The Effect of Intramolecular Hydrogen Bond Type on the Gas-Phase Deprotonation of Ortho-Substituted Benzenesulfonic Acids. A

molecules

Article The Eﬀect of Intramolecular Hydrogen Bond Type on the Gas-Phase Deprotonation of ortho-Substituted Benzenesulfonic Acids. A Density Functional Theory Study

Nina I. Giricheva 1,*, Sergey N. Ivanov 1 , Anastasiya V. Ignatova 1, Mikhail S. Fedorov 1 and Georgiy V. Girichev 2

1 Department of Fundamental and Applied Chemistry, Ivanovo State University, 153025 Ivanovo, Russia; [email protected] (S.N.I.); [email protected] (A.V.I.); [email protected] (M.S.F.) 2 Department of Physics, Ivanovo State University of Chemistry and Technology, 153000 Ivanovo, Russia; [email protected] * Correspondence: [email protected]; Tel.: +7-4932-373703

Academic Editor: Giuseppe Arena Received: 31 October 2020; Accepted: 7 December 2020; Published: 9 December 2020

Abstract: Structural factors have been identified that determine the gas-phase acidity of ortho-substituted benzenesulfonic acid, 2-XC H –SO H, (X = –SO H, –COOH, –NO , –SO F, –C N, 6 4 3 3 2 2 ≡ –NH2, –CH3, –OCH3, –N(CH3)2, –OH). The DFT/B3LYP/cc-pVTZ method was used to perform conformational analysis and study the structural features of the molecular and deprotonated forms of these compounds. It has been shown that many of the conformers may contain anintramolecular hydrogen bond (IHB) between the sulfonic group and the substituent, and the sulfonic group can 0 –1 be an IHB donor or an acceptor. The Gibbs energies of gas-phase deprotonation ∆rG 298 (kJ mol ) were calculated for all compounds. It has been set that in ortho-substituted benzenesulfonic acids, 0 the formation of various types of IHB is possible, having a significant effect on the ∆rG 298 values of gas-phase deprotonation. If the –SO3H group is the IHB donor, then an ion without an IHB is formed upon deprotonation, and the deprotonation energy increases. If this group is an IHB acceptor, then a 0 significant decrease in ∆rG 298 of gas-phase deprotonation is observed due to an increase in IHB strength and the A− anion additional stabilization. A proton donor ability comparative characteristic 0 of the –SO3H group in the studied ortho-substituted benzenesulfonic acids is given, and the ∆rG 298 energies are compared with the corresponding values of ortho-substituted benzoic acids.

Keywords: benzenesulfonic acids; conformer; deprotonation energy; intramolecular hydrogen bond; ortho-eﬀect

1. Introduction Compounds with increased acidic properties have attracted the attention of researchers [1–8]. Among them, a special place was occupied by substituted arenesulfonic acids (ASA), which have found application in homogeneous catalysis [9–12], electrochemical technologies [13–22], and as components of ionic liquids [23–25]. Sulfonic groups of ASA are structural fragments responsible for proton transfer and providing electrical conductivity of proton exchange membranes. This makes it possible to use various substituted ASA as modiﬁers of polymer proton-exchange membranes of chemical current sources [14,15]. The branched hydrophobic chain of ﬂuorocarbon membranes [16–18], membranes based on polyimides and styrenes [22], contains hydrophilic sulfonate-anionic groups, the hydration shells of which provide the membrane electrical conductivity due to the relay mechanism of proton transfer [19–21].

Molecules 2020, 25, 5806; doi:10.3390/molecules25245806 www.mdpi.com/journal/molecules Molecules 2020, 25, 5806 2 of 23

The problem of increasing the proton conductivity of polymer membranes remains actual [21,22], and the benzene sulfonic acid (BSA) molecule remains the basis for studies of the conductivity of a hydrocarbon membrane. When creating membranes with desired properties, it is necessary to understand the mechanisms and regularities of the influence of the substituted BSA structural features on the proton-donating ability of sulfonic groups and the proton-conducting ability of the corresponding hydration shells. The proton-donor properties of BSA can be controlled by introducing functional groups into it that ensure the stabilization of anionic fragments due to the intramolecular effects of delocalization of the negative charge of the anion, the formation of stable conformers with an intramolecular H-bond (IHB) [26–29], and the subsequent formation of mono- and polyhydrate complexes [15–17]. The results of studying the proton conductivity and computer modeling of anhydrous aromatic sulfonic acid molecules and their crystal hydrates showed that some hydrates of substituted benzenesulfonic acid have increased proton-donor properties and conductivity: phenol-2,4-di-BSA [30], 2-hydroxy-4-methyl-BSA [31], 2-sulfobenzoic [32], calixarensulfonic [33], hexasulfonic [34] acids. A distinctive feature of the molecules of the listed compounds is the presence of carboxyl, hydroxy, nitro and even second sulfonic groups in the ortho-position to the sulfonic group, which exhibit electronic and steric effects of a different nature. We have previously shown that the molecules of such ASA are characterized by several non-rigid coordinates, difficulty ofconjugating ortho-substituents with the benzene ring, competition of orbital and steric interactions, and the formation of an IHB in a number of conformers between substituents and acidic groups –SO3H or –COOH. Increased proton-donating properties are inherent in ASA molecules containing an electron-withdrawing group [35–38]. 0 It has been shown in [2–8] that the Gibbs free energy ∆rG 298 of gas-phase deprotonation 0 (GD), can be used as a criterion for the proton-donating ability of organic acids. The value ∆rG 298 GD is used to build the scales of molecular acidity and to identify compounds with superacidic properties. In several works (for example [2,37,39,40]), a correlation between the energies of gas phase deprotonation and pKa values was noted. The authors [41] introduced a classification of the strength of acids, according to which an acid is considered superstrong if the Gibbs free energy of gas phase deprotonation <300 kcal/mol (1256 kJ mol–1). Analysis of the changes in these values for various substituted acids can identify the effects that are directly related solely to the effect of a substituent and IHB on the proton-donating ability of the compounds excluding the effect of the medium. The presence of functional groups in BSA is the reason for the formation of conformers with different types of IHB, their different thermodynamic stability, and theirdeprotonate ability [37]. In [37], the thermodynamic characteristics of the GD of nitro-substituted BSA have been 0 calculated. The smallest value of ∆rG 298 was obtained for the compound 2,4,6-(NO2)3C6H2SO3H, as a compound with super acidic properties [37]. Along with GD, the geometric and electronic structure of ortho-nitro-substituted BSAs [35,36], as well as BSA itself [42], were studied. In the literature, the features of GD of benzoic acid (BA) as the simplest representative of substituted aromatic acids are discussed in sufficient detail [26,43–46]. The influence of the nature of substituents on the energy of GD of meta- and para-substituted BA have been considered in [43]. The ∆Hacid values of substituted Bas are calculated by the MP2 method increase from 1379.1/1377.5 to 1 1428.1/1434.8 kJ mol− (meta-/para-) and correlate with the Hammett constants σM and σP for many small substituents from –NO2 through the halogens and to –OH and –NH2. Note that, in this work, the GD energy was calculated as the difference between the energies of the most stable conformers of anions and molecular forms of acids. For ortho-substituted BA, along with the factors that occur in meta- and para-substituted BA, the steric factor and the possibility of IHB formation are added [44,45]. However, IHB is absent in most 2-substituted benzoic acids, but in the compounds where H-bonds is present, for instance 2-N(CH3)2-BA and 2-OCH3-BA, it affects the acidity only moderately [44]. Molecules 2020, 25, 5806 3 of 23 Molecules 2020, 25, x FOR PEER REVIEW 3 of 23

In Inanother another work work [45], [45 the], the effect effect of ofthe the orthoortho-substituent-substituent on on the the acidity acidity of offour four orthoortho-substituted-substituted benzoicbenzoic acids, acids, 2-X-BA 2-X-BA (X (X = =2-OH,2-OH, 2-NH 2-NH2,2 ,2-COOH, 2-COOH, and and 2-SO 2-SO22NHNH22),), was was considered considered in detail. EachEach of of thethe acidsacids has has several several conformers, conformers, including including the the conformers conformers with with IHB. IHB. It was It was shown shown that theirthat their anions anionsare stabilized are stabilized by H-bonds, by H-bonds, and both and destabilizing both destabilizing (2-COOH, (2-COOH, 2-SO2NH 22-SO) and2NH stabilizing2) and stabilizing interactions interactions(2-OH, 2-NH (2-OH,2) are 2-NH observed2) are inobserved acid molecules. in acid molecules. BSABSA and and its itssubstituted substituted ones ones have have a significantly a significantly higher higher deprotonation deprotonation ability ability as ascompared compared to to 0 0 −1 1 substitutedsubstituted BA. BA. It Itis isshown shown that that the the values values Δ∆rGrG298298 of ofGD GD for for substituted substituted BA BA are are ~92 ~92 kJkJ mol mol −higherhigher thanthan the the corresponding corresponding values values for for substituted substituted BSA. BSA. [37] [37 ] It Itis isnatural natural toto expectexpect that that the the formation formation of IHB of inIHBortho in-substituted ortho-substituted BSA has BSA its own has peculiarities its own peculiaritiesdue to the pyramidaldue to the naturepyramidal of the nature sulfonic of groupthe sulfonic and stronger group polarizationand stronger of polarization O–H bonds thanof O–H those bondsin substituted than those BA. in Ofsubstituted course, it isBA. also Of important course, it that is also the structurallyimportant that nonrigid the structurally BSA molecule nonrigid exists in BSAthe molecule form of twoexists mirror in the conformers form of two of mirror C1 symmetry conformers (enantiomers), of C1 symmetry capable (enantiomers), of mutually transformingcapable of mutuallyinto each transforming other through into the each transition other through state of Cthes symmetry transition due state to of rotation Cs symmetry of the –OH duegroup to rotation around of thethe S–O(H)–OH group bond around [42]. In the addition, S–O(H) in bond substituted [42]. In BSA, addition, the –SO in 3substitutedH group can BSA, occupy the –SO different3H group spatial canorientations occupy different relative spatial to the orientations substituent relative and the to benzene the substituent ring [35 and–37 ].the In benzene this regard, ring [35–37]. it should In be thisexpected regard, that it orthoshould-substituted be expected BSA canthat formortho a-substituted greater number BSA of can conformers form a thangreater the correspondingnumber of conformerssubstituted than BA, the and corresponding have stronger substituted proton-donor BA properties,, and have andstronger some proton-donor of them have properties, prospects as andprecursors some of them for using have high-conductivity prospects as precursors polymer for electrolytes. using high-conductivity polymer electrolytes. TheThe question question of ofIHB’s IHB’s influence influence on on the the acidic acidic properties properties of oforthoortho-substituted-substituted BSA BSA is isthe the subject subject of ofthis this work. work. Particular Particular attention attention is paid is paid to tothe the consideration consideration of ofmolecules molecules that that have have conformers conformers withwith different different types types of ofIHB, IHB, in inwhich which the the –SO –SO3H3 Hgroup group can can be beeither either a donor a donor or oran anacceptor acceptor of ofIHB. IHB. ToTo predict predict the the gas-phase gas-phase acidity acidity of of ortho-substituted BSA,BSA, thethe relationshiprelationship between between the the geometric geometric and andelectronic electronic structure structure of of molecules molecules and and deprotonation deprotonation energies energies was was studied studied using using the the example example of of ten tenortho ortho-substituents-substituents BSA BSA of of a a di differentfferent nature nature (Scheme (Scheme1). 1).

X sulfonic acid

–H BSA –COOH 2-COOH-BSA –NO2 2-NO2-BSA –SO2F 2-SO2F-BSA –CN 2-CN-BSA –NH2 2-NH2-BSA –CH3 2-CH3-BSA –OCH3 2-OCH3-BSA –N(CH3)2 2-N(CH3)2-BSA –OH 2-OH-BSA –SO3H 2-SO3H-BSA

Scheme 1. Benzene sulfonic acid and set of studied substituents. Scheme 1. Benzene sulfonic acid and set of studied substituents. 2. Calculation Details 2. Calculation Details Quantum-chemical calculations were performed by the DFT/B3LYP method with the cc-pVTZ basis setQuantum-chemical [47] using Gaussian 09calculations package [48 were]. It hasperforme been shownd by the in [ 37DFT/B3LYP] that the use method of this theoreticalwith the cc-pVTZ level gives basis set [47] using Gaussian 09 package [48]. It has been 1shown in [37] that the use of this 1 satisfactory agreement between the calculated (1410.1 kJ mol− ) and experimental (1395.0(84) kJ mol− ) theoretical level gives satisfactory 0agreement between the calculated (1410.1 kJ mol−1) and values of the Gibbs free energy ∆rG 298 of benzoic acid gas-phase deprotonation. The best agreement experimentalwith experiment (1395.0(84) is observed kJ mol−1 in) values the calculations of the Gibbs with free theenergy more ΔrG costly0298 of methodbenzoic MP2acid /gas-phase6-311++G** deprotonation. The1 best agreement with experiment is observed in the calculations with the more0 (1390.4 kJ mol− ). However, both methods reveal similar tendencies in the change in the ∆rG 298 of costlyGD formethodortho -,MP2/6-311++G**meta-, para-nitro-substituted (1390.4 kJ mol BSA−1). [However,37]. both methods reveal similar tendencies in the changeIt should in the be notedΔrG0298 that of GD the for structural ortho-, meta parameters-, para-nitro-substituted and the potential BSA function [37]. of internal rotation forIt BSA, should as be well noted as the that relative the structural energy parameters of conformers and of the a numberpotential of function substituted of internal BSA derivatives rotation for BSA, as well as the relative energy of conformers of a number of substituted BSA derivatives calculated by two methods B3LYP/cc-pVTZ and MP2/cc-pVTZ with experimental electron diffraction data, were compared [35,36,42,49–51]. Both methods give the same functions of the

Molecules 2020, 25, 5806 4 of 23 calculated by two methods B3LYP/cc-pVTZ and MP2/cc-pVTZ with experimental electron diffraction data, were compared [35,36,42,49–51]. Both methods give the same functions of the internal rotation of the sulfonic group for benzenesulfonic acid [42], moreover, for all substituted derivatives of the acid, good agreement is observed between the experimental geometric parameters and the calculated ones by both the B3LYP method and the MP2 method [35,36,42] (see Supplementary Materials, Tables S1 and S2). Possible conformers of ortho-substituted BSA molecules were determined by geometric optimization (DFT/B3LYP/cc-pVTZ) of all starting structures differing in the mutual position of ortho-substituents, as well as using data on the conformational diversity of these compounds from [35–37,42]. When calculating the energy of GD, a complete optimization of the geometric parameters of both neutral AH and deprotonated A− acid forms was carried out. The correspondence of the optimized geometry to the minimum on the potential energy surface was verified by calculating the vibration frequencies. For the deprotonated form, the total charge was taken as 1, and the multiplicity was 1. − For acid conformers with IHB, the Natural Bond Orbital (NBO [52]) analysis was performed for estimating a relative strength of IHB. The sum of the donor-acceptor stabilization energy E(2), calculated by the 2nd-order perturbation theory, between the lone electron pairs (LP) of the atom-acceptor HB and the antibonding natural orbital σ*(O–H) is considered (Table 2 and Table S3). The dissociation energies of gaseous acids ∆rE were estimated as the difference between the electronic energies E(A−) of deprotonated forms of acids and the energies E(AH) of their molecular + + 1 forms: ∆rE = E(A−) E(AH). In this case, we took: EH ,0 = 0, EH ,298 = Etransl = 3/2RT = 3.7 kJ mol− , 0 + − 1 0 + 1 1 0 + 1 H H ,298 = 5/2RT = 6.2 kJ mol− ,S H ,298 = 108.9 J mol− K− )[37,53], G H ,298 = 26.3 kJ mol− . 0 0 − The values of ∆rH 298 and ∆rG 298 were calculated using Equations (1) and (2)

0 0 0 1 ∆rH = H − H , + 6.2, kJ mol− , (1) 298 A ,298− AH 298 0 0 0 1 ∆rG = G − G 26.3, kJ mol− (2) 298 A ,298− AH,298 − The diﬀerence between our approach to assessing the gas-phase acidity of 2X-BSA from the approaches [43–45] is that we take into account the conformity between the acid conformer geometric structure and its anion that forms when the proton is removed from this conformer. When discussing the strength of IHB, the geometric criteria of HB were used [54].

3. Conformational Diversity of ortho-Substituted BSA Molecules A specific situation arises if the substituent is in the ortho position. All studied objects have several non-rigid torsion coordinates, which determines the presence of several conformers. In the molecules under consideration, rotation of the sulfonic acid group about the C–S bond and the –OH group about the S–O bond is possible. In the case of substituents –CH3, –OH, –NO2, –SO2F, –NH2, –COOH, their rotation about the C–X bond is possible. In the case of the –NH2 substituent, along with this type of rotation, pyramidal inversion is possible, and in the case of the –COOH substituent, rotation of the –OH fragment about the C–O bond is possible. Depending on the ortho-substituent nature of the molecules, both conformers without IHB and conformers with one or two IHBs can appear. The formation of IHB in such conformers is accompanied by a redistribution of the electron density, which has a significant effect on the characteristics of the GD process and the acidity of compounds. Therefore, hereinafter, when analyzing the conformational properties of ortho-substituted BSA, special attention is paid to IHB. Table1 lists the compounds studied and shows the total number of their conformers and the number of conformers with IHB.

Table 1. The number of acid conformers

Compound Total Number of Conformers a Number of Conformers with IHB b BSA 1 - 2-COOH-BSA c 9 2 2-NO2-BSA 5 1 Molecules 2020, 25, 5806 5 of 23

Molecules 2020, 25, x FOR PEER REVIEW 5 of 23 Table 1. Cont. 2-CN-BSA 3 - 2-NHCompound2-BSA Total Number2 of Conformers a Number of Conformers 2 with IHB b 2-CH3-BSA 3 - 2-SO2F-BSA 9 4 2-OCH2-CN-BSA3-BSA 3 3 1 - 2-N(CH2-NH3)2-BSA-BSA 3 2 1 2 2-OH-BSA2-CH3-BSA 5 3 3 - 2-OCH -BSA 3 1 2-SO3H-BSA3 6d 3 2-N(CH ) -BSA 3 1 a 3 2 The conformational2-OH-BSA composition of gas 5phase (Boltzmann distribution, 298 3K) and Cartesian coordinates of optimized geometry (DFT/B3LYP/cd c-pVTZ) for acid conformers and deprotonated 2-SO3H-BSA 6 3 forms are given in ESI. b IHB—intramolecular hydrogen bond. c Only low-energy conformers with a The conformational composition of gas phase (Boltzmann distribution, 298 K) and Cartesian coordinates ofthe optimized H–O–C=O geometry torsion (DFT angle/B3LYP close/cc-pVTZ) to 0° were for acidconsidered. conformers d The and molecule deprotonated has a forms greater are number given in ESI.of bconformers.IHB—intramolecular This work hydrogen considers bond. sixc Only conformers, low-energy which conformers include with all the the H–O–C main=O types torsion of angle mutual close to 0 were considered. d The molecule has a greater number of conformers. This work considers six conformers, arrangement◦ of two sulfonic groups. which include all the main types of mutual arrangement of two sulfonic groups.

4. The Conformers Structure of Molecules of ortho-Substituted BSA 4. The Conformers Structure of Molecules of ortho-Substituted BSA The 2-COOH-BSA molecule has nine conformers (Figure 1), in which the torsion angle The 2-COOH-BSA molecule has nine conformers (Figure1), in which the torsion angle H–O–C =O H–O–C=O of the –COOH group is 0°. The corresponding conformers with a torsion angle of the –COOH group is 0 . The corresponding conformers with a torsion angle H–O–C=O of the H–O–C=O of the –COOH◦ substituent equal to 180° were not considered, since they have a higher –COOH substituent equal to 180 were not considered, since they have a higher energy (by 25 kJ mol–1; energy (by ≈ 25 kJ mol–1; B3LYP/6-311++G**)◦ [55]. In conformers 1 and 2 of 2-COOH-BSA,≈ IHB is B3LYP/6-311++G**) [55]. In conformers 1 and 2 of 2-COOH-BSA, IHB is formed between the hydrogen formed between the hydrogen atom of the –SO3H group and the oxygen atoms of the –COOH atom of the –SO H group and the oxygen atoms of the –COOH group (C=O or C–OH). The hydrogen group (C=O or 3C–OH). The hydrogen bond with the carboxyl oxygen atom in conformer 1, r(O···H) bond with the carboxyl oxygen atom in conformer 1, r(O H) = 1.735 Å, is stronger than the bond with = 1.735 Å, is stronger than the bond with the hydroxyl··· O atom in conformer 2, r(O···H) = 1.920 Å. the hydroxyl O atom in conformer 2, r(O H) = 1.920 Å. The presence of IHB makes conformers 1 and The presence of IHB makes conformers··· 1 and 2 energetically more stable than other conformers in 2which energetically this bond more is absent. stable than other conformers in which this bond is absent.

conformer 1 conformer 2 conformer 3 conformer 4 conformer 5 ΔE = 0 ΔE = 16.2 ΔE = 31.3 ΔE = 33.9 ΔE = 35.9

conformer 6 conformer 7 conformer 8 conformer 9 ΔE = 35.9 ΔE = 38.1 ΔE = 39.6 ΔE = 41.1

−1 1 FigureFigure 1. 1.The The structurestructure ofof thethe 2-COOH-BSA2-COOH-BSA conformersconformers and their relative energies ( (Δ∆E,E, kJ kJ mol mol−).).

TheThe 2-NO2-NO2-BSAmolecule2-BSAmoleculehas has ﬁve five conformers conformers diﬀering differing in the in spatial the arrangementspatial arrangement of functional of groupsfunctional [35], groups and in [35], one ofand them, in one an IHBof them, is formed an IHB between is formed the hydrogenbetween the atom hydrogen of the–SO atom3H of group the and–SO the3H oxygengroup and atom the of oxygen the –NO atom2 group, of the which –NO2 makes group, this which conformer makes this energetically conformer more energetically favorable comparedmore favorable to the compared other conformers to the other (Figure conformers2). In the conformer(Figure 2). 1,In sulfonicthe conformer group is1, thesulfonic IHB donor.group is the IHBThe donor. 2-SO2F-BSA molecule has nine conformers (Figure3), formed as a result of the –SO 2F and –SO3H rotation about the corresponding C–S bonds. In conformers 1, 2, and 3, an IHB is formed between the hydrogen atom of the –SO H group and the oxygen atom of the –SO F group. The O H 3 2 ··· distances are 1.825, 1.850 and 1.846 Å, respectively. The presence of IHB makes these conformers energetically more stable. In conformer 4, a less strong IHB is formed between the hydrogen atom of

Molecules 2020, 25, x FOR PEER REVIEW 6 of 23

Molecules 2020, 25, 5806 6 of 23

conformer 1 conformer 2 conformer 3 conformer 4 conformer 5 the –SOΔ3EH = group 0 and theΔ ﬂuorineE = 23.0 atom of the –SOΔE =2F 27.8 group, r(F H)Δ=E2.101 = 28.3 Å. In these fourΔE = conformers, 30.2 conformer 1 conformer 2 conformer 3 ··· conformer 4 conformer 5 the acid group is the IHB donor. IHB is absent in other conformers. MoleculesΔ 2020EFigure = ,0 25 , x2. FOR The PEER structureΔ REVIEWE = 23.0of the 2-NO2-BSAΔ Econformers = 27.8 and theirΔ relativeE = 28.3 energies (kJ ΔmolE =−1 ).30.2 6 of 23

Figure 2. The structure of the 2-NO2-BSA conformers and their relative energies (kJ mol−1). The 2-SO2F-BSA molecule has nine conformers (Figure 3), formed as a result of the –SO2F and

–SO3HThe rotation 2-SO2 F-BSAabout themolecule corresponding has nine conformersC–S bonds. (Figure In conformers 3), formed 1, as2, aand result 3, anof theIHB –SO is formed2F and between–SO3H rotation the hydrogen about theatom corresponding of the –SO3 HC–S group bonds. and In the conformers oxygen atom1, 2, andof the 3, an–SO IHB2F group.is formed The O···Hbetween distances the hydrogen are 1.825, atom 1.850 of the and –SO 1.8463H group Å, respectively. and the oxygen The atompresence of the of –SOIHB2F makesgroup. theseThe conformersO···H distances energetically are 1.825, more 1.850 st able.and In1.846 conformer Å, respectively. 4, a less Thestrong presence IHB is offormed IHB makes between these the conformer 1 conformer 2 conformer 3 conformer 4 conformer 5 hydrogenconformers atom energetically of the –SO 3moreH group stable. and In the conformer fluorine atom4, a lessof the st rong–SO2 FIHB group, is formed r(F···H) between = 2.101 Å.the In ΔE = 0 ΔE = 23.0 ΔE = 27.8 ΔE = 28.3 ΔE = 30.2 thesehydrogen four conformers,atom of the –SOthe acid3H group group and is the the IHB fluorine donor. atom IHB of is the absent –SO 2inF group,other conformers. r(F···H) = 2.101 Å. In −1 1 these fourFigureFigure conformers, 2. 2.The The structure structure the acid of of group the the 2-NO 2-NO is the22-BSA-BSA IHB conformersconformers donor. IHB and is their absent relative in other energies energies conformers. (kJ (kJ mol mol−). ).

The 2-SO2F-BSA molecule has nine conformers (Figure 3), formed as a result of the –SO2F and –SO3H rotation about the corresponding C–S bonds. In conformers 1, 2, and 3, an IHB is formed between the hydrogen atom of the –SO3H group and the oxygen atom of the –SO2F group. The O···H distances are 1.825, 1.850 and 1.846 Å, respectively. The presence of IHB makes these conformersconformer energetically 1 conformer more st 2able. In conformerconformer 4,3 a less stconformerrong IHB 4is formed conformer between 5the hydrogenconformerΔE = atom0 1 of the –SOconformerΔE3H = group8.2 2 and theconformer fluorineΔE = 11.2 atom 3 of theconformer –SOΔE 2=F 24.7 group, 4 r(F···H)conformerΔ =E 2.101 = 26.8 Å.5 In these fourΔE = conformers, 0 theΔ Eacid = 8.2 group is the IHBΔE =donor. 11.2 IHB is absentΔE =in 24.7 other conformers.ΔE = 26.8

conformer 6 conformer 7 conformer 8 conformer 9

conformerΔE = 30.6 6 conformerΔE = 32.9 7 conformerΔE = 33.6 8 conformerΔE = 35.2 9 conformerΔE = 30.6 1 conformerΔE = 32.9 2 conformerΔE = 33.6 3 conformerΔE = 35.2 4 conformer 5 ΔFigureE = 0 3. The structureΔE of= 8.2the 2-SO2F-BSAconformersΔE = 11.2 and their relativeΔE = 24.7 energies (ΔE, kJΔ molE = −26.81). Figure 3. The structure of the 2-SO2F-BSAconformers and their relative energies (ΔE, kJ mol−1).1 Figure 3. The structure of the 2-SO2F-BSAconformers and their relative energies (∆E, kJ mol− ). The 2-CN-BSA moleculehas three conformers, differing in the spatial orientation of the sulfonicTheThe group 2-CN-BSA 2-CN-BSA (Figure molecule molecule 4). Therehashas is three nothree IHB conformers, conformers, in the conformers. diﬀ differingering in Note the in spatial thatthe spatialin orientation conformer orientation of 1, thethere sulfonicof isthe an sulfonic group (Figure 4). There is no IHB in the conformers. Note that in conformer 1, there is an groupinteraction (Figure between4). There the is hydrogen no IHB in theatom conformers. of the –SO Note3H group that in and conformer the nitrogen 1, there atom is an of interaction the –CN interaction between the hydrogen atom of the –SO3H group and the nitrogen atom of the –CN betweengroup, the the OH···N hydrogen distance atom is of 2.638 the –SO Å, 3 whichH group stab andilizes the the nitrogen structure atom and ofthe makes –CN this group, conformer the OH theN group, the OH···N distance is 2.638 Å, which stabilizes the structure and makes this conformer the··· distancemostconformer stable. is 2.638 6 Å, whichconformer stabilizes 7 the structureconformer and makes 8 thisconformer conformer 9 the most stable. most stable. ΔE = 30.6 ΔE = 32.9 ΔE = 33.6 ΔE = 35.2

Figure 3. The structure of the 2-SO2F-BSAconformers and their relative energies (ΔE, kJ mol−1).

The 2-CN-BSA moleculehas three conformers, differing in the spatial orientation of the sulfonic group (Figure 4). There is no IHB in the conformers. Note that in conformer 1, there is an

interaction between the hydrogen atom of the –SO3H group and the nitrogen atom of the –CN conformer 1 conformer 2 conformer 3 group, the OH···N distanceconformer is 2.638 1 Å, whichconformer stabilizes 2 the structureconformer and makes 3 this conformer the most stable. ΔE = 0 ΔE = 10.0 ΔE = 18.1 ΔE = 0 ΔE = 10.0 ΔE = 18.1 Figure 4. The structure of the 2-CN-BSA conformers and their relative energies (ΔE, kJ mol−1). FigureFigure 4. 4.The The structurestructure ofof thethe 2-CN-BSA2-CN-BSA conformersconformers and their relative energies ( Δ∆E, kJ kJ mol mol−−1).).

The 2-NH 2-BSA-BSA molecule molecule hashas two two conformers, conformers, the the structure structure ofof which which is shown is shown in Figure in Figure 5. 5In. The 2-NH22-BSA molecule has two conformers, the structure of which is shown in Figure 5. In Inboth both conformers conformers of ofthe the 2-NH 2-NH2-BSAmolecule,-BSAmolecule, an an IHB IHB is is observed observed between between the the hydrogen hydrogen atom atom of the both conformers of the 2-NH2-BSAmolecule,2 an IHB is observed between the hydrogen atom of the –NH2 group and the oxygen atom of the –SO3H group, where nitrogen is the donor of the hydrogen bond, and oxygen is the acceptor.

In conformer 1, anconformer IHB is formed,1 whichconformer is characterized 2 byconformer an NH O3 distance of 2.064 Å. ΔE = 0 ΔE = 10.0 ΔE = 18.1··· The hydrogen atoms of the –NH2 group lie below the plane of the benzene ring and their position is Figure 4. The structure of the 2-CN-BSA conformers and their relative energies (ΔE, kJ mol−1).

The 2-NH2-BSA molecule has two conformers, the structure of which is shown in Figure 5. In both conformers of the 2-NH2-BSAmolecule, an IHB is observed between the hydrogen atom of the

Molecules 2020, 25, x FOR PEER REVIEW 7 of 23 Molecules 2020, 25, x FOR PEER REVIEW 7 of 23

–NH2 group and the oxygen atom of the –SO3H group, where nitrogen is the donor of the hydrogen Moleculesbond,–NH2 andgroup2020 oxygen, 25 and, 5806 the is theoxygen acceptor. atom of the –SO3H group, where nitrogen is the donor of the hydrogen7 of 23 bond, and oxygen is the acceptor. associated with the tendency of one of the hydrogen atoms to form an IHB with the oxygen atom of the –SO3H group, i.e., the sulfonic group is a hydrogen bond acceptor. In the second conformer, a less strong IHB is formed between the same atoms, which can be judgedMolecules from2020, 25 the, x FOR NH PEERO distance,REVIEW which is 2.133 Å. However, conformer 2 is characterized7 by of an23 ··· interaction between the hydrogen atom of the –SO3H group and the nitrogen atom of the –NH2 group, conformer 1 conformer 2 the–NH OH2 groupN distance and the isoxygen 2.484 Å,atom which of the also –SO stabilizes3H group, the where structure nitrogen and leadsis the todonor close of energies the hydrogen of the ··· conformer 1 conformer 2 two conformers. ΔE = 0 ΔE = 0.3 bond, and oxygen is the acceptor. ΔE = 0 ΔE = 0.3 Figure 5. The structure of the 2-NH2-BSAconformers and their relative energies (ΔE, kJ mol−1). Figure 5. The structure of the 2-NH2-BSAconformers and their relative energies (ΔE, kJ mol−1). In conformer 1, an IHB is formed, which is characterized by an NH···O distance of 2.064 Å. The In conformer 1, an IHB is formed, which is characterized by an NH···O distance of 2.064 Å. The hydrogen atoms of the –NH2 group lie below the plane of the benzene ring and their position is hydrogen atoms of the –NH2 group lie below the plane of the benzene ring and their position is associated with the tendency of one of the hydrogen atoms to form an IHB with the oxygen atom of associated with the tendency of one of the hydrogen atoms to form an IHB with the oxygen atom of the –SO3H group, i.e., the sulfonic group is a hydrogen bond acceptor. the –SO3H group, i.e., the sulfonic group is a hydrogen bond acceptor. In the second conformer, a less strong IHB is formed between the same atoms, which can be In the second conformer, a lessconformer strong IHB1 is formedconformer between 2 the same atoms, which can be judged from the NH···O distance, which is 2.133 Å. However, conformer 2 is characterized by an judged from the NH···O distance, whichΔE = 0is 2.133 Å. However,ΔE = 0.3 conformer 2 is characterized by an interaction between the hydrogen atom of the –SO3H group and the nitrogen atom of the –NH2 interactionFigure between 5. The structurethe hydrogen of the 2-NH atom2-BSAconformers of the –SO3H andgroup their and relative the energiesnitrogen ( ΔatomE, kJ molof −the1). –NH2 group, theFigure OH···N 5. The distance structure is of 2.484 the 2-NH Å, which2-BSAconformers also stabilizes and theirthe structure relative energies and leads (∆E, to kJ molclose− ).energies group, the OH···N distance is 2.484 Å, which also stabilizes the structure and leads to close energies of the two conformers. of theTheIn two conformer 2-CH conformers.3-BSAmolecule 1, an IHB is formed,has three which conformers is char (Figureacterized6). by These an NH···O conformers distance have of close 2.064 energies Å. The The 2-CH3-BSAmolecule has three conformers (Figure 6). These conformers have close hydrogenThe 2-CHatoms3-BSAmolecule of the –NH2 group has threelie below conformers the plane (Figure of the 6).benzene These ring conformers and their have position close is andenergies diﬀer and in thediffer sulfonic in the group sulfonic position group relative position to therelative plane to of the the plane benzene of the ring. benzene In two ring. conformers, In two associatedenergies and with differ the tendencyin the sulfonic of one group of the position hydrogen relative atoms to to the form plane an IHB of the with benzene the oxygen ring. atomIn two of theconformers, S=O bond the has S=O the bond coplanar has the position coplanar relative position to therelative benzene to th ring,e benzene and in ring, the thirdand in conformer, the third theconformers, –SO3H group, the S=O i.e., bond the sulfonic has the group coplanar is a hydrogenposition relative bond acceptor. to the benzene ring, and in the third theconformer, S–O(H) the bond S–O(H) is coplanar bond tois coplanar the benzene to the ring. benzene ring. conformer,In the secondthe S–O(H) conformer, bond is acoplanar less strong to the IHB benzene is formed ring. between the same atoms, which can be judged from the NH···O distance, which is 2.133 Å. However, conformer 2 is characterized by an interaction between the hydrogen atom of the –SO3H group and the nitrogen atom of the –NH2 group, the OH···N distance is 2.484 Å, which also stabilizes the structure and leads to close energies of the two conformers. The 2-CH3-BSAmolecule has three conformers (Figure 6). These conformers have close

energies and differ in the sulfonic group position relative to the plane of the benzene ring. In two conformer 1 conformer 2 conformer 3 conformers, the S=O bondconformer has the 1 coplanarconformer position 2 relative toconformer the benzene 3 ring, and in the third ΔE = 0 ΔE = 2.5 ΔE = 7.2 conformer, the S–O(H) bondΔE = is 0 coplanar to theΔE benzene= 2.5 ring. ΔE = 7.2

3 −1 FigureFigure 6.6. TheThe structurestructure ofof thethe 2-CH2-CH -BSA conformers andand theirtheir relativerelative energiesenergies ((∆ΔE,E, kJkJ molmol−1 ).). Figure 6. The structure of the 2-CH33-BSA conformers and their relative energies (ΔE, kJ mol−).

A feature of the structurestructure ofof 2-CH2-CH33-BSA conformers is that twotwo hydrogenhydrogen atomsatoms ofof thethe –CH–CH33 A feature of the structure of 2-CH3-BSA conformers is that two hydrogen atoms of the –CH3 group tendtend toto be be as as close close as as possible possible to twoto two oxygen oxygen atoms atoms of the of –SO the3 H–SO group.3H group. In this In case, this the case, CH theO group tend to be as close as possible to two oxygen atoms of the –SO3H group. In this case, the··· distanceCH···OCH···O distancedistance in conformers inin conformersconformers lies in the lies range in the from range 2.6 from to 2.7 2.6 Å. to This 2.7 Å. distance This distancedistance is close is tois closeclose the sum toto thethe of thesumsum van ofof derthe Waalsvan der radii Waals of oxygen radii of and oxygen hydrogen and atoms.hydrogen The at interactionoms. The interaction of CH O stabilizes of CH···O the stabilizes structure the of the van der Waals radii of oxygen and hydrogen atoms. The interaction··· of CH···O stabilizes the eachstructurestructure of the ofof conformers. eacheach ofof thetheconformer conformers.conformers. 1 conformer 2 conformer 3 The 2-OCH3-BSAmolecule-BSAmolecule has three conformers (Figure 7 7).). The 2-OCH33-BSAmoleculeΔE = 0 has three conformersΔE = 2.5 (Figure 7). ΔE = 7.2

Figure 6. The structure of the 2-CH3-BSA conformers and their relative energies (ΔE, kJ mol−1).

A feature of the structure of 2-CH3-BSA conformers is that two hydrogen atoms of the –CH3 group tend to be as close as possible to two oxygen atoms of the –SO3H group. In this case, the CH···O distance in conformers lies in the range from 2.6 to 2.7 Å. This distance is close to the sum of the van der Waals radii of oxygen and hydrogen atoms. The interaction of CH···O stabilizes the structure of each of the conformers. Theconformer conformer2-OCH3-BSAmolecule 11 conformer has three conformers 2 conformer(Figure 7). 2 conformerconformer 33 ΔΔEE == 00 ΔE = 8.0 Top view ΔΔEE == 14.714.7

1 Figure 7. The structure of the 2-OCH3-BSA conformers and their relative energies (∆E, kJ mol− ).

conformer 1 conformer 2 conformer 2 conformer 3 ΔE = 0 ΔE = 8.0 Top view ΔE = 14.7

Molecules 2020, 25, 5806x FOR PEER REVIEW 8 8of of 23 Molecules 2020, 25, x FOR PEER REVIEW 8 of 23

Figure 7. The structure of the 2-OCH3-BSA conformers and their relative energies (ΔE, kJ mol−1). Figure 7. The structure of the 2-OCH3-BSA conformers and their relative energies (ΔE, kJ mol−1). In all conformers, the O-C bond of the –OCH3 group practically eclipses the C2-C3 bond of the benzeneIn all ring, conformers, which indicates the O-C thebond presence of the –OCH of an3anomeric group practically eﬀect between eclipses the the oxygen C2-C3 lonebond pair of the of In all conformers, the O-C bond of the –OCH3 group practically eclipses the C2-C3 bond of the benzenepπ-character ring, and which the πindicates*-MO of the the presence benzene ring.of an In anomeric conformer effect 1, a between weak IHB the is formedoxygen betweenlone pair the of benzene ring, which indicates the presence of an anomeric effect between the oxygen lone pair of phydrogenπ-character atom and of the the π*-MO –SO3H of group the benzene and the ring. oxygen In conformer atom of the 1, a –OCH weak3 IHBgroup is formed (r(O H) between= 2.176 the Å), pπ-character and the π*-MO of the benzene ring. In conformer 1, a weak IHB is formed··· between the whichhydrogen stabilizes atom of the the structure –SO3H andgroup makes and thisthe conformeroxygen atom the of most the stable.–OCH3 group (r(O···H) = 2.176 Å), hydrogen atom of the –SO3H group and the oxygen atom of the –OCH3 group (r(O···H) = 2.176 Å), whichThe stabilizes 2-N(CH the3)2 -BSAstructure molecule and mahaskes three this conformer conformers, the the most structure stable. of which is shown in Figure8. which stabilizes the structure and makes this conformer the most stable. The nitrogenThe 2-N(CH atom3)2 of-BSA the –N(CHmolecule3)2 grouphas three lies conformers, in the plane the of the structur benzenee of ring,which and is theshown –CH in3 groupsFigure The 2-N(CH3)2-BSA molecule has three conformers, the structure of which is shown in Figure 8.are The located nitrogen above atom and belowof the this–N(CH plane.3)2 Ingroup conformer lies in 1,the an plane IHB is of formed the benzene between ring, the hydrogenand the –CH atom3 8. The nitrogen atom of the –N(CH3)2 group lies in the plane of the benzene ring, and the –CH3 groupsof the –SO are Hlocated group andabove the and nitrogen below atom this ofplane. the –N(CH In conformer) group, 1, r(H an N)IHB= is1.765 formed Å. This between conformer the groups are3 located above and below this plane. In conformer3 2 1, an··· IHB is formed between the hydrogenis the most atom stable. of the –SO3H group and the nitrogen atom of the –N(CH3)2 group, r(H···N) = 1.765 hydrogen atom of the –SO3H group and the nitrogen atom of the –N(CH3)2 group, r(H···N) = 1.765 Å. This conformer is the most stable. Å. This conformer is the most stable.

conformer 1 conformer 2 conformer 3 conformer 1 conformer 2 conformer 3 ΔE = 0 ΔE = 23.2 ΔE = 26.9 ΔE = 0 ΔE = 23.2 ΔE = 26.9

Figure 8. The structure of the 2-N(CH3)2-BSAconformers and their relative energies (ΔE, kJ mol−11). FigureFigure 8. 8.The The structure structure of of the the 2-N(CH 2-N(CH33))22-BSAconformers and and their their relative relative energies energies ( (Δ∆E,E, kJ kJ mol mol−1−). ).

TheThe 2-HO-BSA 2-HO-BSA2-HO-BSA molecule moleculemoleculehas hashas ﬁve fivefive conformers conformersconformers (Figure (Figure9). Three 9).9). ofThreeThree them ofof have themthem an IHB. havehave In an conformersan IHB.IHB. InIn 1conformers and 2, a IHB 1 and is formed 2, a IHB between is formed the oxygen between atom the of oxygen the –SO atomH group of the and –SO the3H hydrogen group and atom the of conformers 1 and 2, a IHB is formed between the oxygen 3atom of the –SO3H group and the hydrogenthe –OH group, atom of r(O theH) –OH is 1.820group, and r(O···H) 1.791 Å,is 1.820 respectively. and 1.791 The Å, sulfonic respectively. group The is an sulfonic acceptor group of the is hydrogen atom of the··· –OH group, r(O···H) is 1.820 and 1.791 Å, respectively. The sulfonic group is anIHB.an acceptor acceptor In conformer of of the the IHB. 3,IHB. the InIn IHB conformerconformer arises between 3,3, thethe IHB the arises oxygen between atom of thethe the oxygenoxygen –OH group atomatom of andof thethe the –OH –OH hydrogen group group andatom the of hydrogen the –SO H atom group, of the r(O –SOH)3H= 2.253group, Å; r(O···H) the sulfonic = 2.253 group Å; the is sulfonic a donor group of the IHB.is a donor This IHBof the is and the hydrogen3 atom of the ···–SO3H group, r(O···H) = 2.253 Å; the sulfonic group is a donor of the 3 weaker;IHB.IHB. This This its IHB formationIHB isis weaker;weaker; requires itsits formationformation a greater turn requiresrequires of the a –SOgreater3H groupturnturn ofof relative thethe –SO–SO to3H itsH group initialgroup positionrelativerelative to into its theits initialunsubstitutedinitial position position BSA. inin thethe Therefore, unsubstituunsubstitu thetedted energy BSA.BSA. ofTherefore,Therefore, conformer the 3 energy is higher ofof thanconformerconformer the energy 33 isis higherhigher of conformers thanthan the the 1 energyandenergy 2. of of conformers conformers 1 1 and and 2.2.

conformerconformer 1 1 conformerconformer 22 conformer 3 conformer 44 conformerconformer 5 5 ΔΔEE = = 0 0 ΔΔEE == 1.71.7 ΔE = 19.3 ΔEE == 27.827.8 ΔΔEE = = 35.0 35.0

FigureFigure 9. 9. The The structure structure ofof thethe 2-HO-BSA2-HO-BSA conformers and their relativerelative energiesenergies ( (ΔΔE,E, kJ kJ mol mol−1−).1). Figure 9. The structure of the 2-HO-BSA conformers and their relative energies (∆E, kJ mol− ).

InIn conformers conformers 4 4 and and 5,5, thethe oxygenoxygen atomsatoms of the –SO3HH group group areare arrangedarranged soso thatthat one one of of the the O O atomsatoms practically practically lies lies inin thethe planeplane of of thethe benzenebenzene ring. In In this this case, case, thethe otherother twotwo oxygenoxygen atoms atoms are are almostalmost equidistant equidistant from from thethe oxygenoxygen atomatom ofof thethe –OH–OH group. IHB is is not not formed formed in in these these conformers. conformers. ForFor thethe 2-SO2-SO33H-BSAH-BSA molecule molecule,, sixsix conformersconformers are considered considered (Figure (Figure 10),1010),), which which include include all all thethe main main types types ofof mutualmutual arrangementarrangement of of twotwo sulfonicsulfonic groups. ThreeThree ofof them them contain contain IHBs IHBs formed formed betweenbetween the the hydrogenhydrogen andand oxygenoxygen atomsatoms ofof neighboringneighboring sulfonic groups. groups. DueDue toto thethe formation formation of of twotwo strong strong IHBs, IHBs, r(Or(O···H)r(O···H)H) == 1.7281.728 Å, Å, conformerconformer 1 is the most energeticallyenergetically favorable. favorable. Conformers Conformers 2 2 ··· andand 3, 3,3, with withwith one oneone IHB IHBIHB and and distancesand distancesdistances r(O H)r(O···H)r(O···H) equal toeq 1.781ual to and 1.781 1.796 andand Å, respectively,1.7961.796 Å,Å, respectively,respectively, have signiﬁcantly havehave ··· significantlyhighersignificantly energies higher higher (Figure energiesenergies 10). The (Figure(Figure relative 10).10). electronicTheThe relative energy electronic of conformers energyenergy ofof 4, conformersconformers 5, and 6, in 4, 4, which 5, 5, and and IHB 6, 6, in in is which IHB is not formed, reaches1 81.0 kJ mol−1. Comparison of the ΔE conformers allows us to whichnot formed, IHB is reaches not formed, 81.0 kJ molreaches− . Comparison81.0 kJ mol of. theComparison∆E conformers of the allowsΔE conformers us to conclude allows that us theto −1 conclude that the energy of IHB in conformers 1, 2, and 3 is not less1 than 37 kJ mol −1. concludeenergy of that IHB the in conformersenergy of IHB 1, 2, in and conformers 3 is not less 1, 2, than and 37 3 is kJ not mol less− . than 37 kJ mol .

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conformer 1 conformer 2 conformer 3 conformer 1 conformer 2 conformer 3 ΔE = 0 ΔE = 36.0 ΔE = 44.4 ΔE = 0 ΔE = 36.0 ΔE = 44.4

conformer 4 conformer 5 conformer 6 conformer 4 conformer 5 conformer 6 ΔE = 75.4 ΔE = 77.1 ΔE = 81.0 ΔE = 75.4 ΔE = 77.1 ΔE = 81.0

Figure 10. The structure of the 2-SO3H-BSAconformers and their relative energies (ΔE, kJ mol−1). −1 FigureFigure 10.10. TheThe structurestructure ofof thethe 2-SO2-SO33H-BSAconformers and their relative energiesenergies ((∆ΔE,E, kJkJ molmol− ).). 5. Structure of Deprotonated Forms of ortho-Substituted BSA 5. Structure of Deprotonated Forms of ortho-Substituted BSA Despite the significant number of conformers in the ten considered molecules of Despite thethe signiﬁcant significant number number of conformers of conformers in the ten in considered the ten molecules considered of ortho molecules-substituted of ortho-substituted BSA, the deprotonated forms (by sulfonic group) of A−, seven of them are realized BSA,ortho-substituted the deprotonated BSA, the forms deprotonated (by sulfonic forms group) (by of sulfonic A−, seven group) of them of A are−, seven realized of them as single are (unique)realized as single (unique) structures shown in Figure 11. structuresas single (unique) shown instructures Figure 11 shown. in Figure 11.

(a) 2-COOH-BSA anion (b) 2-NO2-BSA anion (c) 2-CN-BSA anion (a) 2-COOH-BSA anion (b) 2-NO2-BSA anion (c) 2-CN-BSA anion

(d) 2-NH2-BSA anion (e) 2-CH3-BSA anion (f) 2-OCH3-BSA anion (d) 2-NH2-BSA anion (e) 2-CH3-BSA anion (f) 2-OCH3-BSA anion

(g) 2-N(CH3)2-BSA anion (g) 2-N(CH3)2-BSA anion Figure 11. The structure of deprotonated forms of BSA (by sulfonic group), containing ortho Figure 11.11.The The structure structure of deprotonatedof deprotonated forms forms of BSA of (by BSA sulfonic (by group),sulfonic containing group), orthocontainingsubstituents: ortho –COOH,substituents: –NO –COOH,2, –CN, –NH –NO2,2, –CH –CN,3, –NH –OCH2, 3–CH, –N(CH3, –OCH3)2. 3, –N(CH3)2. substituents: –COOH, –NO2, –CN, –NH2, –CH3, –OCH3, –N(CH3)2.

AtAt thethe samesame time,time, thethe anionsanions ofof thethe acidsacids 2-SO2-SO22F-BSA,F-BSA, 2-OH-BSA2-OH-BSA andand 2-SO2-SO33H-BSAH-BSA eacheach havehave At the same time, the anions of the acids 2-SO2F-BSA, 2-OH-BSA and 2-SO3H-BSA each have severalseveral conformers. The The deprotonated deprotonated form form of of2-SO 2-SO2F-BSA2F-BSA has has three three conformers conformers (Figure (Figure 12a–c). 12a–c). The several conformers. The deprotonated form of 2-SO2F-BSA has three conformers (Figure 12a–c). The The deprotonated forms A− of molecules 2-OH-BSA and 2-SO3H-BSA have two conformers

MoleculesMolecules 20202020,, 2525,, x 5806 FOR PEER REVIEW 1010 of of 23 23 deprotonated forms A− of molecules 2-OH-BSA and 2-SO3H-BSA have two conformers (Figure 12d,e)(Figure and 12d,e) (Figure and 12f,g), (Figure and 12f,g), one andof the one anions of the of anions the molecules of the molecules contains containsIHB and IHBhas anda lower has 2 energya lower compared energy compared to anion to without anion withoutIHB. Figu IHB.re 12h Figure also 12 showsh also the shows structure the structure of the A of2− theanion, A − whichanion, correspondswhich corresponds to the doubly to the doubly deprotonated deprotonated form of form the 2-SO of the3H-BSA. 2-SO3H-BSA.

Anion A−

(a) (b) (c) 2-SO2F-BSA

(d) (e) 2-OH-BSA

(f) (g)

2-SO3H-BSA Anion A2−

(h)

2-SO3H-BSA

− FigureFigure 12. The deprotonated forms structure of A−acidacid 2-SO 2-SO22F-BSAF-BSA ( (aa––cc),), 2-OH-BSA 2-OH-BSA acid acid ( (dd,,ee)) and and − 2−2 formsforms A A− (f(,fg,g) )and and A A −(h()h acid) acid 2-SO 2-SO3H-BSA.3H-BSA.

WhenWhen a a proton proton is is removed removed from from the the –SO –SO3H3H group, group, the the –SO –SO3− 3fragment− fragment significantly signiﬁcantly changes changes its geometry,its geometry, which which obtains obtains a symmetry a symmetry close close to to C C3. 3The. The S=O S= Odouble double bonds bonds become become longer, longer, and and the the S–O(H) bond is shorter (by ≈ 0.2 Å) than in the initial –SO3H structure. All bond angles O–S–O are close to 115°, in contrast to the bond angles O=S=O ≈ 123° and O=S–O ≈104° in the –SO3H group.

Molecules 2020, 25, 5806 11 of 23

S–O(H) bond is shorter (by 0.2 Å) than in the initial –SO H structure. All bond angles O–S–O are ≈ 3 close to 115 , in contrast to the bond angles O=S=O 123 and O=S–O 104 in the –SO H group. ◦ ≈ ◦ ≈ ◦ 3 The insigniﬁcant total natural charge +0.123 e− of the –SO3H group in the molecular form of the acid changes to 0.65 e on the –SO fragment of the deprotonated form (the example, for the − − 3− conformer 1 of acid 2-OH-BSA, Figure9; and the anion A −, Figure 12a).The rest of the negative charge is delocalized on the remaining part of the anion. It is interesting to note that the IHB in deprotonated forms of A− is stronger than in the corresponding acid conformers of AH (2-NH2-BSA, 2-NO2-BSA, and 2-SO3H-BSA, as evidenced by a longer distance r(D H) and a shorter distances r(A H) and r(A...D) in the anions A (Table2). This fact ··· ··· − was noted in [43,44] when considering the molecular and anionic forms of ortho-substituted BA. (2) For all conformers of 2-NH2-BSA, 2-OH-BSA and 2-SO3H-BSA acids, the sum ΣE of the donor-acceptor stabilization energies characterized the strength of the formed IHB is presented in Table2. As an example, the Figure 13 shows the interacting orbitals and the result of their interaction, which leads to the formation of the bonding area between O H atoms (deprotonated form of ··· 2-OH-BSA).

Figure 13. Deprotonated form of 2-OH-BSA. The natural bond orbitals and the donor-acceptor stabilization energy E(2): I (a) donor LP1(O), (b) acceptor σ*(O-H), (c) LP1(O) σ*(O-H), E(2) = 29.7 kJ → mol 1; II (a) donor LP2(O), (b) acceptor σ*(O-H), (c) LP2(O) σ*(O-H), E(2) = 118.5 kJ mol 1. − → − (2) Thus, the sum ΣE in the conformers of 2-NH2-BSA and 2-OH-BSA(1) is much lower than in the deprotonated forms of these acids (Figure 12), which, along with the geometric characteristics (Table2) illustrates an increase in the IHB strength at the transition from the neutral to the deprotonated form (AH A ). → − When comparing IHB in three conformers of 2-SO3H-BSA acid, one may conclude that IHB in conformer 1 is stronger than in conformers 2 and 3. This is conﬁrmed by the sum of the donor–acceptor stabilization energies (Table2). In the deprotonated form of the dibasic 2-SO3H-BSA acid, IHB is so strong that in NBO analysis the Hδ+ stands out as an independent unit and does not form a σ(O–H) bond with any of the two O atoms, while the O1 H O2 triad contains only donor–acceptor interactions between LP(O1), LP(O2) ··· ··· and 1s-AO(H). The fact that IHB is very strong is conﬁrmed by the values of natural charges in the O1 H O2 fragment ( 0.92...+ 0.51... 1.00), which practically coincide with O1 and O2 atoms. ··· ··· − −

Molecules 2020, 25, 5806 12 of 23

Table 2. Geometric characteristics of IHB in conformers of AH acids and deprotonated forms A− (D–IHB donor, A—IHB acceptor, interatomic distances in Å, angles in (2) 1 degrees, the sum of donor-acceptor stabilization energies ΣE in kJ mol− ).

Acid Molecule AH Deprotonated Form A− (Conformer) r(D–H) r(A H) r(A D) ∠D-H A ΣE(2) r(D–H) r(A H) r(A D) ∠D-H A ΣE(2) ··· ··· ··· ··· ··· ··· 2-NH2-BSA (1) 1.009 2.064 2.857 133.8 17.2 1.020 1.915 2.700 142.0 41.4 2-OH-BSA (1) 0.976 1.820 2.700 148.4 53.6 1.003 1.611 2.566 157.3 148.2 2-OH-BSA (2) 0.977 1.791 2.680 150.0 61.5

2-SO3H-BSA (1) 0.992 1.728 2.670 157.0 82.1

2-SO3H-BSA (2) 0.983 1.781 2.697 152.1 59.5 1.061 1.412 2.466 172.0 506.6

2-SO3H-BSA (3) 0.983 1.796 2.704 152.1 55.3 Molecules 2020, 25, 5806 13 of 23

For hydrogen bonds of medium strength, as in the deprotonated form 2-OH-BSA, these charges in the O1–H O2 fragment are ( 0.69...+ 0.50... 1.04). ··· − − 0 6. Influence of IHB on ∆rG 298Gas-Phase Deprotonation Value of Different Conformers of ortho-Substituted BSA In the works [44,45], the possibility of an IHB presence in the conformers of some ortho-substituted BA and its insignificant effect on their acidity was noted [44]. The role of the –COOH group in the IHB formation (either a donor or an acceptor of IHB) was left without discussion. 0 This section presents the results of calculations of the ∆rG 298 gas-phase deprotonationvalues for various conformers of the considered ortho-substituted BSA and the effect of the presence of IHB on the gas-phase acidity. 0 When calculating ∆rG 298, the correspondence of the neutral form structure of the acid AH and the anion A− formed during deprotonation was determined. For example, deprotonation of conformers 1 and 2 of the 2-OH-BSA molecule (Figure9) leads to the formation of an anion conformer (Figure 12d), and deprotonation of conformers 3, 4, and 5 leads to another anion conformer (Figure 12e). Table3 shows the correspondence between the conformers of the acids AH and those anions that are formed during their deprotonation. Three types of deprotonation process can be distinguished, which differ in the presence or absence of IHB in the conformers of acids AH and the corresponding anions A−.

Table 3. Conformers of acids AH and anions A−, which are formed under their deprotonation.

1. The Acid Conformer AH and Conformer Anion A− do not Contain IHB Acid Conformer numbers Anion 2-COOH-BSA 3–9, Figure1 Figure 11a 2-NO2-BSA 2–5, Figure2 Figure 11b 2-SO2F-BSA 5–7, 9 and 7, Figure3 Figure 12a,b accordingly 2-CN-BSA 1–3, Figure4 Figure 11c 2-CH3-BSA 1–3, Figure6 Figure 11e 2-OCH3-BSA 2,3, Figure7 Figure 11f 2-N(CH3)2-BSA 2,3, Figure8 Figure 11g 2-OH-BSA 4,5, Figure9 Figure 12e 2-SO3H-BSA 4–6, Figure 10 Figure 12g

2. The Acid Conformer Contains the IHB; the –SO3H Group is a IHB Donor 2-COOH-BSA 1,2, Figure1 Figure 11a 2-NO2-BSA 1, Figure2 Figure 11b 2-SO2F-BSA 1–4, Figure3 Figure 12a–c accordingly 2-OCH3-BSA 1, Figure7 Figure 11f 2-N(CH3)2-BSA 1, Figure8 Figure 11g 2-OH-BSA 3, Figure9 Figure 12e 2-SO3H-BSA 1, Figure 10 Figure 12f

3. The Acid Conformer Contains the IHB. The –SO3H Group is an Acceptor of the IHB; Anion Conformer Preserves this Connection

2-NH2-BSA 1,2, Figure5 Figure 11d 2-OH-BSA 1,2, Figure9 Figure 12d 2-SO3H-BSA 2,3, Figure 10 Figure 12f

0 Table4 shows the ∆rG 298 values for the three considered types of deprotonation processes. Molecules 2020, 25, 5806 14 of 23

1 Table 4. Gibbs free energies of GD kJ mol− ) for conformers of ortho-substituted BSA with a diﬀerent type of IHB (conformer numbers in parentheses).

With IHB Without IHB Acid/ Type 1 –SO3H is IHB Donor –SO3H is IHB Acceptor Type of IHB Type 2 Type 3 0 0 0 ∆rG 298 ∆rG 298 ∆rG 298 BSA 1313.0 - - 2-COOH-BSA 1294.1(4) a 1320.9(1) b -

2-NO2-BSA 1277.0(2) 1295.8(1) - 1291.2(1) 1286.2(2) 2-SO F-BSA 1268.6(5) - 2 1282.8(3) 1270.7(4) 2-CN-BSA 1270.3(3) - - 1310.0(2) 2-NH -BSA - - 2 1311.3(1)

2-CH3-BSA 1308.8(1) - -

2-OCH3-BSA 1320.5(3) 1332.7(1) -

2-N(CH3)2-BSA 1313.8(2) 1333.1(1) - 2-OH-BSA 1324.3(4) 1331.4(3) 1278.2(1) 1 stage 1 stage 1 stage 1279.9(4) 1306.3(3) 1224.2(2) 2-SO H-BSA 3 2 stage 2 stage 2 stage 1605.2(4) 1695.7(3) 1695.7(2) a b 0 For the conformer number, see Figures1–10. The ∆rG 298 values for the conformers, which have the lowest energy and predominant concentration in the conformational mixture, are marked in bold.

0 7. The Effect of the X Substituent Nature on the ∆rG 298 Values By varying the nature of the substituent, it is possible to change the value of the Gibbs free energy of the GD process. The first type of deprotonation process in the absence of a hydrogen bond will be discussed below. All molecules, except for BSA and 2-NH2-BSA, have several conformers without IHB (Table1). When these conformers are deprotonated (with the exception of 2-SO2F-BSA), a single form of the 0 anion appears. As a result, the Gibbs free energies GD (∆rG 298) of acid conformers without IHB differ by the same values as the energies of the conformers themselves (Scheme2). For conformers without IHB (Table4, column 3, Type 1), there is a tendency for a decrease in 0 ∆rG 298upon the introduction of electron-withdrawing ortho-substituents in the BSA in the sequence –COOH, –NO , –SO F, –C N, –SO H. 2 2 ≡ 3 The introduction of a weak electron-donating substituent –CH3 practically does not change 0 the value of ∆rG 298 as compared to unsubstituted BSA, while the introduction of a stronger donor substituent –OH increases the Gibbs free energy of the GD. Since the ortho effect is a combination of steric and electronic factors that cannot be separated or identified as a dominant factor, it is not possible to construct simple correlations between any 0 characteristics of conformers without IHB and ∆rG 298. A similar situation was observed in a series of ortho-substituted BA [43,44]. The second type of deprotonation process is shown in (Table4, column 4, Type 2). The proton of the –SO3H group is involved in the formation of IHB, i.e., the –SO3H group is a donor to the IHB. Molecules 2020, 25, x FOR PEER REVIEW 15 of 23 Molecules 2020, 25, 5806 15 of 23

Δ G0 , kJ mol–1 1360 r 298

1320 Anion A–

1280

1240

1200

1160

1308.8 1308.0 1303.4 100

0 Conformer 1 Conformer 2 Conformer 3

Scheme 2. Deprotonation of 2-CH -BSA conformers. Scheme 2. Deprotonation of 2-CH3-BSA conformers.

In this type of deprotonation, an increase in ∆ G0 is observed (Table4, Type 2) compared to the For conformers without IHB (Table 4, columnr 3,298 Type 1), there is a tendency for a decrease in deprotonation of conformers without an IHB (Table4, Type 1). The stronger the formed IHB, the more Molecules∆rG0298upon 2020, 25the, x FORintroduction PEER REVIEW of electron -withdrawing ortho-substituents in the BSA in the sequence16 of 23 signiﬁcantly the energy of the conformer decreases, and the more diﬃcult it is to convert it into the –COOH, –NO2, –SO2F, –C≡N, –SO3H. deprotonated form (Scheme3). The introduction of a weak electron-donating substituent –CH3 practically does not change the value of ∆rG0298 as compared to unsubstituted BSA, while the introduction of a stronger donor 1360 0 –1 substituent –OH increases theΔ GibbsrG 298, kJfree mol energy of the GD.

Since the ortho effect1320 is a combination of steric and electronic factors that cannot be separated or identified as a dominant factor, it is notAnion possible A– to construct simple correlations between any characteristics of conformers1280 without IHB and ∆rG0298. A similar situation was observed in a series of ortho-substituted BA [43,44]. The second type of1240 deprotonation process is shown in (Table 4, column 4, Type 2). The proton of the –SO3H group is involved in the formation of IHB, i.e., the –SO3H group is a donor to the IHB. 1200 In this type of deprotonation, an increase in ΔrG0298 is observed (Table 4, Type 2) compared to

the deprotonation of conformers1160 without an IHB (Table 4, Type 1). The stronger the formed IHB, the more significantly the energy of the conformer decreases,1277.0 and the more difficult it is to convert it into the deprotonated form (Scheme 3). 100 1295.8

20 Conformer 2 0 Conformer 1

Scheme 3. Deprotonation of 2-NO2-BSA conformers. Scheme 3. Deprotonation of 2-NO2-BSA conformers.

In the third type of deprotonation (Table 4, Type 3) the –SO3H group is an acceptor of the IHB. In the third type of deprotonation (Table4, Type 3) the –SO 3H group is an acceptor of the IHB. Upon deprotonation of such conformers (2-NH2-BSA (1,2), 2-OH-BSA (1,2), 2-SO3H-BSA (2,3)) the IHB is retained in the anionic form A−, and, as noted above, its strength increases. This leads to additional stabilization of the A− anion and a decrease in the energy ΔrG0298. At first glance, it seems that the reason for the decrease in ΔrG0298 GD in the conformers, where the –SO3H group is the IHB acceptor, is the redistribution of the electron density in this group and the change in the electronic characteristics of the S–OH fragment compared to similar characteristics in conformers without the IHB. However, it turned out that both the atomic natural charges and the S–O and O–H interatomic distances change very little. For example, in conformer 1 with the IHB and conformer 4 without the IHB, the 2-OH-BSA molecule has natural charges on the atoms q(S) = 2.348/2.346 e−, q(O) = −0.875/−0.873 e−, q(H) = 0.501/0.497 e−, and the distances r(S-O) = 1.625/1.625Å, r(O–H) = 0.968/0.968 Å and the valence angle S–O–H = 108.2/107.2°, respectively. Therefore, the main reason for the differences in the ΔrG0298 GD of such conformers is the difference in the structure and energy of the anions formed on the deprotonation of the conformers. Upon deprotonation of conformer 1, the IHB is retained and, moreover, becomes stronger. The energy of this anion A1− is significantly lower (Scheme 4) than the A4− anion without IHB, which is formed upon deprotonation of conformer 4.

Molecules 2020, 25, 5806 16 of 23

Upon deprotonation of such conformers (2-NH2-BSA (1,2), 2-OH-BSA (1,2), 2-SO3H-BSA (2,3)) the IHB is retained in the anionic form A−, and, as noted above, its strength increases. This leads to 0 additional stabilization of the A− anion and a decrease in the energy ∆rG 298. At first glance, it seems 0 that the reason for the decrease in ∆rG 298 GD in the conformers, where the –SO3H group is the IHB acceptor, is the redistribution of the electron density in this group and the change in the electronic characteristics of the S–OH fragment compared to similar characteristics in conformers without the IHB. However, it turned out that both the atomic natural charges and the S–O and O–H interatomic distances change very little. For example, in conformer 1 with the IHB and conformer 4 without the IHB, the 2-OH-BSA molecule has natural charges on the atoms q(S) = 2.348/2.346 e , q(O) = 0.875/ 0.873 e , − − − − q(H) = 0.501/0.497 e−, and the distances r(S-O) = 1.625/1.625Å, r(O–H) = 0.968/0.968 Å and the valence angle S–O–H = 108.2/107.2◦, respectively. 0 Therefore, the main reason for the differences in the ∆rG 298 GD of such conformers is the difference in the structure and energy of the anions formed on the deprotonation of the conformers. Upon deprotonation of conformer 1, the IHB is retained and, moreover, becomes stronger. The energy ofMolecules this anion 2020, 25 A1, x− FORis significantly PEER REVIEW lower (Scheme4) than the A4 − anion without IHB, which is formed17 of 23 upon deprotonation of conformer 4.

0 –1 ΔrG 298, kJ mol 1360 Anion A4– 1320

– 1280 Anion A1

1240

1200

1160 1324.3

100 1278.2

0 Conformer 4

Conformer 1

Scheme 4. The deprotonation of 2-OH-BSA conformers (the –SO3H group is a acceptor of the IHB). Scheme 4. The deprotonation of 2-OH-BSA conformers (the –SO3H group is a acceptor of the IHB).

TheThe deprotonationdeprotonation energyenergy dependsdepends bothboth onon thethe structurestructure ofof thethe acidacid conformersconformers andand onon thethe structurestructure ofof thethe anionsanions thatthat areare formedformed onon theirtheirdeprotonation. deprotonation.

8.8. FeaturesFeatures ofof 2-SO2-SO33H-BSAH-BSA Deprotonation:Deprotonation: TheThe InﬂuenceInfluence of of IHB IHB on on Proton Proton Donor Donor Properties Properties of ofDiacid Diacid

TheThe eeffectﬀect ofof thethe IHBIHB onon thethe deprotonationdeprotonation energyenergy ofof 2-SO2-SO33H-BSAH-BSA demonstratesdemonstrates thethe uniqueunique structuralstructural featuresfeatures of of this this acid acid due due to to the the existence existence of of a large a large number number of variousof various conformers conformers (Figure (Figure 10). In10). conformers In conformers 1, 2 and 1, 2 3, and the 3, proton the proton of the of –SO the3H –SO group3H group is involved is involved in the formationin the formation of the IHB, of the and IHB, in 0 0 theand conformers in the conformers 4, 5 and 6,4, the5 and IHB 6, is the not IHB formed. is not For formed. conformers For conformers 4, 5 and 6, the4, 5∆ andrG 2986, theGD Δ valuesrG 298 GD for 1 thevalues ﬁrst for stage the arefirst 1279.9, stage 1277.8,are 1279.9, and 1277.8, 1275.3 kJand mol 1275.3− . kJ mol−1. InIn conformersconformers 22 andand 33 (Scheme(Scheme5 5),), the the separation separation of of a a proton proton from from the the sulfonic sulfonic group, group, which which is is 00 −11 anan IHBIHB acceptoracceptor (∆(ΔrGrG 298298 = 1224.2,1224.2, 1215.8 kJ mol− ),), is is greatly greatly facilitated, and the separationseparation ofof aa proton from another sulfonic group, which is a donor IHB, is significantly hindered (1306.3 kJ mol−1). Again, the reason for this trend is the IHB strengthening on the transition from conformers 2 and 3 to the A−anion (Figure 12f, Table 2). In conformer 1, both H atoms of sulfonic groups participate in the formation of the IHB. The hydrogen bonds in this conformer are the strongest, which leads to a shortening of r (O···H) = 1.728 Å, compared with r (O···H) = 1.781/1.796 Å in conformers 2 and 3 with one H-bond. Both sulfonic groups of conformer 1 are both donors and acceptors of the IHB. Therefore, for the first stage of GD, the value ΔrG0298 (1254.8 kJ mol−1) of conformer 1 is close to the average value of the deprotonation energies of the sulfonic groups—the IHB acceptor (1215.8 kJ mol−1) and the sulfonic group—the IHB donor (1306.3 kJ mol−1) in the conformer 3 (Table 4, Scheme 5).

Molecules 2020, 25, 5806 17 of 23

1 proton from another sulfonic group, which is a donor IHB, is signiﬁcantly hindered (1306.3 kJ mol− ). Again,Molecules the reason2020, 25, x for FOR this PEER trend REVIEW isthe IHB strengthening on the transition from conformers18 2 andof 23 3 to the A−anion (Figure 12f, Table2).

1360 0 –1 Anion without IHB ΔrG 298, kJ mol 1320 MoleculesMolecules 2020 2020, 25,, 25, x,, FORxx FORFOR PEER PEERPEER REVIEW REVIEWREVIEW 1818 of of 23 23 1280 Anion with IHB 1306.3 1240

136012001360 0 0 –1 –1 AnionAnion without without IHB IHB ΔrΔGrrG298298, kJ, kJ mol mol

132011601320 1215.8 1275.3

12801280 100 AnionAnion with with IHB IHB 1306.31306.3 1240124080 1254.8 1200120060 Conformer 6 40 1160 1160 1215.81215.8 1275.31275.3 20 Conformer 3

1001000 Conformer 1 8080 1254.81254.8 6060 Conformer 6 4040 Conformer 6

2020 ConformerConformer 3 3 Scheme 5. The deprotonation of 2-SO3H-BSA conformers in the first stage. 0 0 Scheme 5. The deprotonation of 2-SO3H-BSA conformers in the first stage. In conformer 1,Conformer bothConformer H 1 atoms1 of sulfonic groups participate in the formation of the IHB. The hydrogenThe proton bonds in separation this conformer at the are second the strongest, stage of which deprotonation leads to a shortening of various of conformers r (O H) = 1.728 of Å, ··· compared2-SO3H- withBSA r diacid (O H) leads= 1.781 to / the1.796 formation Å in conformers of a dianion 2 and (Figure 3 with 12h),one H-bond. which has a geometric structure of symmetry··· C2. The second stage deprotonation requires more significant energy costs Both sulfonic groups of conformer 1 are both donors and acceptors of the IHB. Therefore, for the (Table 5). 0 1 first stage of GD, the value ∆rG 298 (1254.8 kJ mol− ) of conformer 1 is close to the average value of the SchemeScheme 5. 5. The The deprotonation deprotonation of of 2-SO 2-SO3H-BSA3H-BSA conformers conformers in in the the first first stage. 1stage. deprotonation energies of the sulfonic groups—the IHB acceptor (1215.8 kJ−1 mol ) and the sulfonic Table 5. Gibbs energies of GD of different conformers 2-SO3H-BSA (kJ mol ) in two− stages. 1 group—theTheThe protonIHBproton donor separationseparation (1306.3 kJ at molat thethe− ) second insecond the conformer stagestage ofof 3 deprotonation (Tabledeprotonation4, Scheme of5of). variousvarious conformersconformers ofof The proton separation at the1 second stage of deprotonation3 of various conformers6 of 2-SO H-BSA 2-SO2-SO3H-BSA3H-BSA diacid diacid leads leads to to the the formation formation of of a adianion dianion (Figure (Figure 12h), 12h), which which has has a ageometric 3geometric diacid leads to the formation of a dianion (Figure 12h), which has a geometric structure of symmetry structurestructureConformer of of symmetry symmetry C C2. 2The. The second second stage stage deprotonation deprotonation requires requires more more significant significant energy energy costs costs C2(Table.(Table The second5). 5). stage deprotonation requires more significant energy costs (Table5).

1 Table 5. Gibbs energies of GD of diﬀerent conformers 2-SO3H-BSA (kJ mol− ) in−1 two stages. TableTable 5. 5. Gibbs Gibbs energies energies of of GD GD of of different different conformers conformers 2-SO 2-SO3H-BSA3H-BSA (kJ (kJ mol mol−1) in) in two two stages. stages. 1215.8 a (∆rG0298)I 1254.8 1275.3 1 1 1306.33 b 3 6 6 (∆rG0298)II 1695.7 1695.7 1605.2 ∑(∆rG0298) 2950.4 2911.5 2880.5 ConformerConformerConformer a when a removed proton is not involved in the IHB. b when a removed proton is involved in the IHB, and the sulfonic group is IHB donor.

The deprotonation energy in two stages substantially1215.81215.8 a a adepends on the structure of the 0 0 1215.8 (∆ G(∆0(r∆GrG)298298)I )II 1254.81254.81254.8 0 1275.31275.31275.3 2-SO3Hr-BSA298 conformers.I An interesting fact is that ΔrG1306.32981306.3 in the b bb first stage is minimal for conformer 0 3, however,0 Δr0G 298 GD in the second stage is minimal for conformer 4 with a maximum value of (∆rG(∆(298r∆GrG0)298II 298)II) IIII 1695.71695.71695.7 1695.7 1695.7 1605.2 1605.2 1605.2 0P 0 − ΔrG 298 GD in first0 0 stage. Upon2950.4 deprotonation of the anion 2911.5 of A conformers 1–3 (Figure 2880.5 12e, Scheme (∆∑rG∑(∆(298r∆GrG)298298) ) 2950.42950.4 2911.5 2911.5 2880.5 2880.5 6),a the proton is removed from the sulfonic group,b which is the donor of IHB, and this increases the whena whena when a removed a aremoved removed proton proton proton is not is involved is not not involved involved in the IHB. in in the thewhen IHB. IHB. a removedb whenb when a proton aremoved removed is involved proton proton in is theis involved involved IHB, and in thein the the valuesulfonic of groupΔrG0298 is. IHBThe donor. separation of a proton from A−anion without an IHB (Figure 12g, Scheme 6) IHB,IHB, and and the the sulfonic sulfonic group group is is IHB IHB donor. donor. requires significantly lower energy costs. As a result, the formation of the A2− dianion, which has a

TheThe deprotonation deprotonation energy energy in in two two stages stages substantially substantially depends depends on on the the structure structure of of the the 2-SO2-SO3H-BSA3H-BSA conformers. conformers. An An interesting interesting fact fact is is that that Δ ΔrGrG02980298 in in the the first first stage stage is is minimal minimal for for conformer conformer 3,3, however, however, Δ ΔrGrG02980298 GD GD in in the the second second stage stage is is minimal minimal fo for rconformer conformer 4 4with with a amaximum maximum value value of of ΔΔrGrG02980298 GD GD in in first first stage. stage. Upon Upon deprotonation deprotonation of of the the anion anion of of A A− conformers− conformers 1–3 1–3 (Figure (Figure 12e, 12e, Scheme Scheme 6),6), the the proton proton is is removed removed from from the the sulfonic sulfonic group, group, which which is is the the donor donor of of IHB, IHB, and and this this increases increases the the valuevalue of of Δ ΔrGrG02980298. The. The separation separation of of a aproton proton from from A A−anion−anion without without an an IHB IHB (Figure (Figure 12g, 12g, Scheme Scheme 6) 6) requiresrequires significantly significantly lower lower energy energy costs. costs. As As a aresult, result, the the formation formation of of the the A A2− 2dianion,− dianion, which which has has a a singlesingle structurestructure (Figure(Figure 12h),12h), fromfrom thethe anionanion withoutwithout thethe IHBIHB (conformers(conformers 4–6)4–6) isis moremore advantageousadvantageous than than that that from from the the anion anion with with the the IHB IHB (conformers (conformers 1–3). 1–3).

Molecules 2020, 25, 5806 18 of 23

The deprotonation energy in two stages substantially depends on the structure of the 2-SO3H-BSA 0 conformers. An interesting fact is that ∆rG 298 in the first stage is minimal for conformer 3, however, 0 0 ∆rG 298 GD in the second stage is minimal for conformer 4 with a maximum value of ∆rG 298 GD in first stage. Upon deprotonation of the anion of A− conformers 1–3 (Figure 12e, Scheme6), the proton is 0 removed from the sulfonic group, which is the donor of IHB, and this increases the value of ∆rG 298. The separation of a proton from A−anion without an IHB (Figure 12g, Scheme6) requires significantly 2 lower energy costs. As a result, the formation of the A − dianion, which has a single structure (Figure 12h), from the anion without the IHB (conformers 4–6) is more advantageous than that from theMolecules anion 2020 with, 25, thex FOR IHB PEER (conformers REVIEW 1–3). 19 of 23

Scheme 6. The deprotonation of 2-SO3H-BSA conformers in the second stage.

Data analysisanalysis of of Table Table3 shows 3 shows that the that IHB the plays IHB a signiﬁcantplays a significant role in the processrole in of the deprotonation process of ofdeprotonationortho-substituted of ortho BSA.-substituted Acid conformers, BSA. Acid in which conformers, IHB is present, in which are the IHB most is energeticallypresent, are favorablethe most andenergetically predominate favorable in the conformationaland predominate mixture. in the In conformersconformational of ortho mixture.-substituted In conformers BSA without of IHB,ortho-substituted the introduction BSA ofwithout electron-withdrawing IHB, the introduction substituents of electron-withdrawing promotes a decrease, substituents and the introduction promotes 0 ofa decrease, electron-donor and the substituents introduction promotes of electron-d an increaseonor substituents in ∆rG 298 promotesGD. However, an increase the presence in ΔrG0298 of GD. the IHBHowever, of diﬀ theerent presence type in ofortho the-substituted IHB of different BSA may type change in ortho this-substituted tendency commonBSA may for changemeta- andthis paratendency-substituents. common for meta- and para-substituents. Thus, the presence of IHB in 2-OH-BSA (with an electron-donating substituent and the sulfonic group—an acceptor of IHB) increa increasesses the ability of the 2-OH-BSA conformer (1) (1) to to lose the proton, compared to the corresponding ability of thethe 2-SO2-SO22F-BSA conformer (1) (with electron withdrawing substituent and the sulfonicsulfonic group—an IHB donor).donor).

9. Conclusions Using the DFTDFT/B3LYP/cc-pVTZ/B3LYP/cc-pVTZ method, the conformationalconformational properties of ten orthoortho-substituted-substituted BSAs (2-X-BSA, X = –SO3H, –COOH, –NO2, –SO2F, –C N, –NH2, –CH3, –OCH3, –N(CH3)2, –OH). BSAs (2-X-BSA, X = –SO3H, –COOH, –NO2, –SO2F, –C≡N,≡ –NH2, –CH3, –OCH3, –N(CH3)2, –OH). The Theorthoortho-substituted-substituted BSAs BSAs differ di ﬀfromer from the the corresponding corresponding orthoortho-substituted-substituted BAs BAs by by the the presence presence of of a larger number of conformers (up to nine for 2-COOH-BSA and 2-SO F-BSA). The conformers may or larger number of conformers (up to nine for 2-COOH-BSA and 2-SO2 2F-BSA). The conformers may or may not contain the IHB between the sulfonic group and the substituent, and the sulfonic group can be a donor or an acceptor IHB. The GD of the –SO3H group leads to the geometry of the –SO3– anion with symmetry close to C3. For all conformers of seven acids, the deprotonated A−forms have the single structure. However, the deprotonated A− forms of 2-SO2F-BSA, 2-OH-BSA, and 2-SO3H-BSA have several conformers. The double-deprotonated A2−form of 2-SO3H-BSA acid has C2 symmetry with equivalent SO3− groups. The deprotonation energy of various conformers of the considered acids was calculated. It was established that the presence of the IHB in ortho-substituted BSAs has a significant effect on the values of ΔrG0298 GD. The energy of the GD depends both on the structure of the conformers of the initial acid and on the structure of the formed anion. If the –SO3H group is an IHB donor, then anion without IHB is formed during deprotonation, and the deprotonation energy increases. If this

Molecules 2020, 25, 5806 19 of 23 may not contain the IHB between the sulfonic group and the substituent, and the sulfonic group can be a donor or an acceptor IHB. The GD of the –SO3H group leads to the geometry of the –SO3– anion with symmetry close to C3. For all conformers of seven acids, the deprotonated A−forms have the single structure. However, the deprotonated A− forms of 2-SO2F-BSA, 2-OH-BSA, and 2-SO3H-BSA have several conformers. 2 The double-deprotonated A −form of 2-SO3H-BSA acid has C2 symmetry with equivalent SO3− groups. The deprotonation energy of various conformers of the considered acids was calculated. It was established that the presence of the IHB in ortho-substituted BSAs has a significant effect on the values 0 of ∆rG 298 GD. The energy of the GD depends both on the structure of the conformers of the initial acid and on the structure of the formed anion. If the –SO3H group is an IHB donor, then anion without IHB is formed during deprotonation, and the deprotonation energy increases. If this group is an IHB 0 acceptor, then a significant decrease in ∆rG 298 GD is observed due to an increase in the strength of the IHB and additional stabilization of the A− anion. The presence of different types of IHB in 2-SO3H-BSA conformers affects the energy of 0 deprotonation at the first and second stages. The value ∆rG 298 in the first stage of GD is minimal for conformer in which one of the sulfonic groups is a donor of IHB, and the other one is an acceptor of IHB. The total energy of deprotonation in two stages is minimal for the 2-SO3H-BSA conformers without IHB. It has been shown that the acidity of BSA derivatives in the gas phase increases when anortho-substituent exhibiting donor properties of IHB with respect to the sulfone group is introduced.Therefore, the fragments containing a benzenesulfonic groups with such ortho-substituents into the polymer chain can be used as a precursor of high-conductivity polymer membranes.

Supplementary Materials: The following are available online. Table S1. Experimental (gas-phase electron diffraction—GED) and calculated (B3LYP/cc-pVTZ//MP2/cc-pVDZ//МР2/cc-pVTZ) geometries (angstroms and degrees) of unsubstituted BSA [42], Table S2. Experimental (GED) and calculated (B3LYP/cc-pVTZ//МР2/cc-pVTZ) geometries (angstroms and degrees) of 4-CH3-BSA molecule and conformer I of 3-NO2-BSA molecule [49], Table S3. The conformational composition of gas phase (Boltzmann distribution, 298 K) and the sum of the donor-acceptor stabilization energies (ΣE(2)) characterized the strength of the formed IHB in conformers with IHB, Data: Cartesian coordinates (Å) of optimized geometry (DFT/B3LYP/cc-pVTZ) of acid conformers and deprotonated forms. Author Contributions: Conceptualization, S.N.I. and G.V.G.; methodology, N.I.G. and M.S.F.; formal analysis, A.V.I., N.I.G. and M.S.F.; investigation, S.N.I., A.V.I. and N.I.G.; resources, N.I.G.; writing—original draft preparation, N.I.G. and G.V.G.; writing—review and editing, S.N.I. and M.S.F.; visualization, M.S.F. and A.V.I.; project administration, G.V.G. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by Russian Science Foundation, grant number 20-13-00359. Conflicts of Interest: The authors declare no conflict of interest.

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