table 1. Primarily we used the CNDO/S CI method3’ to predict the ,h2UV spectra of the compounds studied. Unfortunately the 63N12 ’3 derived characteristics (k,positions of electronic transitions 5 10 4 and oscillator strengths) corresponded very poorly to the (1) experimental absorption spectra.In particular the method did Numeration of atoms in acridin-9-amines.” not predict any bands in the long-wavelength region i.e. Amino form lmino form aci form isomer (symbol ref. 17) R = [CHA3N(Me)2 R = Me 1 -nitro (C-283) (C.-283) RN .O RN 2 -nitroAN”(C-264) (C. -264) 3-nitro (C-257) (C’ -257) RNH RN RN 4 -nitro (C-265) (C’-265) N oJ *o H OM N*o OJN‘OH Scheme. Tautomeric equilibria in nitro isomers of N,N-dimethyl-N’-(nitro-9-acridyl)propane-1,3-diamines and N-(nitro-9-acridyl)methanamines. J. CHEM. SOC. PERKIN TRANS. 2 1990 1503 Table 1. Physicochemical and spectral characteristics for isomers of N-(nitro-9-acridyl)methanamine. Physicochemical characteristics Spectral characteristics MNDO for the long-wavelength Compound region Dipole Energy of INDO Symbol AHfI moment Oscillator (see Scheme 1) Tautomer kcal mol-’ p/D HOMO/eV LUMO/eV E,,,/eV PID hlnm strength C-283 amino 104.0 3.45 -8.796 -1.661 -4708.471 2.97 485.8 0.225 342.3 0.142 324.5 0.189 imino 91.1 6.48 -8.723 -0.882 -4709.302 7.61 433.5 0.633 427.5 0.169 296.4 0.133 C’-264 amino 93.0 6.20 -8.742 -1.700 -4 708.871 5.33 478.7 0.189 399.9 0.097 345.8 0.256 imino 88.1 8.32 -8.929 -1.142 -4 709.530 8.46 466.7 0.731 407.0 0.210 309.6 0.117 aci 112.9 1.36 -8.249 -1.851 -4705.916 3.29 412.3 1.186 309.9 0.167 311.4 0.259 aci-anion 541.6 1.154 416.3 0.260 320.0 0.088 C’-257 amino 93.1 7.67 -8.929 -1.142 -4 708.929 7.34 498.5 0.141 450.8 0.123 319.6 0.146 imino 89.8 6.60 -8.804 -1.282 -4 709.428 6.35 495.6 0.141 439.2 0.504 386.2 0.159 C’-265 amino 108.6 8.29 -8.644 -1.640 -4 708.241 8.51 461.8 0.350 370.5 0.100 316.9 0.339 imino 94.4 4.54 -8.747 -1.203 -4709.488 3.76 516.7 0.555 403.0 0.260 306.2 0.046 aci 112.7 1.65 -8.120 -1.661 -4694.984 2.67 483.4 0.528 377.4 0.330 322.1 0.055 aci-anion 585.5 0.589 390.6 0.323 36 1.4 0.062 1 cal = 4.184J.1 D = 3.34564Cm. Table 2. PPP Parameters for -N02H and -NO2 -groups. group were assigned following Gordon and Ne~mer.~’ For nitrogen atoms in an acridine ring and in the amino group the Valance state values of the PPP parameters were estimated using the results ofionization One-centre Resonance Group Atom potential integrals integrals MNDO optimizations and employing a procedure described el~ewhere.~~.~~For these evaluations the core charges obtained C -11.57 11.33 from the MNDO calculations were used to derive the valence- =N Po N -22.27 15.72 PC-N 2.55 state ionization energies and these values were then employed ‘OH Ot -21.24 15.35 Pro2-58 to evaluate the one-centre electron-repulsion integrals on the 0-28.54 17.80 PN4 2-11 basis of the method described by Dewar and M~rita.~~ The -12.14 11.61 values of resonance integrals (pi,j) were estimated following the -22.31 15.74 Pc-N 2-14 empirical expression of Kulkarni et uI.,~’ which relates pi,j-0 -19.58 14.74 PN-0 2-70 values with changes in the valence-state ionization potential of the i-th atomic centre.Similarly the values of the PPP parameters for the nitro group in either neutral aci or h > 400 nm. Therefore we made an attempt to employ the PPP appropriate anionic forms were derived. For this purpose we method for spectral evaluation^.^^ Another reason for using the used values of core charges derived by the MNDO method for PPP method was that predictions regarding the energy of both the neutral aci form and the appropriate anionic form of electronic transitions by this method are usually better than in nitromethane. To our knowledge PPP parameters for the nitro the case of the CNDO/S method.33 The parametrizations for group in the aci form have not so far been reported.Thus they carbon atoms were The PPP parameters for the nitro are shown in Table 2. C‘-283 amino d d d imino C‘-264 d d amino imino aci Figure 1. The stereoviews of C’-283 and C’-264 molecules in their accessible tautomeric forms. To estimate the changes in values of resonance integrals with distance Kon’s formula was applied.39 The changes in pi,,integrals caused by nonplanarity of the central ring in the imino form or by the twist of nitro or amino groups against the acridine nucleus were accounted for by making them dependent on the appropriate torsion angle.40 The two-centre repul- sion integrals were evaluated using the Mataga-Nishimoto formula.41 J. CHEM.SOC. PERKIN TRANS. 2 1990 Results and Discussion Structural Features of N-(Nitro-9-acridyl)methanamines.-The views of the C’-283 and C’-264 molecules in their accessible tautomeric forms are presented in Figure 1. Examination of all four isomers in all their possible tautomeric forms revealed that the structural features of both amino and imino forms of the 1-nitro isomer differ from those characteristic of other isomers. This particularly concerns the arrangement of the nitro group. The torsion angle of the -NO group against the closest aro- matic ring is 40 and 87” for the amino and imino forms of C’- 283 respectively. In the amino and imino tautomers of the other three isomers the nitro group is much less tilted from planarity with the benzene ring to which it is attached.The optimization procedure also predicted that the -N02H fragment of the aci nitro group in C’-264 and C’-265 is almost planar with the acridine ring. In the latter compound the OH fragment of the aci nitro group is directed outwards N(10). Because of the steric hindrances caused by the R substituent at N(18) the amino group is always twisted against the acridine ring at angles of 69 57 63 and 59” for C’-283 C’-264 C’-257 and C’-265 respectively. In the imino and aci tautomers the arrangement of the imino group is governed by the double-bond character of the C(9)-N( 18) bond. Further information provided values of some dihedral angles showing the nonplanarity of the central acridine ring in the imino form.So for example the C(l4)-C(9)-C(ll)-C(12) angle is 25 27 24 and 21” for the C’-283 (7-264 C’-257 and C’-265 isomers respectively. The above discussion as well as further examination of structures reveals that the 1-nitro isomer occupies a distinctive position among the compounds studied. This results from the presence of two relatively large groups close together in the C’-283 molecule namely the nitro group and the substituted amino group. Physicochemical Characteristics and Relative Stability of Tautomerx-Some physicochemical characteristics obtained after optimization by the MNDO method as well as those obtained using the INDO method enable a comparison of the expected stability and behaviour of various isomers and their tautomeric forms to be undertaken.Both the MNDO heats of formation and the total energies (I?*,,) from the INDO method seem to indicate that imino tautomers should be thermodynamically more stable than the corresponding amino ones. On the other hand the aci forms in structures C’-264 and C’-265 are characterized by higher values of AH (from MNDO) and E, (from INDO) which means that the existence of the compounds in these structures is not very likely either in the gaseous phase or in solution. It may however be noted that the INDO total energy for the aci-C’-264 tautomer is lower in comparison with that for the aci-C‘-265 one. The values of the dipole moment (p) evaluated by both the MNDO and INDO methods are comparable.Generally the lowest p values characterize the aci tautomeric forms. The examination of the data in Table 1 reveals that for 1-nitro and 2-nitro isomers p values for imino tautomers are higher than those for the appropriate amino tautomers. For C‘-257 and C-265 isomers the tendency is reversed. Additional information provided values of energies of HOMO and LUMO orbitals. Among others they may be related to the redox properties of the compounds studied. UV Spectra of N,N‘-Dimethyl-N’-(nitro-9-acridyl)propane-1,3-diamine Isomers.-The experimental absorption spectra of the four N,N-dimethyl-N’-(nitro-9-acridyl)propane-1,3-diamine isomers studied are shown in the upper graphs in Figures 2-5. These spectra reveal the existence of essentially two bands in the long-wavelength region.The lowest energy band with a maximum at ca. 450 nm extends up to 600 nm. The J. CHEM. SOC. PERKIN TRANS. 2 1990 Unm 200 240 280 350 400 500 600 ,II1 1 I I 0.8 2 0.4 2 0.0 50 42 34 26 18 iT/1 o3 ern-’ Figure 2. The experimental (A c 4.6 x lC5 mol dm-3 in hexane; B spectrum amplified 8 times) absorption spectra of N,N-dimethyl-”-( 1-nitro-9-acridyl)propane-1,3-diamine[absorbance log,o(Zo/I)] together with the calculated transition frequencies for amino ( I ) and imino (A ) tautomeric forms. Unm 200 240 280 350 400 500 600 a 0.8r t I I I I -1.0 o.o- ili,~11I1,.hh dJ1 ,/I I JI I,I I Unm 200 240 280 350 400 500 600 50 42 34 26 18 v/1o3cm-’ Figure 4.The experimental (c 4.6 x lO-’ rnol dm-3 in hexane)absorption spectrum of N,N-dimethyl-N’-(3-nitro-9-acridyl)propane-1,3-diamine together with the calculated transition frequencies for amino ( I ) and imino (A ) tautomers. position of this band is affected only slightly by the properties of the medium in the case of C-264,I8 C-257,I8 and C-265’ isomers. However the long-wavelength band of the 1-nitro ‘isomer is observed only in non-polar and aprotic solvents (Figure 2). ’ Unm 200 240 280 350 400 500 600 8 1.2 c a 0.8 2 a 0.4 0.0 r 2.0 1 .o 3.0 50 42 34 26 18 w o3em-’ Figure 5. The experimental (A c 4.6 x mol dme3; and B c 9.3 x lW5 mol dm-3; both in hexane) and predicted (C) absorption spectra of N,N-dimethyl-N‘-(4-nitro-9-acridyl)propane-1,3-diamine together with the calculated transition frequencies for amino ( I ) imino (A ) and aci (1) forms. On moving towards the higher energy region a second band system occurs between 300 and 400nm.Contrary to the long- wavelength absorption presented above the latter one i.e. between 300-400 nm is somehow characteristic of a given isomer. Moreover it is influenced noticeably by the properties of the solvent.’-’8 In the case of the C-283 isomer the long- wavelength band (at 450 nm) declines in polar and protic solvents whereas the band between 300-400 nm becomes stronger.I8 All the above facts would suggest that both band systems discussed i.e. the one at ca. 450 nm and that occurring between 300-400 nm might arise from two different forms of the compounds co-existing in the liquid phase.Experimental versus Theoretical Electronic Absorption Spectra.-The above hypothesis necessitates further confirm- ation which is provided by the results of theoretical evaluations. They are presented on the lower graphs in Figures 2-5 in which calculated energy transitions are drawn as lines. The height of each line is proportional to the evaluated oscillator strength df)for a given electronic transition. To facilitate the comparison of experimental absorption charac- teristics with theoretical ones let us primarily assume that the spectra result from the existence of the compounds studied in accessible tautomeric forms. As demonstrated in Figures 2-5 in the region discussed above the PPP method predicts electronic transitions for all possible tautomers.Since the thermochemical data in Table 1 tend to exclude the possibility of the occurrence of isomers C-264 and C-265 in aci tautomeric forms it may be assumed that only electronic transitions for amino and imino forms actually determine the absorption spectra. It is somewhat difficult to imagine the shape of the analysed spectra on the basis of the predicted electronic transitions. Thus for the C-265 isomer we made an effort to evaluate the spectrum by assuming that each transition can be approximated by a Gaussian curve. Further we chose band widths and a ratio between both tautomers such as to obtain the best fit to the experimental absorption spectrum.As seen in Figure 5 the shape of the predicted spectrum approximates well to the experimental curve at a ratio of [amino]:[imino] 0.65:0.35. For other isomers such a procedure did not lead to such a good reproduction of the shape of the experimental absorption J. CHEM. SOC. PERKIN TRANS. 2 1990 Unm Unm 300 350 400 450 500550 300 350 400 450500 550 I I I Ill \I I I I 0 9 (A) -\ i -0 7-be-€5-E 4--0 m 3-z2-1-O; 34 30 26 22 18 34 30 26 22 18 VIIo3cm-l VIIo3 cm-’ Figure 6. The absorption spectra of compounds (I) (a) and (11) (b) with known imino structure in hexane (-. -) methanol (-) and toluene (-)a 7 v-‘5-5 54E “E“’ 2 Z1’3 0 280 360 440 520 600 680 760 Unm Figure 7.The absorption spectra of N,N-dimethyl-N’-(2-nitro-9-acridyl)propane-l,3-diamine in ethanolic sodium ethanolate (A) and N,N-dimethyl-N’-(4-nitro-9-acridyl)propane-1,3-diaminein ethanol (B) and ethanolic sodium ethanolate (C) together with the calculated transition frequencies for aci-anionic forms of C-264(1) and C-265(A )* spectra as shown for C-265. Data in Figures 2-4 demonstrate that for C-283 C-264 and C-257 isomers the first long-wave- length transition corresponds to amino forms whereas for the C- 265 isomer it corresponds to the imino form. The separation of the predicted transitions corresponding to the amino and imino forms is not generally large enough to enable one to ascribe the observed long-wavelength bands in the experimental spectra to certain tautomeric forms of a given isomer.Owing to the lack of symmetry elements in the compounds studied it is rather difficult to describe these electronic transitions on the basis of group theory as has been done for related symmetric compounds.42 Analysis of the direction of the transition moment indicates however that electronic excitation corresponding to the first long-wavelength transition is always accompanied by a shift of electronic density towards .the nitro group. To gather more information regarding the above analysis of the long-wavelength absorption region we have presented in Figure 6 the spectra of two available compounds in which the imino structure was blocked. It can be seen that compounds (I) and (11) are structural analogues of the 1-nitro isomer in the imino form.Compound (I) was synthesized by Horowska et The second compound (11) was prepared by Wysocka- Skrzela and its structure was confirmed by X-ray analysis.44 The substituents at N( 10)of these derivatives are such that they should not influence the long-wavelength electronic transitions. Indeed comparison of the spectra shown in Figure 5 with those &I The compounds with blocked imino structure. reported earlier in ref. 18 (Figure 2) clearly indicate that the band system occurring between 350-400 nm corresponds to the imino tautomer of N,N-dimethyl-”-( 1-nitro-9-acridy1)- propane- 1,3-diamine. The Existence of aci Tautomers.-As has been noted above the aci tautomers of isomers C-264 and C-265 are thermo- dynamically much less stable than the other two forms. This led to the conclusion that essentially both the above compounds cannot exist in the aci form.Nevertheless it would be interesting to show that the aci structure can exist. In the case of the equilibria studied such structures would be constrained by the imposition of certain conditions. Some published reports suggest that the tautomeric conversion of the nitro group into the aci structure takes place in an EtOH-EtONa medi~m.~~.~~ The absorption spectra of the 2- and 4-nitro isomers in an EtOH solution of sodium ethanolate are presented in Figure 7. The spectrum of the 2-nitro isomer exhibits a new strong absorption with a maximum at ca.550 nm. The band ascribed to the amino form which generally occurs between 450 and 500 nm [Figure 2(B) ref. 181 completely disappears. In moving towards higher energy transitions a second band with two maxima between 400 and 420 nm is seen. This remarkable change in the absorption spectrum of the 2-nitro isomer may of course be observed visually. Solutions of N,N-dimethyl-N‘-(2-nitro-9-acridyl)pro-pane- 1,3-diamine in ethanol (or neutral media) are red-yellow whereas the compound dissolved in ethanolic sodium ethano- late is blue-violet. The 4-nitro isomer dissolved either in ethanol or in EtOH-EtONa does not change its colour noticeably. The absorption spectra of C-265 in both media are very similar (Figure 7) although the spectrum in EtOH-EtONa exhibits a characteristic tail.It is worth mentioning that the absorption of 2-nitro and 4-nitro isomers observed in the EtOH-EtONa medium described above disappears in neutral and acidic media and reoccurs in EtONa solution. Isomers C-283 and C-257 naturally cannot exhibit the absorption which is characteristic of aci structures although in the EtOH-EtONa medium the intensity of the bands resulting from amino and imino forms changes in comparison with that observed in neutral media. The latter phenomenon is presumably due to the changes in the polarity of the medium which is used. It is worth mentioning also that the existence of an aci form of 2-nitroacridin-9-amines has also been put forward on the basis of polarographic st~dies.~~,~~ In strongly alkaline media the structure which can actually exist is an anionic form of the appropriate aci tautomer.For such structures obtained by the removal of the proton from the -N02H group the electronic transitions were evaluated by the PPP method. The predicted long-wavelength transitions for the aci anionic structure of C- 264 correspond well to the experimental absorption bands. For the C-265 aci anionic form the PPP method also predicts transitions in the long-wavelength region. The corresponding bands are not however observed in the experimental absorp- tion spectrum. It is difficult to explain why the C-264 isomer can be forced into an aci anionic structure and C-265 can not. The explanation might be that the total energy value from INDO is J.CHEM. SOC. PERKIN TRANS. 2 1990 much higher for the aci-C-265 form than for the aci-C-264 tautomer. If the transition state for the formation of anionic forms were the appropriate mi forms it would mean that the conditions chosen were not sufficient to force a C-265 molecule of relatively lower thermal stability compared with that of aci- C-264 into an anionic form. Influence of Solvent on the Electronic Absorption Spectra and Tautomeric Equilibria.-The results of theoretical calculations regarding structural examinations as well as the physico- chemical characteristics and spectral properties of the nitro isomers of N,N-dimethyl-N’-(nitro-9-acridyl)propane-1,3-di-amine imply that the two long-wavelength bands probably arise from the two tautomeric forms of the compounds existing in the liquid phase.The imino structure of the 1-nitro isomer in which the compound exists in the solid phase is also retained in polar or protic solvents.18 However the equilibrium moves towards the amino tautomeric form in non-polar and aprotic solvents.’ This phenomenon can partially be accounted for by the difference in polarity between different forms. The imino form which is characterized by a relatively high p is stabilized in polar media. On the other hand the amino-foim much less polar should predominate in an inert media. This latter behaviour does not correlate with the relative energies of both tautomeric forms. As shown in Table 1 the amino forms are always less thermodynamically stable than the correspond- ing imino tautomers.The influence of polarity of the medium on the tautomeric equilibria can be considered analogously in the case of the remaining compounds studied. Both the amino and imino tautomers of C-264 and C-257 are characterized by having comparable p values. Thus both forms should behave similarly in polar and inert media as was demonstrated by the absorption spectra.I8 The difference in polarity again shows C-265 to have an imino form which is much less polar than its amino form. Examination of the long-wavelength absorption of the compound in various solvents indicated that the bands between 350 and 400 nm disappear and at the same time there is a simultaneous increase of the lowest energy band.’ This means that the equilibrium in the case of the 4-nitro isomer would move towards the amino tautomer in the liquid phase.The tautomeric equilibrium state should be influenced also by the possibility of interaction with the solvent through hydrogen bonding. The effect can be predominant in protic solvents. The results of our present calculations do not however enable us to draw any further conclusions due to the complexity of this type of interaction. The above discussion clearly demonstrates that in the liquid phase the tautomeric equilibrium state depends on the properties of the medium. Examination of this problem was not the primary aim of the present work. Nevertheless to have some idea of the order of the value of the equilibrium constant in inert solvents we estimated the c,,/ci ratio for C-283 dissolved in hexane.For this purpose it was assumed that the absorption coefficient at h, is proportional to the concentration of a given species. Furthermore we assumed the absorption coefficient of the imino tautomer of C-283 to be identical with that characteristic of compound (11) (Figure 6). Since the electronic absorption is characterized by many bands overlapping each other we deconvoluted the spectra of C-283 (Figure 2) and the reference substance (Figure 6) by assuming Gaussian profiles of individual bands and by using the Marquardt optimization method.49 This procedure gives a value for the equilibrium constant of ca.0.17. This roughly estimated value indicates that in the inert liquid phase the equilibrium moves greatly towards the amino structure. This structure is not represented in the crystal phase of the compound. Conclusions.-The MNDO method applied in this work enabled evaluation of the structures of several tautomeric forms of N-(nitro-9-acridy1)methanamines.Moreover the theoretical calculations performed provided some information not pre- viously available regarding the physicochemical characteristics of these derivatives. The important conclusion of the present study is that nitracrine and its nitro isomers in solution do not exclusively maintain the structure characteristic of the crystal phase. Furthermore the structure in the liquid phase depends heavily on the properties of the medium.It may thus be expected that under physiological conditions the structure can also change. Consequently this feature of the compounds examined can affect transport phenomena as well as the mechanism of their biological action. For further insight into this problem it would seem to be important to investigate the influence of the properties of the medium and temperature on the tautomeric equilibria. Another interesting subject is the tautomerism of protonated forms of the compounds. This is of special interest since the dihydrochlorides of these derivatives are soluble in water and thus are suitable for medical applications. We are currently working on these problems.Acknowledgements We would like to express our gratitude to Professor J. Konopa and his research group from the Technical University of Gdansk for providing the samples of the compounds studied. We would also like to thank Dr. A. Liwo for his valuable comments. The partial financing of this work by The Polish Academy of Sciences is also gratefully acknowledged. References 1 A. Tempczyk J. Rak M. Majczyna and J. Blaiejowski presented in part at the 2nd International Symposium on Molecular Aspects of Chemotherapy Gdansk Poland 5-8 July 1988; Abstract p. 52. 2 R. M. Acheson ‘Acridines,’ 2nd edn. Interscience New York 1973. 3 V. Loeber 2. Chem. 1971,11,135. 4 A. Albert Med. Chem. Ser. Monogr. 1972,11,229. 5 A. K. 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ISSN:1472-779X    

DOI:10.1039/P29900001501

出版商:RSC    

年代:1990

数据来源: RSC