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Dependence of the Substituent Effect on Solvent Properties Halina Szatylowicz, Anna Jezuita, Tomasz Siod#a, Konstantin S. Varaksin, Krzysztof Ejsmont, Izabela D. Madura, and Tadeusz Marek Krygowski J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.7b12023 • Publication Date (Web): 29 Jan 2018 Downloaded from http://pubs.acs.org on January 30, 2018

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The Journal of Physical Chemistry

Dependence of the Substituent Effect on Solvent Properties Halina Szatylowicz,a,* Anna Jezuita,b Tomasz Siodła,c Konstantin S. Varaksin,d Krzysztof Ejsmont,b Izabela D. Madura,a Tadeusz M. Krygowskie a

Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland. Email: [email protected] b Faculty of Chemistry, Opole University, Oleska 48, 45-052 Opole, Poland. c Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznań, Poland. d Department Organic Chemistry, Omsk F.M. Dostoevsky State University, Mira 55A, 644077 Omsk, Russia. e Department of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland.

Abstract The influence of a solvent on the substituent effect (SE) in 1,4-disubstituted derivatives of benzene (BEN), cyclohexa-1,3-diene (CHD) and bicyclo[2.2.2]octane (BCO) is studied by the use of PCM method. In all X-R-Y systems for the functional group Y: NO2, COOH, OH, NH2 the following substituents X have been chosen: NO2, CHO, H, OH, NH2. The substituent effect is characterized by cSAR(X), SESE and substituent constants σ or F descriptors, the functional groups by cSAR(Y) whereas π-electron delocalization of transmitting moieties (BEN and CHD) is characterized by a geometry based aromaticity index HOMA. All computations were carried out by means of B3LYP/6-311++G(d,p) method. An application of quantum chemistry SE models (cSAR and SESE) allows to compare the SE in water solutions and in the gas phase. Results of performed analyses indicate an enhancement of the SE by water. The obtained Hammett type relationships document different nature of interactions between Y and X in aromatic and olefinic systems (a coexistence of resonance and inductive effects) than in aliphatic ones (only the inductive effect). An increase of electric permittivity clearly enhances communications between X and Y for BEN and CHD systems.

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Introduction The influence of a solvent on chemical and physicochemical properties of chemical species has been known for a long time. It is observed in chemical equilibria, kinetically controlled reactions as well as in a plethora of physicochemical properties with various spectroscopies at the head.1 It is sufficient to mention that some reactions with a participation of bases are 1013 times faster in dimethyl sulfoxide than in methanol.2 Although the problem of the solvent effect is very complex, it has to be stated that there are three general ways to describe the solvent effect on physicochemical properties of molecules: (i) taking into account only electrostatic kinds of interactions, by the use of Kirkwood-Westheimer approaches,3,4 (ii) taking into account mostly chemical kinds of interactions assuming Lewis acid/base properties of solvents,5,6,7,8,9,10,11,12,13,14,15,16,17 and finally, (iii) when both approaches are applied together.18,19 Detailed analysis of the Palm and Koppel data19 revealed that for solvents with electric permittivity ε < 10 the electrostatic approaches work well, whereas for more polar solvents more effective is the approach taking into account Lewis acidity/basicity of solvents.20 Substituent effects, described traditionally by substituent constants (SC), also depend on a solvent, or more generally, on a kind of medium applied to their estimations.21,22,23 An application of the Hammett substituent constants24,25 σ to the reference reaction for SC, i.e. acid-base equilibria of substituted benzoic acids measured in various solvents reveals that the reaction constant, ρ, describing a sensitivity of the reaction to the substituent effects (SE) strongly depends on the solvent used.26 ρ-Values for the above mentioned reaction is 1.00 for water (by a definition), 1.14 for ethanol, 1.02 for methanol,27 0.966 for n-butanol28 and 2.4 in 85.1 wt% N-methylacetamide in water.29 Moreover, the estimation of the reaction constant for gas phase data shows a tremendous increase of its sensitivity on the substituent effect, with ρ = 5.6.30 Differences in ρ-values seem not be related to electrostatic interactions described by electric permittivity constants: ε for water and methanol at 20° C are 80.37 and 32.35,31 respectively, whereas difference in ρ is insignificant.27 Most probably, ρ-values describing intramolecular interactions between the reaction site (COOH) and substituents may be influenced by chemical interactions between solvent molecules and either reaction site or the substituents, or with both of them. Most frequently SE is modified by H-bonding at either the substituent or the reaction site or at both.32 Despite the very wide use of Hammett’s substituent constants24 and alike,33,34,35 many attempts to model SE by quantum chemistry approaches have appeared. One of a very often applied model is based on electrostatic potentials estimated on particular atoms, at atoms of


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the reaction sites or in other defined sites of molecules, and in all cases they correlate with SCs.36,37,38,39,40 An application of the energy decomposition analysis41 allowed to show that the π-electron energy of SE can be correlated with substituent constants.42 Other very important issue of the SE is its energetic characteristics named as SESE (substituent effect stabilization energy) obtained by the use of isodesmic or homodesmotic reactions approach.43,44,45,46,47 It was demonstrated in many cases that SESE values correlate well with substituent constants.48,49,50,51 Recently, it was shown that SC's may be successfully replaced by quantum chemistry modeling parameter named as charge of the substituent active region, abbreviated as cSAR(X). It is defined as the sum of atomic charges at the substituent (X) and the ipso carbon atom. The cSAR(X) values correlate well with the Hammett SCs.48,49,50,52,53 It is important to notice that cSAR(X) values determined by various methods of the atomic charge assessment are mostly equivalent.54 Motivation of this report is to show and compare the influence of a solvent on the substituent effect realized in three different types of 1,4-disubstituted X-R-Y systems: (i) aromatic – benzene (BEN), (ii) olefinic – cyclohexa-1,3-diene (CHD) and (iii) aliphatic – bicyclo[2.2.2]octane (BCO); objects of this study are presented in Scheme 1. Water, the most popular and widely used environment, is selected as a solvent. In other words, the aim is to identify and evaluate how the electrostatic interactions between water and X-R-Y derivatives affect a transmission of the SE through these moieties. An application of the PCM method (for review see Tomasi et al.55) will allow to estimate these interactions via electrostatic modeling with electric permittivity as a key parameter. Undoubtedly, this kind of the approach eliminates chemical interactions between solvent molecules and the reaction sites/substituents and will indicate the pure electrostatic effect on the transmission of the SE. Moreover, one can also find information about a sensitivity of three mentioned above transmitting moieties on electrostatic interactions. Y

a)

X

Y

b)

X

Y

c)

X

Scheme 1. Disubstituted X-R-Y systems: R = BEN (a), CHD (b) and BCO (c) derivatives; Y = NO2, COOH, OH, NH2 and X = NO2, CHO, H, OH, NH2.


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Theoretical Methods Benzene (BEN), cyclohexa-1,3-diene (CHD) and bicyclo[2.2.2]octane (BCO) 1,4disubstituted X-R-Y systems (Scheme 1) were used to investigate the influence of a solvent on the substituent effect. For each studied system an optimization without any symmetry constraints was performed (in the gas phase and solution) using the Gaussian09 program.56 The B3LYP/6-311++G(d,p) method was used for all calculations as the one which was proven to give fine results.50 The vibrational frequencies were calculated at the same level of theory to confirm that all calculated structures correspond to the minima on potential energy surface. The polarizable continuum model (PCM)55,57,58 was used to simulate water as a solvent. The substituent properties were characterized by SESE (substituent effect stabilization energy) and cSAR (charge of the substituent active region) descriptors, whereas transmitting moieties (R = BEN and CHD) by HOMA index. SESE characteristics were obtained using a homodesmotic reaction44 X-R-Y + R = X-R + R-Y and calculated as a difference in energy of products and reactants, according to an equation (1). SESE = E(R-X) + E(R-Y) – E(X-R-Y) – E(R)

(1)

The cSAR parameter52,53 was calculated as a sum of charges at all atoms of the substituent X or Y and the charge at the ipso carbon atom. The Hirshfeld method of the atomic charge assessment59 was applied to calculate all cSAR values. A geometry-based aromaticity index HOMA (Harmonic Oscillator Model of Aromaticity)60 was used to describe SE on a transmitting moiety. It is defined as a normalized sum of squared deviations of bond lengths from the values for a system assumed to be fully aromatic. For hydrocarbons, the appropriate expression is given by an equation (2).

HOMA = 1 −

1 n α (d opt −d i )2 ∑ n i =1

(2)

where n is the number of CC bonds taken into consideration, α=257.7 is an empirical normalization constant chosen to give HOMA=0 for non-aromatic system and HOMA=1 for a system where all bonds are equal to dopt=1.388 Å, and di are the experimental or computed bond lengths. In the case of CHD derivatives changes of π-electron delocalization, characterized by HOMA index, were obtained for the butadiene unit of the molecule.


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Results and Discussion This section is divided into four parts. The first one is devoted to the influence of a solvent on substituent effects descriptors. In part two an impact of electrostatic interactions between water and X-R-Y systems on structural changes in studied series is presented. The next subsection shows the solvent effect on the substituent effect from the energetic point of view. Finally, the fourth part concentrates on the solvent effect on π-electron delocalization of the transmitting moiety. In most cases the discussed regressions are illustrated for systems with extremal electron-donating/accepting Y properties whereas the remaining are gathered in the Supporting Information. Additionally, values of all SE characteristics used for 1,4disubstituted X-R-Y derivatives (Scheme 1) obtained in the gas phase and water are provided in Tables S1-S3 (Supporting Information).

Solvent effect on interrelations between substituent effect characteristics Two kinds of quantum chemistry models of the substituent effect – the structural and the energetic ones – are used to examine to what extent the substituent effect acting by three different moieties is affected by the environment. Additionally, the Hammett σ constants are also applied.24 It should be stressed that their values were obtained based on measurements in water but are used successfully in any environment. The first quantum chemistry approach of SE deals with the electron structure of substituents and "reaction sites" by means of the application of the cSAR treatment. The cSAR(X) and cSAR(Y) quantify the charge at C-X and C-Y fragments of the X-R-Y system, respectively. The obvious advantage of the cSAR approach is the ability to describe the properties of a substituent and a functional group (reaction site) on the same scale. The difference cSAR(Y) - cSAR(X), named as a charge flow index and abbreviated CFI, describes the flow of the electron charge from X to Y (or vice versa). It was found that in the gas phase this difference is correlated with the Hammett σ of X.53 The energetic approach is based upon an application of the homodesmotic reactions (SESE, eq. 1) carried out for the same reaction series in the gas phase and water. SESE describes the overall energetic aspects of the SE taking into account changes in electron and geometric structures of all components of X-R-Y systems. It has recently been shown in the gas phase studies of para-X-substituted anilines,50 phenols,61 benzoic acids,51 nitrobenzenes62 and 4‐X-CHD-NH2 derivatives63 that cSAR(X)


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and SESE are both well correlated with each other and with the Hammett constants. The question that needs to be asked is whether a solvent affects these dependencies. Results of the comparison of interrelations between substituent effect descriptors obtained in solution (water) and in the gas phase are presented in Figures 1 and S1-S4 (Supporting Information) and all data gathered in Table S4 (Supporting Information). For relationships of SESE vs cSAR(X) (Fig. 1 and S1) in all cases the determination coefficient (R2) values are very high (greater than 0.926) except the data for BCO derivatives. For series with the same transmitting moiety similar slope values (Table S4) are found in water and the gas phase, but for BEN derivatives they are a bit greater in the gas phase than in water.

(a)

(b) Figure 1. The relationships between SESE and cSAR(X) for amino (a) and nitro (b) substituted derivatives of BEN, CHD and BCO estimated in water and the gas phase; SESE in kcal/mol. For all reaction sites absolute values of the slope decrease from olefinic, through aromatic to aliphatic systems. Moreover, in the case of CHD and BEN series for electron-


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accepting Y (NO2 and COOH) the slopes are positive, whereas they are negative for electrondonating ones (NH2 and OH). This is not a case for BCO series, where the resulting slopes are always positive. Furthermore, it should be noted that the obtained slope values for X-R-Y series increase in line with changes of electronic properties of the fixed groups, this is from electron-donating Y = NH2 up to the electron-accepting Y = NO2. Figure S2 illustrate well this dependence, where the slopes are related to σ constants. The worst determination coefficients characterize data for BCO series, but they are well correlated with inductive substituent effect descriptor F (Figure S3). It turned out that for mutual linear regressions between cSAR(X), SESE and σ (σp is used) estimated for the BEN and CHD data either for water or the gas phase the R2 values are greater than 0.901, whereas for BCO correlations are much worse. These deviations are due to a different mechanism of X···Y interactions in the investigated systems. For BEN and CHD they are realized by a combination of resonance and induction, which are well described by σ, whereas interactions in BCO systems are purely inductive. When σ are replaced by an inductive parameter F, then the correlations become very good The appropriate statistical data, the determination coefficients R2 and the slopes, are collected in Table S4. Therefore, for π-electron systems three descriptors of SE: cSAR(X), SESE and σ, are mostly equivalent whereas for cycloalkane system BCO the most appropriate is the empiric descriptor F instead of σ. These equivalencies are nicely illustrated by Figure S4 (Supporting Information). Thus, cSAR and SESE models as well as the substituent constants σ or F as the characteristics of the SE can be used for a general description of the interaction between X and Y in the series studied in this paper.

Electronic structure analysis The dependences of cSAR(X), cSAR(Y) and the differences of them (CFI) obtained in water on these in the gas phase are considered as the basic relations. The functional groups Y, fixed in the series X-R-Y, are NO2, COOH, OH, NH2, whereas the applied substituents X are NO2, CHO, H, OH, NH2. As mentioned above R = BEN, CHD or BCO. The dependences of the calculated cSAR, for both the X and Y, in water (PCM) on these in the gas phase (GP) are presented in Figures 2 and S5-S7 (Supporting Information) and the slopes of the obtained linear equations are gathered in Table 1. It should be stressed that all these linear relationships are characterized by very high determination coefficients (R2 > 0.99).


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(a)

(b) Figure 2. Dependences of cSAR(X) in water on these in the gas phase (a) and of cSAR(NH2) in water on these in the gas phase (b) for X-R-NH2 series. Table 1. The obtained slopes of linear equations for dependence of cSAR in water (PCM) on these in the gas phase (GP) for X and Y in X-R-Y systems. (a) cSAR(X)PCM on cSAR(X)GP R\Y NO2 COOH OH NH2 range average CHD 1.518 1.428 1.469 1.618 0.189 1.508 BEN 1.403 1.307 1.354 1.438 0.131 1.375 BCO 1.305 1.302 1.306 1.302 0.005 1.304 range 0.213 0.127 0.163 0.316 average 1.409 1.346 1.376 1.452 (b) cSAR(Y)PCM on cSAR(Y)GP R\Y NO2 COOH OH NH2 range average CHD 2.000 1.610 1.630 1.822 0.390 1.765 BEN 1.725 1.429 1.472 1.720 0.296 1.586 BCO 1.392 1.315 1.449 1.362 0.134 1.380 range 0.607 0.295 0.181 0.460 average 1.706 1.451 1.517 1.635


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Based on the data given in Table 1, for both relationships (for X and Y) the obtained slope values are clearly greater than 1.0. This indicates a greater sensitivity of the electronic structures of X and Y on the SE acting in water solution than that observed in the gas phase. Furthermore, taking into account a transmitting moiety, their averaged values and the ranges of the slopes decrease in a sequence CHD, BEN and BCO. This is particularly well observed for regressions of cSAR(Y), where functional group Y is fixed in the series. This may be related to a substantial impact of electrostatic interactions of the medium on the mechanism of the substituent effect transmission in the moieties: inductive in BCO,

mixed

inductive/resonance in BEN and with a stronger contribution of the resonance effect in CHD systems. The more effective π-electron contribution to the transmitting moiety, the greater electrostatic impact of the medium on the transmission. Additionally, the slope values for relation shown in Table 1 document a greater impact of the medium on electronic structure of substituents for series with the strongest electron-accepting/donating properties of the fixed groups (Y = NO2 and NH2) than found in the case of Y = COOH and OH. Moreover, negative values of cSAR(Y) for Y = OH (Figure S7b) suggests electro-accepting properties of this fixed group in BCO series. One more analysis may be carried out taking into account a flow of the charge from cSAR(Y) towards cSAR(X) (or vice versa) expressed by a charge flow index CFI = cSAR(Y) – cSAR(X), plotted for systems in water against these in the gas phase. Table 2 presents statistics of these regressions whereas Figures 3 and S8 show their shapes. An important advantage of these dependencies is the ability to easily compare the electronic properties of the fixed group Y and substituent X. Negative values of the CFI show stronger electronaccepting properties of Y than X whereas positive ones indicate the opposite electron abilities of Y and X (Figures 3 and S8). Similarly to the aforementioned relationships, the determination coefficient is very high (R2 > 0.99). The resulting slope values, their average values and ranges also decrease in the same order of the transmitting moieties (from CHD, through BEN to BCO) and document the greatest impact of a solvent on charge flow for πelectron series with the strongest electron-accepting/donating abilities of the Y group.


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Table 2. The slopes of the obtained linear dependences of CFIPCM on CFIGP. R\Y NO2 COOH OH NH2 range average CHD 0.200 1.589 1.673 1.485 1.513 1.685 BEN 0.183 1.436 1.496 1.342 1.381 1.525 BCO 0.015 1.309 1.312 1.302 1.317 1.306 range 0.361 0.183 0.196 0.379 average 1.494 1.376 1.404 1.505

(a)

(b) Figure 3. Dependences of CFI in water (PCM) on these in the gas phase (GP) for Y=NO2 (a) and Y=NH2 (b) investigated systems. Another approach to the problem of the solvent effect on the SE is to characterized by Hammett type relationships – the dependences of cSAR(Y) on cSAR(X), presented in Table 3 and exemplified by Figures 4 and S9 (Supporting Information). It is important to notice that the correlations are usually very high for BEN and CHD (R2 > 0.969) and slightly lower for BCO data (R2 between 0.886 and 0.935).


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(a)

(b) Figure 4. Dependences of cSAR(Y) on cSAR(X) for amino (a) and nitro (b) substituted derivatives of BEN, CHD and BCO estimated in water and the gas phase Table 3. The slopes of linear dependences of cSAR(Y) on cSAR(X) and statistical data. BEN CHD BCO Y GP PCM GP PCM GP PCM NO2 -0.414 -0.509 -0.476 -0.627 -0.111 -0.118 COOH -0.410 -0.447 -0.459 -0.517 -0.117 -0.117 OH -0.312 -0.337 -0.363 -0.404 -0.093 -0.102 NH2 -0.443 -0.530 -0.489 -0.550 -0.100 -0.104 range 0.131 0.194 0.125 0.223 0.024 0.015 average -0.395 -0.456 -0.447 -0.524 -0.105 -0.110 In all cases presented in Table 3 the absolute values of the slopes are greater for the data estimated in water than these in the gas phase. The greatest averaged value of the slope is for CHD, then for BEN and BCO derivatives. The order agrees with the previously observed relations for: SESE vs cSAR(X) (Table S4), cSAR(X)PCM vs cSAR(X)GP and cSAR(Y)PCM vs cSAR(Y)GP (Table 1) as well as CFIPCM vs CFIGP (Table 2). It should be also noted that the


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average values for BCO, both in water and in the gas phase, are ~4 times lower than these in other systems. Again, this is a good support of the previous interpretation of the great role of solvent interactions with π-electron structure of the transmitting moiety. Alike in the case of dependences in Table 1, an increase of electric permittivity of an enviroment enhances communications between X and Y for π-electron systems. This is not a case of BCO system – the slopes are lower and differences between the data in the gase phase and in water are very small. Additionally, it has to be mentioned that electron attracting or donating abilities (properties) of Y do not differentiate, but rather the power of these properties is important. In the case of CHD and BEN systems for Y = NO2 and NH2 series the slopes are greater than those for Y = COOH and OH ones. The Hammett constants33 for NO2, COOH, OH and NH2 are 0.78, 0.45, -0.37 and -0.66, respectively. The next Hammett type approach is a relation between cSAR(Y) and substituent constants (Table 4 and Figure S10 in Supporting Information). The application of σ for πelectron systems and the inductive constants F for BCO leads to very high determination coefficients (R2 > 0.938). The slopes for BEN and CHD derivatives are always greater for stronger electron accepting/donating groups (Y=NO2 or NH2) than these for the weaker ones (Y=OH or COOH). For BCO no significant differences are observed for these two kinds of Y. However, the resulting slopes for the latter systems reveal stronger impact of the substituent (characterized by F constant) on properties of the Y in water than in the gas phase. Table 4. The obtained slopes of linear relationships between cSAR(Y) and substituent constants (σ or F) for BEN, CHD and BCO series in the gas phase and water. BEN(a) CHD(a) BCO(b) Y GP PCM GP PCM GP PCM NO2 0.075 0.128 0.106 0.209 0.023 0.032 COOH 0.073 0.105 0.101 0.161 0.024 0.033 OH 0.060 0.088 0.077 0.125 0.020 0.029 NH2 0.083 0.143 0.117 0.212 0.021 0.029 range 0.023 0.055 0.040 0.087 0.004 0.004 average 0.073 0.116 0.100 0.177 0.022 0.031 (a) cSAR(Y) vs σ. (b) cSAR(Y) vs F.

Relations between structural and energetic analyses An application of the SESE concept allows to look at the solvent impact on the substituent effect from the energetic point of view. Table 5 presents slopes of the linear dependences of SESE values estimated in water on these estimated in the gas phase, whereas Figures S11 and


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S12 (Supporting Information) exemplify these relationships. It should be stressed that for all studied systems the determination coefficients are very high (R2 > 0.99). Table 5. The slopes of linear dependences of SESEPCM on SESEGP and statistical data. NO2 COOH OH NH2 range average CHD 1.623 1.428 1.320 1.541 0.304 1.478 BEN 1.361 1.272 1.128 1.290 0.232 1.263 BCO 1.209 1.423 1.451 1.547 0.338 1.408 range 0.414 0.156 0.323 0.257 average 1.398 1.374 1.300 1.460 The resulting slope values indicate the enhancement of the substituent effect by a solvent; the same as observed for cSAR relations (Table 1). In addition, again for CHB and BEN series the obtained slope values document a greater impact of the medium on the SESE characteristic for series with the strongest electron-accepting/donating properties of the fixed groups (Y = NO2 and NH2) than these found in the case of Y = COOH and OH. Interestingly, for X-BCO-Y derivatives the obtained slopes depend on changes of inductive characteristic F of the Y group as presented in Figure 5.

Figure 5. The relationship between slope values of linear equation SESEPCM vs SESEGP for X-BCO-Y series and F constants of the fixed group (0.65, 0.34, 0.33 and 0.08 for NO2, COOH, OH and NH2, respectively.33 The dependence of cSAR(Y) on SESE is another Hammett type relationship (Table 6 and Figure S13 in Supporting Information). All linear equations for BEN, CHD and BCO series estimated in water and the gas phase are characterized by high determination coefficients with the lowest values for BCO series (R2 = 0.909). The obtained results again


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document different nature of intramolecular interactions between Y and X in aromatic and olefinic systems than in aliphatic ones. Table 6. The slopes of linear dependences of cSAR(Y) on SESE and statistical data. BEN CHD BCO GP PCM GP PCM GP NO2 -0.0151 -0.0192 -0.0158 -0.0195 -0.0055 COOH -0.0228 -0.0256 -0.0224 -0.0253 -0.0152 OH 0.0201 0.0262 0.0205 0.0254 -0.0122 NH2 0.0182 0.0243 0.0189 0.0223 -0.0261 range 0.0429 0.0519 0.0430 0.0507 0.0206

PCM -0.0063 -0.0141 -0.0123 -0.0231 0.0167

Similarly as in the case of SESE vs cSAR(X) relations (Table S4), for BEN and CHD series a sign of the slope of the linear equation depends on electronic properties of the fixed groups. However, for cSAR(Y) vs SESE equations the slopes are negative for electronaccepting Y and positive for electron-donating Y whereas negative for all BCO series (Table 6) [contrary to that found for SESE vs cSAR(X) relation]. According equation (1), the greater stabilization energy due to the substituent effect leads to a greater SESE value and indicates the stronger stabilization in di-substituted system. Thus, as shown in Figures S4, S11, S12 and S13, negative SESE values for BCO systems mean a destabilization of the system by adding of a substituent. In the case of BEN and CHD derivatives electron-donating (attracting) substituents stabilize systems with electron-attracting (donating) fixed groups. Therefore, changes in the slope signs are observed. Additionally, an impact of electrostatic interactions of the medium on intramolecular interactions between X and Y is documented. For BEN and CHD series the obtained slope values (absolute values) are greater in water than in the gas phase.

Solvent effect on π-electron delocalization of the transmitting moiety An estimation of HOMA for four kinds of para-substituted benzene derivatives with Y= NH2, OH, COOH and NO2 reveals substantial differentiation expressed by slope values of the dependence HOMAPCM on HOMAGP, Figure 6a. The slopes for strongly interacting functional groups Y= NO2 and NH2 (σ equal to 0.78 and -0.66) are 2.29 and 2.08, respectively. For weaker interacting OH and COOH groups (with σ = -0.37 and 0.45) the slopes are significantly smaller equal to 1.46 and 1.36, respectively. In all cases determination coefficient is sufficiently high (R2 > 0.91) allowing to assume a significant role of an electrostatic field impact on the transmitting moiety, being mostly in line with a strength of


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interactions between X and Y. Surprisingly, for CHD derivatives with Y= OH and NH2, the slopes are marginally different but greater than that for electron-attracting Y, as shown in Figure 6b.

(a)

(b) Figure 6. Dependences of HOMA values estimated in water on these in the gas phase for para-substituted benzene derivatives, X-BEN-Y, (a) and 1,4- disubstituted cyclohexa-1,3diene systems, X-CHD-Y, (b). Conclusions This paper shows results of investigations of the impact of an environment (water as a solvent, realized by PCM method) on the substituent effect for three different X-R-Y types of studied systems, where R denotes: aromatic, olefin and aliphatic transmitting moieties. For this purpose a broad range of the substituent characteristics has been used, quantum chemistry approaches cSAR and SESE as well as σ or F constants.


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Firstly, an equivalence of the applied SE characteristics to substituent effect description in water and in the gas phase has been documented. The obtained relationships between quantum chemistry models of the SE [cSAR(X) vs SESE] show almost identical impact of the environment on the SE parameters for series with the same fixed group and transmitting moiety. This shows a possibility of an application the these kind of approaches to other systems of similar nature. However, when σ or F constants are used then the absolute slope values are greater for dependences of cSAR(X) or SESE on σ or F calculated in water than in the gas phase. It should be stressed that in the latter case the same constants are used in both phases, σ for π-electron systems and inductive substituent constants F for cycloalkane (BCO) series. The use of quantum chemistry SE models made it possible to compare the substituent effects in both phases. Results of analyses of linear relationships between values of the same parameter in these two phases indicate a clear enhancement of the substituent effect by water (the obtained slope values significantly greater than 1.0). Furthermore, electronic structure parameters of X and Y as well as charge flow between them reveal that this enhancement depends on transmitting moiety and decreases in a sequence from CHD, through BEN to BCO. Additionally, the greatest impact of water is found for π-electron series (CHD and BEN) with the strongest electron-accepting/donating abilities of the Y group. The greater modulo of σ(Y) the greater effect is observed. The results of the analysis of the energetic descriptor of the SE (SESEPCM vs SESEGP) show also this effect for π-electron systems. However, for X-BCO-Y derivatives the obtained slopes depend on changes of inductive characteristic F of the Y group. The obtained results of Hammett type relationships clearly document different nature of intramolecular interactions between Y and X in aromatic and olefinic systems (coexistence of resonance and inductive effects) than in aliphatic ones (only the inductive effect). An increase of electric permittivity enhances communications between X and Y for π-electron systems. The solvent effect on the substituent activity is independent of the electron accepting or donating properties of the substituents, only the strength of these properties decide about the observed effect. This is not so obvious in the case of BCO derivatives where the obtained slope values are ~4 times lower than in the other systems, both in water and in the gas phase. π-Electron delocalization in the transmitting moiety is stronger expressed in water solution than in the gas phase, and this effect depends again on the strength of SE but not on the kind of SE.


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Supporting Information: Figures: The relationships between SESE and cSAR(X) for hydroxy and carboxy substituted derivatives of BEN, CHD and BCO estimated in water and the gas phase (S1); Dependences of slopes of linear relations SESE vs cSAR(X) on σ (S2) and on F constants (S3); The relationships between SESE and substituent constants for nitro, carboxy, hydroxy and amino substituted derivatives of BEN, CHD and BCO estimated in water and gas phase (S4); Dependences of cSAR(X) and cSAR(NO2) in water on these in the gas phase for X-R-NO2 series (S5); Dependences of cSAR(X) and cSAR(COOH) in water on these in the gas phase for X-R-COOH series (S6); Dependences of cSAR(X) and cSAR(OH) in water on these in the gas phase for X-R-OH series (S7); Dependences of CFI in water on these in the gas phase for Y=COOH and Y=OH investigated systems (S8); Dependences of cSAR(Y) on cSAR(X) for hydroxy and carboxy substituted derivatives of BEN, CHD and BCO estimated in water and in the gas phase (S9); Dependences of cSAR(Y) on substituent constants for Y = NO2, COOH, OH and NH2 for substituted derivatives of BEN, CHD and BCO estimated in water and in the gas phase (S10); Dependences of SESE in water on these in the gas phase for X-R-NO2 and for X-R-COOH series (S11); Dependences of SESE in water on these in the gas phase for X-R-OH and for X-R-NH2 series (S12); Dependences of cSAR(Y) on SESE for nitro, carboxy, hydroxy and amino substituted derivatives of BEN, CHD and BCO estimated in water and in the gas phase (S13). Tables: Values of all applied SE characteristics for 1,4-disubstituted X-R-Y derivatives obtained in the gas phase and water (S1-S3); The determination coefficients and slopes of the obtained linear relationships between substituent effect descriptors for BEN, CHD and BCO in the gas phase and water (S4).

Acknowledgments The authors acknowledge the Interdisciplinary Center for Mathematical and Computational Modeling (Warsaw, Poland) and Wrocław Centre for Networking and Supercomputing (http://wcss.pl; grant No. 311) for providing computer time and facilities. K.S.V. thanks the Ministry of Education and Science of the Russian Federation (the project number 4.1657.2017/4.6). H.S. and T.M.K. thank the National Science Centre and Ministry of Science and Higher Education of Poland for supporting this work under the grant no. UMO2013/11/B/ST4/00531.


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Author Information Corresponding Author *H. Szatylowicz. E-mail: [email protected]. A. Jezuita. E-mail: [email protected] T. Siodła. E-mail: [email protected] K. S. Varaksin. E-mail: [email protected] K. Ejsmont. E-mail: [email protected] I. D. Madura. E-mail: [email protected] T. M. Krygowski. E-mail: [email protected] ORCID Halina Szatylowicz: 0000-0002-7034-6985 Izabela D. Madura: 0000-0001-5009-2554 Notes The authors declare no competing financial interest.

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Quantum chemistry models to study substituent effects in solutions and in the gas phase 627x448mm (65 x 65 DPI)


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Dependence of the Substituent Effect on Solvent Properties - The

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