Dual Substituent Parameter Modeling of Theoretical, NMR and IR Spectral Data of 5-Substituted Indole-2,3-diones

Correlations of AM1 and PM3 theoretical data, 13C-NMR substituent chemical shifts (13C-SCS) and IR carbonyl group wave numbers [ν(C3═O)] were studied using dual substituent parameter (DSP) models for 5-substituted indole-2,3-diones. For the C7 atom a reverse substituent effect attributed to extended π-polarization was observed. On the other hand, the DSP approaches for the C3 atom showed normal substituent effects with some contribution of reverse effect supported strongly by 13C-SCS correlations. In the ν(C3═O) and p(C3═O) DSP correlations the field effect contribution predominates over the resonance effect, which justifies the using of earlier suggested vibrational coupling (V-C) model for 5- and 6-substituted indole-2,3-diones.


Introduction
Indole-2,3-dione (isatin) derivatives have shown a wide scale of biological activities. Many of them are antibacterial, antifungal and anticonvulsant compounds [1][2][3]. Moreover, some isatin derivatives exhibit remarkable anti-HIV [4] and cytostatic activity [5]. Recently the substituent effects and the phenomenon of vibrational coupling have been studied in a series of 5-and 6-substituted indole-2,3-diones using IR, NMR and theoretical AM1 data [6]. It was shown that the two ν(C═O) absorption bands of isatins could be attributed to the symmetric and the asymmetric stretching vibrational modes in the mechanically coupled cyclic α-dicarbonyl system. Consequently a vibrational coupling (V-C) model was suggested for mono substituent parameter (MSP) correlations of IR spectral data of 5-and 6-substituted derivatives.
The aim of this work was to study and compare Reynolds' and Taft's dual substituent parameter (DSP) models [7] for correlations of theoretical (AM1 and PM3) as well as 13 C-NMR and IR spectral data of a series of 5-substituted indole-2,3-diones (1-8) (Scheme 2).

Results and Discussion
The correlations of carbonyl vibrational wave numbers ν(C 3 ═O) of the series of compounds Generally the Taft's model approach gave statistically more significant results than the Reynolds' model for both q C and q M correlations. Almost identical correlations were found for the q C and q M property for given atom. Hence we will use the q M value as a representative for interpretation of Taft's model correlations.
The best-chosen resonance parameters were σ R BA values for the carbon atoms and σ R o constants for the oxygen atom of the C 3 =O group. This may justify the lower quality behavior of Reynolds' model mentioned earlier for carbon atoms since this uses σ R o values while the best chosen resonance parameter in Taft's model is σ R BA . According to Taft's model the atoms used in correlations can be classified into two groups: i) those within the benzene ring, namely C 7 and C 7a and ii) those outside the benzene ring, such as C 3 and O 3 '. The atoms C 7 and C 7a alternate in charge sign similarly to their corresponding ρ I and ρ R values, ρ I and ρ R being negative for C 7 and indicating a reverse resonance and field effects respectively. The C 7 atom represents a meta-position in 5-X-isatin series. A similar effect was observed for α-carbon atoms of the side chains in p-disubstituted benzenes on probing 13 C NMR substituent chemical shifts ( 13 C SCS) [14]. Craik et al. [14] have proposed two types of field πpolarizations, namely localized and extended π-polarization. It is believed that the localized π-polarization accounts for non-terminal atoms, whereas both localized and extended π-polarizations contribute to electron charge density at terminal atoms. In our case the reverse substituent effect at the C 7 site can be attributed to extended π-polarization, which predominates over the localized πpolarization in analogy to [8]. This effect can be schematically drawn as structures I and II, respectively (Scheme 1).

I II
It should be noted that it is not necessary to have equal π-polarization at the benzene ring in 5-Xisatins, since the benzene ring is not symmetrically substituted. The data in Table 3 show that the reverse resonance effect in position 7 is larger than the reverse field effect. AM1 charge densities and Mulliken charges seem to overestimate the importance of reverse resonance effect, which is similar to the results published for p-substituted nitrobenzenes [8]. The ρ I and ρ R values at the C 7 atom are for both quantities q M and q C smaller in absolute values than the corresponding ρ I and ρ R at the C 7a atom. This resembles the results obtained in similar correlations at non-conjugative sites in aromatic compounds (meta-position) [9] or at α-carbon atoms of side chains in p-disubstituted benzenes [10]. The C 7 atom in compounds 1 -8 is a non-conjugative site with the substituent on the C 5 atom and represents a meta-position.
Taft's DSP correlation for q M (C 7a ) is similar to those for 13 C SCS in p-disubstituted benzenes for several reasons: i) the best chosen resonance parameter is σ R BA , ii) the field and resonance effects are normal and iii) the ρ R /ρ I ratio is twice [11].
DSP correlation of q M (C 3 ) reveals normal substituent effect (see Table 3). The q M (O 3 ') correlation using Taft's DSP approach shows more contribution of field than resonance effect at the oxygen atom. This agrees with the proposed structure of π-polarization giving more weight to field effect at the oxygen atom of C 3 =O group. However, due to the existing of some reverse effect at C 3 atom the total ρ I and ρ R values for q M (C 3 ) are decreased when compared with ρ I and ρ R for q M (O 3 ') (see I in Scheme 2). The reverse substituent effect at C 3 site is very typical and obvious for α-carbon atom of side chains in p-disubstituted benzenes and is indicated by correlation results for 13 C SCS of C 3 atom in series of compounds 1 -8:  [6] for Hammet type correlations of the IR stretching vibrational wave numbers of 5-and 6substituted isatins.

Conclusions
The following conclusions may be drawn on the basis of the above discussed results for 5-substituted indole-2,3-diones: 1) Application of the Taft's model provides always better correlation results for both Coulson charge densities and Mulliken charges than the use of Reynolds model. 2) For the C 7 site a reverse substituent effects was observed and is believed to be connected with the extended π-polarization. 3) The DSP correlation analysis for the C 3 atom of the investigated molecules shows a normal substituent effect.

4) The Taft's model DSP correlations for C 3 =O bond vibrational wave numbers and bond orders
show that the contribution of the field effect to this bond is roughly twice the contribution of the resonance effect. 5) The previously reported vibrational-coupling model proposed on the basis of MSP correlations was confirmed using the results of DSP correlations studied in this work. Semiempirical molecular orbital calculations for Coulson atomic charge densities (q C ), Mulliken charges (q M ) and bond orders (p) were done by AM1 Hamiltonian [13] using the AMPAC program package [14]. Geometries were completely optimized without any restrictions using the keyword PRECISE. The selected AM1 and PM3 theoretical data for 5-substituted indole-2,3-diones (1-8) are given in Table 2.  Table 2. Selected AM1 and PM3 theoretical data for 5-substituted indole-2,3-diones 1-8 The statistical result for DSP modeling of AM1 charge densities and Mulliken charges for 5-substituted isatins (1-8) according to both Reynolds' and Taft's models [7] using equation q(A) = ρ F σ I + ρ R σ R + q(A) H and σ I and σ R values taken from [15][16][17][18] are given in Table 3. Table 3. DSP correlations for AM1 charge densities and Mulliken charges of compounds 1-8

Reynolds' Model
Taft's Model