Computational and Theoretical Chemistry 1190 (2020) 113024

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Computational and Theoretical Chemistry

journal homepage: www.elsevier.com/locate/comptc

Application of Hammett equation to hydrogen bond interactions of benzoic T

acid in chloroform/water system and explanation for non-linear Hammett
relation to partition coefficients for the same system
Sanjeev Rachurua, Adam A. Skeltonb, , Jagannadham Vandanapuc,
⁎ ⁎

a
Department of Chemistry, Geethanjali College of Engineering and Technology, Cheeryal 501301, India
b
Department of Pharmacy, School of Health Science, University of Kwazulu Natal, Durban, South Africa
c
Department of Chemistry, Osmania University, Hyderabad 500007, India

ARTICLE INFO ABSTRACT

Keywords: It is well known that benzoic acid distributes itself between chloroform and water. The partition coefficients (Kp)
Density functional Theory of seven different benzoic acids in chloroform/water are documented in the literature. Plausible hydrogen
Hydrogen bond bonded structures of these seven benzoic acids with the two immiscible solvents were envisaged and the DFT
Hammett equation and partition coefficients calculation for these hydrogen bonds were carried out. Further, the conformity of Hammett relation to the
hydrogen bond interactions was assessed. Application of Hammett equation to the hydrogen bonding of dis­
tribution of different para-substituted benzoic acids to these immiscible solvents is done for the first time.
Further, an explanation for non-linear plot of partition coefficients logKp of para-substituted benzoic acids in
chloroform-water system versus Hammett σ value has been explained for the first time.

1. Introduction tensions and dipole moments in estimating the associative behavior of

phenols [25]. It is known that benzoic acid distributes itself between
Partition or distribution coefficients has a wide range of applica­ chloroform and water. We have considered the distribution of seven
tions in the fields of pharmacology [1–3], pharmacokinetics [4–6], para-substituted benzoic acids. In the present study we envisaged the
pharmacodynamics [7–9], environmental science [10,11], agrochem­ plausible hydrogen bonded structures (Scheme 1) and found the in­
ical research [12], metallurgy [13] and consumer product development teraction energies in them. Further, we assessed the conformity of
[14]. Octanol is believed to have the lipophilic character of the biolo­ Hammett relationship to these interactions. To comprehend Hammett
gical membranes. The n-octanol/water [15] partitioning system re­ equation, let us suppose a reaction is performed on a substrate molecule
sembles the lipid membrane/water systems in the body. Hence most of [26] that can be represented as XGY where Y is the site of the reaction,
the partition studies appearing in the literature were carried out in X a variable substituent and G is a skeleton group to which X and Y (in
octanol/water system. Over the last century numerous studies on par­ our Scheme 1, X = OH, OCH3, CH3, H, Cl, Br and NO2, Y is hydrogen
tition of organic solutes have appeared in literature. To quote them is bonding between COOH moiety of substituted benzoic acid and sol­
beyond the scope of this article as they run in several hundreds. vents, G is C6H4) are attached and we observe that changing X from H
It is a well-established fact that Hammett [16,17] and Taft [18–21] to CH3, results in the change in the rate of reaction. The change in the
equations are good mechanistic tools in physical-organic chemistry rate of the reaction might be due to factors like mesomeric effect or
[16–21]. We have carried out several studies in our laboratory with inductive effect of the substituent X. The first attempt of quantitative
regard to their application. Non-Linear Taft Relationship is applied to treatment of X on the reaction site was given by Hammett. For the cases
surface tensions of aliphatic acids: Inter-molecular hydrogen bonding of meta and para-XC6H4Y, Hammett set up the equation log (k/ko) = σρ
versus intra-molecular hydrogen bonding [22], Non-Linear Taft Polar and this equation is known as Hammett equation. Here ko is the rate or
Free energy Relationships (TPER), reactions of N-substituted benzyl equilibrium constant for X = H, k the rate or equilibrium constant for
amines with benzyl bromide [23], dipole moments and melting points group X, ρ is a constant known as Hammett reaction constant for a given
and their unsolved miracles on the application of Hammett equation reaction under a given set of conditions, and σ is a constant known as
[24] and application of non-linear Hammett relationship to surface Hammett substituent constant. Hammett substituent constant σ reflects

⁎
Corresponding authors.
E-mail addresses: [email protected] (S. Rachuru), [email protected] (A.A. Skelton), [email protected] (J. Vandanapu).

https://doi.org/10.1016/j.comptc.2020.113024
Received 19 March 2020; Received in revised form 15 August 2020; Accepted 1 September 2020
Available online 04 September 2020
2210-271X/ © 2020 Elsevier B.V. All rights reserved.
S. Rachuru, et al. Computational and Theoretical Chemistry 1190 (2020) 113024

Scheme 1. Depicting the plausible hydrogen bonds between solute and solvent.

the degree of electron withdrawing and electron donating nature. The ρ

value was set to 1.00 for the ionization of XC6H4COOH in water at
25 °C, σ m and σ p values were then calculated for each group. ρ, de­
scribes the susceptibility of the reaction to substituents, compared to
the ionization of benzoic acid. It can be seen that ρ value depends on
solvent and temperature. ρ is characteristic of reaction series, whereas σ
is characteristic of substituent. As already mentioned the ρ value for
ionization of benzoic acid in water is 1 at 25 °C. If the solvent is
changed to methanol the ρ value is 1.54, in ethanol it is 1.96 and in
acetonitrille it is 2.8[27]. There are many research articles which deal
with effect of solvent on ρ [28,29,30,31] and to mention all of them
would be voluminous. The distilled essence is that one of the factors
which effects ρ is the nature of solvent. The sign of Hammett reaction
constant ρ also helps in deciding the charge of the site of attack. Fur­
ther, with the help of the Density Functional Theory (DFT) and Gaus­
sian [32] software the hydrogen bond interactions have been studied.
This study of hydrogen bond interactions would have been difficult, had
we employed experimental techniques.

Fig. 1. Structure IV of Scheme 1 (Chloro substituent).

2. Method

The entire curve fittings were done by KaleidaGraph software ver­ sum of the energies of p-chloro-benzoic acid and water was subtracted
sion 4.1 supplied by Synergy Software INC., Reading, PA, USA.Gaussian to get the hydrogen bond interaction energy that is
(R) 09 program was used for the quantum mechanical calculations. −956.86601772- (-880.41383673–76.44033589) = −0.011841
Density Functional Theory (DFT), using WB97XD functional [33] with hartree which is −7.432906856 kcal/mol or −7.432 kcal/mol. The
6–311 + g(d,p) basis set was utilized for all calculations. The reason for same, if expressed as hydrogen bond interaction between two fragments
employing this functional WB97XD is its ability to treat dispersion in­ say i and j, it can be written as
teractions [34,35]. To understand how the hydrogen bonds were EHB(i , j) = E(i, j) {E (i) + E(j)} (1)
computed between benzoic acid and the solvents water or chloroform,
let us consider structure IV with chloro substituent. First para-chloro where EHB (i, j) is the hydrogen bond between i and j, E(i, j) is the total
benzoic acid in water (solvent water taken implicitly) was optimized energy of hydrogen bonded structure (such as Fig. 1), E (i) is the energy
using WB97XD functional with 6–311 + g(d,p) basis set. The energy of i fragment and E (j) is the energy of j fragment.
turned out to be −880.41383673 hartree. Then water was optimized The preceding example is determination of hydrogen bonds when
using the same functional and basis set. The energy turned out to be there are two fragments (Fig. 1). If there are three fragments (say i, j
−76.44033589 hartree. In similar manner structure IV was optimized and k), analogous to Fig. 6 and if one has to determine the hydrogen
and the energy was −956.86601772 hartree. Fig. 1 shows the output bond interaction energy between the solvent and COOH group of
Gauss view of structure IV. Then, from the energy of structure IV, the benzoic acid (given in Table 4), one can comprehend with the help of

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S. Rachuru, et al. Computational and Theoretical Chemistry 1190 (2020) 113024

Table 1
Quantum mechanical calculations of Hydrogen bond interactions.
Substituent on benzoic acid Hammett σ Kp(a) Hydrogen bond interaction energies (kcal/mol) of
CHCl3/H2O
Structure I Structure II Structure III with CCl4 Structure IV Structure V Structure VI with H2O
with CCl4 with CCl4 with H2O with H2O

4-OH −0.38 3.28 −2.146 −5.295 −4.898 −7.263 −3.008 −4.509

4-OCH3 −0.28 8.04 −2.135 −5.559 −4.903 −7.072 −3.011 −4.546
4-CH3 −0.14 6.61 −2.096 −5.402 −4.833 −7.168 −2.993 −4.433
4-H 0.00 54.0(b) −2.170 −5.140 −4.844 −7.341 −2.952 −4.357
4-Cl 0.24 51.9 −2.214 −5.111 −4.733 −7.432 −2.630 −4.285
4-Br 0.26 30.6 −2.245 −5.201 −4.790 −7.454 −2.660 −4.244
4-NO2 0.81 7.54 −2.321 −5.034 −4.598 −7.755 −2.590 −4.010

a
from reference [29]
b
calculated from the solubility data (O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co.,
Inc., 2006., p. 1140, Opgrande J L et al; Benzoic acid. Kirk-Othmer Encyclopedia of Chemical Technology. (1999–2013). New York, NY: John Wiley & Sons., Bradley J-C,
Neylon C, Guha R, Williams A, Hooker B, Lang A, Friesen Brent J, Bohinski T, Bulger D, Federici M, Hale J, Mancinelli J, Mirza K B, Moritz M, Rein D, Tchakounte C,
and Truong H. Solubilities of Organic Compounds in Organic Solvents: Open Notebook Science Challenge: Available from Nature Proceedings < https://doi.org/10.
1038/npre.2010.4243.3 > (2010).

Table 2
Hydrogen bond Interaction energy between chloroform and para substituent at
benzoic acid.
S.No: Substituent at para position in Interaction energy of chloroform with
benzoic acid. substituent in kcal/mol

1 OH −5.035
2 OCH3 −5.808
3 Cl* −5.958
4 Br −5.164
5 NO2 −5.346

* Chloroform is interacting with ring and not forming Hydrogen bond with
substituent Cl (Fig. 4).

Table 3
Hydrogen bond Interaction energy between water and para substituent at
Fig. 2. Hydrogen bond between chloroform and hydroxyl substituent in benzoic acid.
chloroform layer.
S.No: Substituent at para position in Interaction energy of water with
benzoic acid. substituent in kcal/mol

1 OH −3.579
2 OCH3 −3.994
3 Cl* −2.368
4 Br* −2.404
5 NO2 −3.023

* Water is interacting with ring and not forming Hydrogen bond with sub­
stituent Cl atom or Br atom (Fig. 5).

of solvent forming bond with COOH of benzoic acid.

3. Discussion

As already mentioned in the abstract the data [36] of partition

coefficients of seven different (Table 1) substituted benzoic acids in
chloroform/water are documented. The plausible envisaged hydrogen
bonds of substituted benzoic acids with the two solvents chloroform
and water (six structures) is shown in Scheme 1 [37,38]. Let us digress
Fig. 3. Hydrogen bond between water and hydroxyl substituent in water layer. and understand why Hammett equation is a linear-free energy relation
(LFER). The effect of substituent at para and meta to the reaction centre
on rates of reaction was given by Hammett equation which is already
Eq. (2).
explained in the introduction.
E(i, jk) = E(ijk) E(jk) E(i) (2) logk / k o = (3)

Here E=(i, jk) is the hydrogen bond interaction between i and jk, E The Hammett equation can also be written as
(ijk) is the total energy of ijk (analogous to Fig. 6), E(jk) total energy of log K / K o = (4)
two hydrogen bonded fragments (say hydrogen bond between para
substituent attached to benzoic acid and solvent) and E(i) is the energy where K and Ko are equilibrium constants for substituted and

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S. Rachuru, et al. Computational and Theoretical Chemistry 1190 (2020) 113024

Table 4
Hydrogen bond interaction energies (of Scheme 1) in presence of substituent forming Hydrogen bonds with CCl4 and H2O kcal/mol.
Substituent Structure 1H-bond with Structure 2H-bond with Structure 3H-bond with Structure 4H-bond Structure 5H-bond Structure 6H-bond with
chloroform chloroform chloroform with water with water water

OH −2.236 −5.680 −5.316* −8.446 −3.218 −1.40

OCH3 −6.775* −5.886 −4.982 −7.640 −3.197 −4.585
Cl −5.183* −5.453* −5.004* −8.034* −2.846* −4.338*
Br −5.548* −5.612* −5.163* −8.041* −2.821* −4.316*
NO2 −2.313 −5.481 −6.985 −8.259 −2.731 −4.082

* solvent interacting with ring instead of forming H-bond with substituent (eg: Fig. 7).

Fig. 6. Simultaneous formation of water forming hydrogen bond with sub­

Fig. 4. The ring interacting with H of chloroform (not forming H-bond with Cl). stituent and COOH group of benzoic acid.

Fig. 7. Simultaneous formation of water interacting with benzene ring and H-

bond with COOH group of benzoic acid.

Hammett sigma values. The plots conformed to Hammett relationship

(Plots. 1–6 correspond to structure I to structure VI of Scheme 1). All
the plots have very good correlation coefficients barring Plot 2; but the
trend in Plot 2 is undeniably correct. The six plausible hydrogen bonded
Fig. 5. The ring interacting with Hydrogen atoms of water (not forming H-bond structures between the solute and the solvents are depicted in Scheme
with Cl). 1.
As a representative, output Gauss view file of chloro substituted
unsubstituted benzoic acid derivatives. We know that K is related to compound in water (structure IV) is shown in Fig. 1.
Gibbs free energy by the relation ΔG = −RTln K and for unsubstituted Electron withdrawal by X in benzoic acid would increase the ioni­
case ΔGo = −RTln Ko. The Hammett Eq. (4) can be rewritten as zation of the acid; hence the formation of hydrogen bonding between H
of hydroxyl group of benzoic acid and chlorine of chloroform or oxygen
log K log K o =
of water would be easier, experiencing less interaction energies. In
G/2.3RT + Go /2.3RT = other words electron donating by X would reverse the trend. This is
observed in structures I and IV with a negative Hammett ρ when hy­
G = 2.3RT Go (5) drogen bond interaction energies are plotted against Hammett σ.
For a given reaction under a given set of conditions, ρ, R, T and ΔGo Similarly, electron withdrawal by X in benzoic acid would decrease
are constants, hence there exists a linear relationship between free the electron density on oxygen of either the hydroxyl group or carbonyl
energies (ΔG) and Hammett substituent constant σ. Further, since the group of benzoic acid; hence the formation of hydrogen bonding be­
hydrogen bond interactions are functions of changes in free energies, it tween oxygen and hydrogen of chloroform or hydrogen of water would
is appropriate to plot these hydrogen bond interaction energies against be more difficult experiencing more interaction energies. In other

4
S. Rachuru, et al. Computational and Theoretical Chemistry 1190 (2020) 113024

Plot 1. H-bond energies of structure I versus Hammett sigma. Plot 3. H-bond energies of structure III versus Hammett sigma.

Plot 2. H-bond energies of structure II versus Hammett sigma.

Plot 4. H -bond energies of structure IV versus Hammett sigma.
words electron donating by X would reverse the trend. This is observed
in structures II, III, V and VI with a positive Hammett ρ when hydrogen Ionization of a molecule leads to accumulation of the hydrophilic form
bond interaction energies are plotted against Hammett σ. in aqueous phase. Therefore, as the electron withdrawing power of the
But the the state of affairs in the application of Hammett equation to substituents increase the solubility of benzoic acid increases in aqueous
Kp (CHCl3/H2O) data is different. A plot of log Kp versus Hammett σ phase. Hence the trend; Kp (Corg/Caq) value decreases from H (Hammett
was non-linear (Plot 7) with a break at substituent ‘H’. The prime σ = 0.00) to 4-NO2 (Hammett σ = 0.81). And as the electron donating
possible explanation is that Kp is a composite value and depends on the power of the substituents increase the solubility of benzoic acid de­
solubilities of benzoic acids in both the solvents unlike the H-bonded creases in organic phase. Hence the trend; Kp (Corg/Caq) value increases
interaction energies (which depend on a single solvent). Plot 7 shows an from OH (Hammett σ = − 0.38) to H (Hammett σ = 0.00). This is
excellent application of nonlinear Hammett correlation. The correlation observed in the Hammett plot (Table 1, Fig. 7).
coefficients are > 0.89. But, the trend is undeniably correct. From the There is a possibility of the substituent at para position to form
Hammett ρ values it is evident that the electron donating substituents Hydrogen bonds with chloroform and water layer. The following two
are more effective on Kp values by a factor greater than 2. The possible output structures are examples (Figs. 2 and 3) of such plausible Hy­
explanations are as follows: The lipophilicity oversees the unrest in the drogen bonds in chloroform and water layer.
mass of a solute molecule at the interface of two completely immiscible The strength of all the plausible hydrogen bonds between the sub­
liquids. The more lipophilic a solute molecule is, the more soluble it is stituent with chloroform and water is given in Tables 2 and 3. A point to
in lipophilic organic phase. For the same reason, drug penetration into a be noted is that, in case of p-chlorobenzoic acid, the hydrogen bond is
biological membrane is also influenced by its lipophilicity. When a not formed between chloro substituent and chloroform (in chloroform
molecule is ionizable at solution pH, it can form a more hydrophilic layer); instead chloroform reacts with the pi cloud of the ring as shown
anion or cation and subsequently fail to dissolve in organic phase. in Fig. 4. In a similar manner there is interaction between water and pi

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S. Rachuru, et al. Computational and Theoretical Chemistry 1190 (2020) 113024

Plot 5. H-bond energies of structure V versus Hammett sigma.

Plot 7. Hammett plot of log KP versus Hammett σ.

Table 1 we get Table 5. These values reflect the quantitative affect,

when the solvent forms hydrogen bonds with the substituent on the
Hydrogen bond interaction energies of Scheme 1.

4. Conclusion

The present article is the exploitation of applied quantum mechanics

using Guassian calculations to assess the applicability of Hammett re­
lationship to the plausible hydrogen bond interaction energies in the
distribution of benzoic acid between chloroform and water. The hy­
drogen bond interactions did conform to Hammett’s relation. The sign
of Hammett reaction constant ρ helps in deciding the charge on the site
of attack; a typical application of Hammett reaction constant, is applied
to our structures of Scheme 1. Thus in structure I and IV, the site of
attack is positive and for structures II, III, V and VI the site of attack is
negative. In the long run, this kind of study can be extrapolated to
distributions in biological systems. Further, an explanation for Ham­
mett non-linear plot of log Kp versus Hammett σ is given. Hammett σ
values reflect the quantitative electron withdrawing and electron do­
Plot 6. H-bond energies of structure VI versus Hammett sigma. nating effects. These Hammett σ values have been utilized to assess the
degree of solubility in chloroform and water layers. Log Kp reflects the
ratio of solubilities of the solute in two solvents. Hence in an appro­
cloud of the ring instead of water forming Hydrogen bond with Cl and
priate (where LFER can be applied) partitioning of solute between two
Br at para position (Fig. 5). The possible reason could be the resonance
solvents one can always plot log Kp versus Hammett σ and draw per­
interaction of Cl that is the movement of lone pair of electrons from Cl
tinent conclusion(s)/inference(s), the way we have done in this article.
to the double bonds of benzene is appreciable; as a consequence the
In fact, there is a possibility that one can predict the Kp value of new
negative charge on the ring is intensified. The same reason might be
substituted compound (s) with the help of log Kp versus Hammett σ
true for Br substituent in water layer.
plot.
Further, there is also a possibility of solvent forming simultaneous
Hydrogen bonds with COOH group of benzoic acid and the substituent
as shown in Fig. 6. Declaration of Competing Interest
The strength of hydrogen bonds of Scheme 1 changes due to the
presence of substituent forming Hydrogen bonds with solvent. The
The authors declare that they have no known competing financial
strength of these changed hydrogen bonds (Scheme 1) are given in
interests or personal relationships that could have appeared to influ­
Table 4. If we compare Table 1 and Table 4, it can be observed that in
ence the work reported in this paper.
presence of substituent forming Hydrogen bond with the solvent, the
existing Hydrogen bonds (of Scheme 1) become stronger (with some
exceptions). At this juncture we have no explanation for this stronger
Acknowledgment
Hydrogen bond interaction energy. Again, in some cases, the solvent is
interacting with the pi cloud of benzene ring instead of the substituent
The authors are grateful to the Center for High Performance
at para position (Fig. 7). The possible reason (for most of the structures)
Computing (CHPC), Cape Town, South Africa, for their generous allo­
is already explained. If one subtracts the bond strengths of Table 4 from
cation of super computer time.

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S. Rachuru, et al. Computational and Theoretical Chemistry 1190 (2020) 113024

Table 5
Hydrogen bond interaction energies after subtraction that is values from Table 4 minus corresponding values from Table 1 in kcal/mol.
Substituent Structure 1in CCl4 Structure 2 in CCl4 Structure 3 in CCl4 Structure 4 in H2O Structure 5 in H2O Structure 6 in H2O

OH −0.089 −0.385 −0.418 −1.182 −0.209 3.099

OCH3 −4.639 −0.327 −0.079 −0.567 −0.185 −0.039
Cl −2.969 −0.341 −0.271 −0.601 −0.215 −0.053
Br −3.303 −0.411 −0.373 −0.587 −0.161 −0.071
NO2 0.008 −0.446 −2.387 −0.504 −0.140 −0.072

References Relationship applied to surface tensions of aliphatic acids: Inter-molecular hy­

drogen bonding versus intra-molecular hydrogen bonding, Journal of Molecular
Liquids 224 (2016) 43–46.
[1] Bodor N, Buchwald P (2012).“Chapter 2.2: Pharmacokinetic Phase: ADME”. Retro [23] Non-Linear Taft Polar Free energy Relationships (TPER): Reactions of N-Substituted
metabolic Drug Design and Targeting, John Wiley & Sons, Inc. Benzyl Amines with Benzyl Bromide; R.Ravi, R.Sanjeev and V.Jagannadham;
[2] P.D. Leeson, B. Springthorpe, The influence of drug-like concepts on decision- International Journal of Chemical Kinetics; Wiley Publication; December, 2013, vol.
making in medicinal chemistry, Nat. Rev. Drug Discovery 6 (11) (2007) 881–890. 45, pages 803-810.
[3] M.P. Edwards, D.A. Price, Role of Physicochemical Properties and Ligand [24] R. Sanjeev, V. Jagannadham and R. Veda Vrath, Dipole moments and melting points
Lipophilicity Efficiency in Addressing Drug Safety Risks, Annu. Rep. Med. Chem. 45 and their unsolved miracles on the application of Hammett equation, Education
(2010) 381–391. Journal2012;1(1):1-4Published online December 30, 2012 (http://www.Science
[4] N. Bodor, P. Buchwald, Recent advances in the brain targeting of neuropharma­ publishinggroup.com/j/edu)doi: 10.11648/j.edu.20120101.11.
ceuticals by chemical delivery systems, Adv. Drug Deliv. Rev. 36 (1999) 229–254. [25] R. Sanjeev, V. Jagannadham, Adam A. Skelton, R. Veda Vrath, Application of Non-
[5] H. Kubinyi, Nonlinear dependence of biological activity on hydrophobic character: Linear Hammett Relationship to Surface Tensions and Dipole Moments in
the bilinear model, Farmaco; EdizioneScientifica. 34 (3) (Mar 1979) 248–276. Estimating the Associative Behavior of Phenols: A Chemical Educational Article to
[6] H. Kubinyi, Lipophilicity and biological activity. Drug transport and drug dis­ Graduate Students, Asian J. Chem. 27 (10) (2015) 3297.
tribution in model systems and in biological systems, Arzneimittelforschung 29 [26] Advanced organic chemistry by Jerry March, Fourth edition, John Wiley and Sons
(1979) 1067–1080. (Asia) Pte Ltd. ISBN 9971-51-257-2, year 1992.
[7] D. Eisenberg, A.D. McLachlan, Solvation energy in protein folding and binding, [27] http:// research.cm.utexas.edu/nbauld/unit4.htm.
Nature 319 (6050) (1986) 199–203. [28] H.H. Jaffe, A Reëxamination of the Hammett Equation, Chem. Rev. 53 (2) (1953)
[8] Miyamoto S, Kollman PA (Sep 1993).“What determines the strength of noncovalent 191–261.
association of ligands to proteins in aqueous solution?”,Proceedings of the National [29] Peter R. Wells, Linear Free energy Relationships, Chem. Rev. 63 (2) (1963)
Academy of Sciences of the United States of America.90(18): 8402–6. 171–219.
[9] V. Pliska, B. Testa, H. Van De Waterbed, Lipophilicity in Drug Action and [30] Richard Fuchs, Alex Nisbet, Solvent Effects in the Reaction of p-Substituted-α-
Toxicology, John Wiley & Sons Ltd, New York, 1996, p. 439. chlorotoluenes with thiosulphate, The Relationship of Rho and Dielectric Constant,
[10] D. Cronin, T. Mark, The Role of Hydrophobicity in Toxicity Prediction, Curr. J. Am. Chem. Soc. 81 (10) (1959) 2371–2373.
Comput. Aided Drug Des. 2 (4) (2006) 405–413. [31] Bright U. Emenike, et al., Solvent Modulation of Aromatic Substituent Effects in
[11] B. Heuel-Fabianek, Partition Coefficients (Kd) for the Modeling of Transport Molecular Balances Controlled by CH-# Interactions, J. Phys. Chem. A 122 (4)
Processes of Radionuclides in Groundwater, Curr. Comput. Aided Drug Des. 2 (4) (2018) 909–915.
(2006) 405–413. [32] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R.
[12] A. Noble, Partition coefficients (n-octanol/water) for pesticides, J. Chromatogr. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A.Petersson, H. Nakatsuji, M.
A.642 (1993) 3–14. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L.
[13] Stallman R, Ngan A (2014). “Chapter 3: Solidification”.Modern Physical Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa,M. Ishida, T.
Metallurgy, (8th ed.). Amsterdam: Elsevier/Butterworth-Heinemann. pp. 93–120, Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery Jr, J. E.
esp. 106ff. Peralta, F.Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N.
[14] vanLeeuwin C, Hermens J, eds. (2012). “Transport, Accumulation and Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S.
Transformation Processes (Ch 3.), Properties of Chemicals and Estimation S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B.
Methodologies (Ch. 7), and Procedures of Hazard and Risk Assessment (Ch. 8)”.Risk Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev,
Assessment of Chemicals: An Introduction, Dordrecht: Kluwer Acad. Publ. pp. A. J. Austin, R. Cammi,C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G.
37–102, and 239–338, esp. 39ff, 240ff, 306. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, O¨
[15] The thermodynamics of phase and reaction equilibria by Ismail Tousan, Elsevier . Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski D. J. Fox, Gaussian 09, Revision E.
publication. (2013) Doi: 10.1016/B978-0-44-459497-6.00011-6. 01 2009 (Gaussian, Inc.:Wallingford, CT).
[16] L.P. Hammett, Physical Organic Chemistry, second ed., McGraw-Hill, New York, [33] J.-D. Chai, M. Head-Gordon, Phys. Chem. Chem. Phys. 10 (2008) 6615, https://doi.
1970. org/10.1039/B810189B.
[17] C. Hansch, A. Leo, R.W. Taft, A survey of Hammett substituent constants and re­ [34] A.A. Skelton, N. Aggarwal, J.R. Fried, RSC Adv. 5 (2015) 55033, https://doi.org/
sonance and field parameters, Chem. Rev. 91 (1991) 165–195. 10.1039/C4RA14000A.
[18] E. Eric Anslyn, D.A. Dougherty, Modern Physical Organic Chemistry, University Sci. [35] A.A. Skelton, J.R. Fried, RSC Adv. 15 (2013) 4341.
Books (2006) 455. [36] P.C. Ray, P.K. Das, Measurement of Partition Coefficients of Substituted Benzoic
[19] R.W. Taft, Linear Free Energy Relationships from Rates of Esterification and Acids between Two Immiscible Solvents by Hyper-Rayleigh Scattering, J. Phy.
Hydrolysis of Aliphatic and Ortho-substituted Benzoate Esters, J. Am. Chem. Soc. 74 Chem. 100 (1996) 15631–15633.
(1952) 2729–2732. [37] Toshio Fujita, Junkichi Iwasa, Corwin Hansch, A new substituent constant, π, de­
[20] R.W. Taft, Polar and Steric Substituent Constants for Aliphatic and o-Benzoate rived from partition coefficients, JACS 86 (23) (1964) 5175–5180, https://doi.org/
Groups from Rates of Esterification and Hydrolysis of Esters, J. Am. Chem. Soc. 74 10.1021/ja01077a028.
(1952) 3120–3128. [38] Yasumasa I’haya, Tai-chi Shibuya, The dimerization of benzoic acid in Carbon tetra
[21] R.W. Taft, Linear Steric Energy Relationships, J. Am. Chem. Soc. 75 (1953) chloride and chloroform, Bull. Chem. Soc. Japan 38 (7) (1965) 1144–1147.
4538–4539.
[22] Sanjeev Rachuru, Jagannadham Vandanapu, Adam A. Skelton, Non-Linear Taft