PMC:4264129 / 67022-85741 JSONTXT

{"project":"2_test","denotations":[{"id":"25353178-20649313-52044454","span":{"begin":275,"end":277},"obj":"20649313"},{"id":"25353178-20649313-52044455","span":{"begin":829,"end":831},"obj":"20649313"},{"id":"25353178-11578232-52044456","span":{"begin":884,"end":887},"obj":"11578232"},{"id":"25353178-16833531-52044457","span":{"begin":3506,"end":3509},"obj":"16833531"},{"id":"25353178-23480798-52044458","span":{"begin":5688,"end":5690},"obj":"23480798"},{"id":"25353178-25051009-52044459","span":{"begin":8430,"end":8433},"obj":"25051009"},{"id":"25353178-12720314-52044460","span":{"begin":9165,"end":9168},"obj":"12720314"},{"id":"25353178-17880128-52044461","span":{"begin":11829,"end":11832},"obj":"17880128"},{"id":"25353178-12720314-52044462","span":{"begin":12983,"end":12986},"obj":"12720314"},{"id":"25353178-22353846-52044463","span":{"begin":13959,"end":13962},"obj":"22353846"},{"id":"25353178-22353846-52044464","span":{"begin":15087,"end":15090},"obj":"22353846"},{"id":"25353178-12720314-52044465","span":{"begin":15240,"end":15243},"obj":"12720314"},{"id":"25353178-20701390-52044466","span":{"begin":15263,"end":15266},"obj":"20701390"},{"id":"T4109","span":{"begin":275,"end":277},"obj":"20649313"},{"id":"T47830","span":{"begin":829,"end":831},"obj":"20649313"},{"id":"T7663","span":{"begin":884,"end":887},"obj":"11578232"},{"id":"T95892","span":{"begin":3506,"end":3509},"obj":"16833531"},{"id":"T62590","span":{"begin":5688,"end":5690},"obj":"23480798"},{"id":"T25069","span":{"begin":8430,"end":8433},"obj":"25051009"},{"id":"T84032","span":{"begin":9165,"end":9168},"obj":"12720314"},{"id":"T28987","span":{"begin":11829,"end":11832},"obj":"17880128"},{"id":"T92309","span":{"begin":12983,"end":12986},"obj":"12720314"},{"id":"T11681","span":{"begin":13959,"end":13962},"obj":"22353846"},{"id":"T90925","span":{"begin":15087,"end":15090},"obj":"22353846"},{"id":"T61242","span":{"begin":15240,"end":15243},"obj":"12720314"},{"id":"T1763","span":{"begin":15263,"end":15266},"obj":"20701390"}],"text":"3.1. 3-Member and 4-Member Rings\nAlthough X–H…Y interactions must be present in these “rings”, they cannot be considered as real, intramolecularly H-bonded structures. There are very few examples that may belong to this type of 3-member ring systems. DePrince and Mazziotti [40] pointed out that the nitrone structure in the form of CH2=NHO possesses a semipolar N+–O− bond and a N+–H…O− “hydrogen bond”. This arrangement corresponds overall to a 3-member ring. The structure is a local energy minimum on the potential energy surface when the tautomeric transformation from nitroso methane (CH3NO) to formaldoxime (CH2=N–O–H) is studied. The N–O–H moiety does not form a 3-member ring for the latter. The nitrone structure is more stable than the nitroso methane form in the gas phase by about 6 kJ/mol at the CCSD(T)/CBS level [40] and by 16–17 kJ/mol at the B3LYP/6-311++G** level [118]. The authors of the latter paper studied solvent effects on the tautomeric process. They confirmed that the formaldoxime form is the most stable structure in solution, but no solvent effect results were provided for the nitrone tautomer.\nAlkorta and Elguero [119] studied the 1,2–proton shifts in the gas phase for 3- to 7-member, unsaturated rings with a HN–N moiety within. Through the tautomeric process they found 3-member-ring transitions states (TS) in the form of N…H…N, where the structures could formally be considered as intramolecularly H-bonded species. The calculated zero-point relative enthalpies scatter between 100 and more than 400 kJ/mol for the studied systems. The problem of forming 3-member N…H…N TS’s may also emerge for the tautomerization of 1,2,3 triazoles, tetrazoles, and for substituted 1,2,4 triazoles.\nPyrazole is a representative of the above series that has a 5-member aromatic ring. Alkorta and Elguero paid special interest to this molecule since it is an important small heterocycle in synthetic chemistry. They found that the shifting proton in the transition state stays out of the plane of the heavy atoms, whereas it is in the plane in the energy-minimum ground state. The relative TS energy and zero-point enthalpy are 214 and 198 kJ/mol, respectively, as calculated at the B3LYP/6-31G* level. However, is this intramolecular route with high activation energy is necessary for the 1,2 proton shift?\nRice et al., [120] recently published a paper indicating that the pyrazole dimer was observed in a free jet expansion. Its IR-active N–H stretching frequency was red-shifted by 269 cm−1 relative to the monomer. The symmetry was assigned as C2h, which involves a coplanar system having two intermolecular H-bonds in a six-member ring. The 1,2-proton shift in pyrazole would result in an undistinguishable new structure. However, if there is a ring substituent in position 3, there are two, chemically different tautomers. For their equilibration, the indicated dimer structure is a convenient route through a double proton relay. The authors raised the possibility that even larger, e.g., C3h trimers could also be formed, which are also convenient structures for proton jumps to a neighbor and accepting a proton from the other neighbor in the trimer. Unfortunately, no reference has been found in the literature that such dimers, trimers are stable in aqueous solution.\nThe above intermolecular proton repositioning must be a fundamental equilibration route for a number of systems when the intramolecular route requires too high activation energy. Tsuchida and Yamabe (TY) [121] proposed a tautomerization pathway between hydroxypyridines and pyridones, where one of the described paths could be applied for any system in aqueous/alcohol solutions. A simple way for tautomerization is the double proton-relay through a dimeric form. For H–X–(C)n–Y monomeric substructures (X, Y electronegative atoms), six-member dimeric rings could be formed with n = 0 (pyrazole above), eight-member rings with n = 1 (2-OH pyridine), etc. Formation and stable maintenance of such rings could be favorable in non-polar solvents, and a tautomeric process could conveniently proceed. The shown example was the 2-OH pyridine to 2-pyridone tautomerization. For the realization of the indicated reaction, the only pre-requisite is the stable maintenance of the properly oriented dimeric form.\nThe tautomerization is also possible through the double-proton-relay mechanism in protic solvents without, however, forming a dimer. Upon the basic idea of the TY mechanism (see above), a protic solvent having both proton donor and acceptor sites could catalyze the indicated process. In this case, a proton from the solute’s H-X site jumps over to the acceptor site of the closest protic solvent molecule, and a proton returns from the solvent to the solute’s acceptor site. This reaction mechanism need not be confined to the involvement of a single solvent molecule. Since protic solvents generally form a H-bonded network, a series of the proton jumps along the several-element solvent bridge will carry the extra proton to the proper site of the solute, even when the two sites of the solute are far away from each other.\nThe mechanism could work for the neutral form/zwitterionic equilibration of the 3- and 4-pyridine carboxylic acids [122], aminophenols [123] and for any saturated amino acid in a protic solution. Sometimes the conformational change by rotation about the (H)X–C bond may lead to the disruption of the intramolecular H-bond for small organic solutes in water/alcohol, but the possibility of the solvent catalyzed disruption of this bond through the corresponding TY mechanism was also considered as a competing reaction path for, e.g., 2-F– and 2-Cl ethanol [15].\nOverall, the tautomerization through dimerization or by solvent catalysis could be a likely, low-activation-energy mechanism in the case of a X–X–H substructure, as for 3-substituted pyrazoles, and must be very important in the case of a H–X–C–Y tautomerization to X–C–Y–H, as well. The chance for an intramolecular proton transfer may start for structures where the XH…Y moiety is involved in a ring with at least five members and the chain is flexible for forming a favorably short H…Y separation. A typical example is the zwitterion formation for α-amino acids (see Subsection 3.2.2).\nThe amide and carboxylic groups are two well-known representatives of the H–X–C–Y substructures. In proteins, the H and O atoms of the H–N–C=O peptide bond are in trans position and there is no possibility to form an intramolcular H-bond, not even upon considering the distance criterion. However, one of the protons points toward the carbonyl oxygen in free amides with a H2N–C=O substructure allowing for the formation of the intermittently stable HN=C–OH tautomeric species.\nThe hydroxy hydrogen in syn carboxylic acids (Figure 5) is at a distance of about 230 pm from the carbonyl oxygen, and the O–H…O angle could be as small as about 76° (see above [79]). The syn –COOH group is coplanar for a monomer. Without a deeper analysis of the molecular orbitals, a simple explanation for the syn –COOH preference may be that the electrons of one of the carbonyl’s lone pairs face the carboxylic hydrogen in the syn conformation, whereas this lone-pair would see the lone pairs of the hydroxy oxygen in the anti form. Thus, a conclusion here is that the dominant conformation is basically directed by electrostatic forces. Nonetheless, the solvent effects are more favorable for the anti rather than the syn form in aqueous solution [79,124], so an observable anti conformation of the acetic acid in aqueous solution is likely.\nThe tetrahydrate model of acetic acid placed in a cavity in a continuum water solvent [79] facilitates the syn to anti conformational change not by rotation about the C–O(H) bond, but by a double proton relay involving the TY mechanism. However, it was pointed out in the same study that the syn dimeric form of acetic acid is present in a large fraction in molar aqueous solution, thus the syn to anti transformation is feasible only for the free acetic acid that is expected to predominate in very dilute solutions.\nAccording to the literature search, the acetic acid dimer has been the subject of the most studies dealing with a dimeric system in the liquid phase. This compound assumes about an 87% dimeric form in the gas phase [28] and forms different, mainly cyclic and linear intermolecular H-bonds in neat liquid [125]. The in-solution association depends on the pH of the solution. The pKa of this molecule is 4.76. A simple calculation concludes that if one mole of this acid dissolves in pure water less than 1% of the solutes dissociate, and the pH of the solution decreases to about 2.4. For a 0.1 molar aqueous solution, the degree of the dissociation is slightly larger than 1% and the pH is about 2.8. Thus, under such conditions, consideration of the neutral form as the prevailing protonation state is justified. Acetic acid is, however, almost fully dissociated at pH = 7.4 under physiological conditions.\nThe acetic acid dimer has been investigated theoretically in several different studies during the past decade. Yamabe and Tsuchida [126] studied the water-catalyzed process: Acetic acid dimer → monomer → dissociation (ionization). When a water cluster attacks the dimer, the monomeric and later the ionized form come into existence through the formation of several unstable and stable intermediate structures. This mechanism is important to understand the formation of the hydrated acetate ion, even though the experimental pKa suggests that only a small fraction exists in the ionized form in pure water.\nFor obtaining the pmf via the MC/FEP method, Nagy [79] considered two charge sets. The first set was derived for the monomeric acetic acid optimized at the IEF-PCM/B97D/aug-cc-pvtz level in a continuum water solvent and the charges were fitted to the in-solution MEP by the CHELPG process. In this first approximation, the charge set was applied along the whole considered R(C…C) separation range of 314–1184 pm (C is the carboxylic carbon). The intermolecular H-bonds start forming at R(C…C) 484 pm and two strong intermolecular bonds are expected to come into existence at about 386 pm, which is the optimized C…C distance for the dimer at the IEF-PCM/B97D/aug-cc-pvtz level. The calculated atomic charges were remarkably different in the dimer compared with the monomer. The dimer charges were then applied in the C…C range of 484–384 pm in the second approximation. The charges and the geometries were gradually transformed from the monomer to dimer values in this range. As a result, the pmf showed a minimum deeper by 21 kJ/mol than when monomer charges were only used. Following the method of Ciccotti [127], upon the integration of the R2 exp(−G(R)/RT) curve (R is the C…C separation, G(R) is the free energy of the system with reference G = 0 at 1184 and 261 pm for the molar and 0.2 molar solutions, respectively), the predicted association degree was 38%–45% and 9%–10% at the two concentrations when the first charge set was applied. In contrast, almost 100% association was predicted for a molar aqueous acetic acid solution by the second approach. However, the deepening of the pmf minimum value is overestimated in the second approach because the internal free energies of the solute partners have to increase at that separation. Indeed, under the conditions where a monomer has a geometry and atomic charges equal to those which were derived for the elements of the optimized dimer, the monomer’s internal free energy must be, by definition, higher than that for the optimized, separate monomer in water. Thus a correction (not carried out in [78]) must diminish the difference in the minimum G values upon the two approaches.\nThere are four pmfs presented by Chen et al., [128] for formic, acetic, propionic and butyric acids in aqueous solution. The calculations utilized the CHARMM22 all-atom force field. The G = 0 reference state was taken at R(C…C) 1100–1200 pm. All pmfs show a clear minimum at carboxylic C…C separation of 400–500 pm. Whereas the valleys around the well-defined minima are narrow for HCOOH and CH3COOH, and the pmfs show a small barrier with slightly positive relative G for desolvation, the free energy is negative for butyric acid up to R about 1100 pm. More importantly, the butyric acid pmf runs remarkably below the acetic acid pmf in the R = 600–800 pm range. Thus the pmfs are similar in the intramolecular H-bond formation range but the favorable interactions of the non-polar, aliphatic chains at R \u003e 600 pm help increase the readiness for solute association even with substantially separated carboxylic groups. The derivable calculated association degree for CH3COOH is 37% in a molar solution, close to the results of Nagy above when the first charge set was used. Both theoretical predictions overestimate, however, the upper limit experimental value of 14%, when using pKD from Table I in [126]. In fact, all theoretically predicted pKD values are overestimated but the linear correlation with the upper limit experimental values is good, providing 0.97 for the square of the correlation coefficient.\nChocholoušová et al., [129] concluded that whereas acetic acid takes a doubly H-bonded cyclic dimeric form in the gas phase, the monomeric form prevails when it is dissolved in aqueous solution as found from molecular dynamics simulations. The association state is still a doubly H-bonded cyclic dimeric form in chloroform. The presumably Amber NpT molecular dynamic simulations were performed in the range of 0.3 to 10 molar concentration in aqueous solution. The applied RESP charges [90] were fitted to the HF/6-31G* wave function. These charges must differ remarkably from those derived by Nagy above, and probably differ also from those utilized by Chen et al. above. The different charge sets may lead to very different conclusions.\nRecently Pašalić et al., [130] carried out a DFTB [131] molecular dynamics simulation for the acetic acid dimer within a box of 200 water molecules (about 0.5 molar). In such calculations it is not necessary to predefine a set of net atomic charges, because the interactions between the solute and solvent molecules are recalculated quantum mechanically in every step. The calculations starting from different dimer geometries were relatively short, lasting only for 300 ps. Nonetheless, the authors found that the elements of all acetic acid dimers started to dissociate after about 50 ps. Although a DFT-based molecular dynamics is a large progress compared with MD simulations utilizing empirical force fields with set atomic charges, these calculations predict energies in the NVT ensemble, and according to Elstner et al., [131] “… in order to compare to experimental situations, free energies rather than potential energies have to be calculated. This would involve molecular dynamic (MD) simulations over rather long time scales, ranging from several hundreds of picoseconds up to milliseconds.” Thus the simulations conducted by Pašalić et al., [130] must be at the lower limit at best.\nOn the experimental side, dimerization constants for acids have been determined by several groups, as shown in [126]. D’Amico et al., [132] performed inelastic UV scattering experiments on aqueous acetic acid solutions at different temperatures and solute concentrations. The author found a crossover temperature, Tc ≈ 325 ± 10 K above which “the energy of hydrogen bonds responsible for water-acetic acid and acetic acid-acetic acid interactions is strongly reduced. This leads to a reduction in the average number of water molecule interacting with acetic acid, as well as to a lower number of acetic acid clusters.” Thus at about 300 K, where the MC and MD simulations were conducted, existence of acetic acid clusters has been concluded by D’Amico et al.\nIn summary, experimental data predict association for acetic acid in dilute aqueous solution, although the degree of association may be only 14% or less. This result has not been successfully reproduced theoretically. Different approaches lead to different results including both contradicting and overestimating of the association.\nClose X…H distances can appear in the 2-OH and 2-SH furan and thiophene in the X–C–Y–H cis conformation and also for 3-OH pyrazole, 3-OH and 5-OH isoxazole. These structures are not considered to have an intramolecular H-bond within their four-member rings, although the conformational preference compared with the X–C–Y–H trans form is interesting and could be affected by the solvent. Old HF/STO-3G calculations by Radom et al., predict OH cis and trans conformations for furan and thiophene rings, respectively, in the gas phase [133]. No recent solvent-effect calculations have been found.\nFor 3-OH and 5-OH isoxazoles, a number of theoretical calculations have been carried out in aqueous solution without uniform conclusions [134,135,136]. Different solvation methods and internal energy calculations indicate that the structural problem is subtle. The systems are subject to oxo-hydroxy tautomeric transformations, and the possible intramolecular H-bond issue was not of interest in the studies. In contrast, the conformational problem was investigated for the hydroxy tautomer. For 3-OH isoxazole [134], the NCOH cis form is more stable than the trans in the gas phase by 18.0 kJ/mol at the MP4/6-31G**//3-21G level. By combination of the relative gas-phase energy with the relative solvation free energy from an MD/FEP calculation in aqueous solution, the cis form still remains the more stable conformer by 10.9 kJ/mol. In the same paper, the cis O–C–O–H conformation of 5-OH isoxazole was found to be more stable than the trans form by 8.4 kJ/mol in the gas phase and by 2.1 kJ/mol in solution. Gould and Hillier [135] also found the cis O–C–O–H form to be more stable than the trans structure by 1.3 kJ/mol in aqueous solution. Thus the solvation by water favors the trans conformer, but the cis structure is still maintained for the hydroxy forms of substituted isoxazoles.\nCramer and Truhlar [136] studied the conformational/tautomeric problem for the 5-OH isoxazole. The free energy difference in the gas phase at T = 298 K is less than 1 kJ/mol in favor of the cis form as determined from high-level ab intio calculations. The aqueous solvation favors the trans form by about 1.7 kJ/mol, thus the trans O–C–O–H conformation was predicted by these authors as the more preferable conformation by up to 1.7 kJ/mol in aqueous solution, depending on the applied models. The trans form also remains the more stable conformer for the 3-methyl and 3,4-dimethyl derivatives by up to 3 kJ/mol."}

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3-Member and 4-Member Rings\nAlthough X–H…Y interactions must be present in these “rings”, they cannot be considered as real, intramolecularly H-bonded structures. There are very few examples that may belong to this type of 3-member ring systems. DePrince and Mazziotti [40] pointed out that the nitrone structure in the form of CH2=NHO possesses a semipolar N+–O− bond and a N+–H…O− “hydrogen bond”. This arrangement corresponds overall to a 3-member ring. The structure is a local energy minimum on the potential energy surface when the tautomeric transformation from nitroso methane (CH3NO) to formaldoxime (CH2=N–O–H) is studied. The N–O–H moiety does not form a 3-member ring for the latter. The nitrone structure is more stable than the nitroso methane form in the gas phase by about 6 kJ/mol at the CCSD(T)/CBS level [40] and by 16–17 kJ/mol at the B3LYP/6-311++G** level [118]. The authors of the latter paper studied solvent effects on the tautomeric process. They confirmed that the formaldoxime form is the most stable structure in solution, but no solvent effect results were provided for the nitrone tautomer.\nAlkorta and Elguero [119] studied the 1,2–proton shifts in the gas phase for 3- to 7-member, unsaturated rings with a HN–N moiety within. Through the tautomeric process they found 3-member-ring transitions states (TS) in the form of N…H…N, where the structures could formally be considered as intramolecularly H-bonded species. The calculated zero-point relative enthalpies scatter between 100 and more than 400 kJ/mol for the studied systems. The problem of forming 3-member N…H…N TS’s may also emerge for the tautomerization of 1,2,3 triazoles, tetrazoles, and for substituted 1,2,4 triazoles.\nPyrazole is a representative of the above series that has a 5-member aromatic ring. Alkorta and Elguero paid special interest to this molecule since it is an important small heterocycle in synthetic chemistry. They found that the shifting proton in the transition state stays out of the plane of the heavy atoms, whereas it is in the plane in the energy-minimum ground state. The relative TS energy and zero-point enthalpy are 214 and 198 kJ/mol, respectively, as calculated at the B3LYP/6-31G* level. However, is this intramolecular route with high activation energy is necessary for the 1,2 proton shift?\nRice et al., [120] recently published a paper indicating that the pyrazole dimer was observed in a free jet expansion. Its IR-active N–H stretching frequency was red-shifted by 269 cm−1 relative to the monomer. The symmetry was assigned as C2h, which involves a coplanar system having two intermolecular H-bonds in a six-member ring. The 1,2-proton shift in pyrazole would result in an undistinguishable new structure. However, if there is a ring substituent in position 3, there are two, chemically different tautomers. For their equilibration, the indicated dimer structure is a convenient route through a double proton relay. The authors raised the possibility that even larger, e.g., C3h trimers could also be formed, which are also convenient structures for proton jumps to a neighbor and accepting a proton from the other neighbor in the trimer. Unfortunately, no reference has been found in the literature that such dimers, trimers are stable in aqueous solution.\nThe above intermolecular proton repositioning must be a fundamental equilibration route for a number of systems when the intramolecular route requires too high activation energy. Tsuchida and Yamabe (TY) [121] proposed a tautomerization pathway between hydroxypyridines and pyridones, where one of the described paths could be applied for any system in aqueous/alcohol solutions. A simple way for tautomerization is the double proton-relay through a dimeric form. For H–X–(C)n–Y monomeric substructures (X, Y electronegative atoms), six-member dimeric rings could be formed with n = 0 (pyrazole above), eight-member rings with n = 1 (2-OH pyridine), etc. Formation and stable maintenance of such rings could be favorable in non-polar solvents, and a tautomeric process could conveniently proceed. The shown example was the 2-OH pyridine to 2-pyridone tautomerization. For the realization of the indicated reaction, the only pre-requisite is the stable maintenance of the properly oriented dimeric form.\nThe tautomerization is also possible through the double-proton-relay mechanism in protic solvents without, however, forming a dimer. Upon the basic idea of the TY mechanism (see above), a protic solvent having both proton donor and acceptor sites could catalyze the indicated process. In this case, a proton from the solute’s H-X site jumps over to the acceptor site of the closest protic solvent molecule, and a proton returns from the solvent to the solute’s acceptor site. This reaction mechanism need not be confined to the involvement of a single solvent molecule. Since protic solvents generally form a H-bonded network, a series of the proton jumps along the several-element solvent bridge will carry the extra proton to the proper site of the solute, even when the two sites of the solute are far away from each other.\nThe mechanism could work for the neutral form/zwitterionic equilibration of the 3- and 4-pyridine carboxylic acids [122], aminophenols [123] and for any saturated amino acid in a protic solution. Sometimes the conformational change by rotation about the (H)X–C bond may lead to the disruption of the intramolecular H-bond for small organic solutes in water/alcohol, but the possibility of the solvent catalyzed disruption of this bond through the corresponding TY mechanism was also considered as a competing reaction path for, e.g., 2-F– and 2-Cl ethanol [15].\nOverall, the tautomerization through dimerization or by solvent catalysis could be a likely, low-activation-energy mechanism in the case of a X–X–H substructure, as for 3-substituted pyrazoles, and must be very important in the case of a H–X–C–Y tautomerization to X–C–Y–H, as well. The chance for an intramolecular proton transfer may start for structures where the XH…Y moiety is involved in a ring with at least five members and the chain is flexible for forming a favorably short H…Y separation. A typical example is the zwitterion formation for α-amino acids (see Subsection 3.2.2).\nThe amide and carboxylic groups are two well-known representatives of the H–X–C–Y substructures. In proteins, the H and O atoms of the H–N–C=O peptide bond are in trans position and there is no possibility to form an intramolcular H-bond, not even upon considering the distance criterion. However, one of the protons points toward the carbonyl oxygen in free amides with a H2N–C=O substructure allowing for the formation of the intermittently stable HN=C–OH tautomeric species.\nThe hydroxy hydrogen in syn carboxylic acids (Figure 5) is at a distance of about 230 pm from the carbonyl oxygen, and the O–H…O angle could be as small as about 76° (see above [79]). The syn –COOH group is coplanar for a monomer. Without a deeper analysis of the molecular orbitals, a simple explanation for the syn –COOH preference may be that the electrons of one of the carbonyl’s lone pairs face the carboxylic hydrogen in the syn conformation, whereas this lone-pair would see the lone pairs of the hydroxy oxygen in the anti form. Thus, a conclusion here is that the dominant conformation is basically directed by electrostatic forces. Nonetheless, the solvent effects are more favorable for the anti rather than the syn form in aqueous solution [79,124], so an observable anti conformation of the acetic acid in aqueous solution is likely.\nThe tetrahydrate model of acetic acid placed in a cavity in a continuum water solvent [79] facilitates the syn to anti conformational change not by rotation about the C–O(H) bond, but by a double proton relay involving the TY mechanism. However, it was pointed out in the same study that the syn dimeric form of acetic acid is present in a large fraction in molar aqueous solution, thus the syn to anti transformation is feasible only for the free acetic acid that is expected to predominate in very dilute solutions.\nAccording to the literature search, the acetic acid dimer has been the subject of the most studies dealing with a dimeric system in the liquid phase. This compound assumes about an 87% dimeric form in the gas phase [28] and forms different, mainly cyclic and linear intermolecular H-bonds in neat liquid [125]. The in-solution association depends on the pH of the solution. The pKa of this molecule is 4.76. A simple calculation concludes that if one mole of this acid dissolves in pure water less than 1% of the solutes dissociate, and the pH of the solution decreases to about 2.4. For a 0.1 molar aqueous solution, the degree of the dissociation is slightly larger than 1% and the pH is about 2.8. Thus, under such conditions, consideration of the neutral form as the prevailing protonation state is justified. Acetic acid is, however, almost fully dissociated at pH = 7.4 under physiological conditions.\nThe acetic acid dimer has been investigated theoretically in several different studies during the past decade. Yamabe and Tsuchida [126] studied the water-catalyzed process: Acetic acid dimer → monomer → dissociation (ionization). When a water cluster attacks the dimer, the monomeric and later the ionized form come into existence through the formation of several unstable and stable intermediate structures. This mechanism is important to understand the formation of the hydrated acetate ion, even though the experimental pKa suggests that only a small fraction exists in the ionized form in pure water.\nFor obtaining the pmf via the MC/FEP method, Nagy [79] considered two charge sets. The first set was derived for the monomeric acetic acid optimized at the IEF-PCM/B97D/aug-cc-pvtz level in a continuum water solvent and the charges were fitted to the in-solution MEP by the CHELPG process. In this first approximation, the charge set was applied along the whole considered R(C…C) separation range of 314–1184 pm (C is the carboxylic carbon). The intermolecular H-bonds start forming at R(C…C) 484 pm and two strong intermolecular bonds are expected to come into existence at about 386 pm, which is the optimized C…C distance for the dimer at the IEF-PCM/B97D/aug-cc-pvtz level. The calculated atomic charges were remarkably different in the dimer compared with the monomer. The dimer charges were then applied in the C…C range of 484–384 pm in the second approximation. The charges and the geometries were gradually transformed from the monomer to dimer values in this range. As a result, the pmf showed a minimum deeper by 21 kJ/mol than when monomer charges were only used. Following the method of Ciccotti [127], upon the integration of the R2 exp(−G(R)/RT) curve (R is the C…C separation, G(R) is the free energy of the system with reference G = 0 at 1184 and 261 pm for the molar and 0.2 molar solutions, respectively), the predicted association degree was 38%–45% and 9%–10% at the two concentrations when the first charge set was applied. In contrast, almost 100% association was predicted for a molar aqueous acetic acid solution by the second approach. However, the deepening of the pmf minimum value is overestimated in the second approach because the internal free energies of the solute partners have to increase at that separation. Indeed, under the conditions where a monomer has a geometry and atomic charges equal to those which were derived for the elements of the optimized dimer, the monomer’s internal free energy must be, by definition, higher than that for the optimized, separate monomer in water. Thus a correction (not carried out in [78]) must diminish the difference in the minimum G values upon the two approaches.\nThere are four pmfs presented by Chen et al., [128] for formic, acetic, propionic and butyric acids in aqueous solution. The calculations utilized the CHARMM22 all-atom force field. The G = 0 reference state was taken at R(C…C) 1100–1200 pm. All pmfs show a clear minimum at carboxylic C…C separation of 400–500 pm. Whereas the valleys around the well-defined minima are narrow for HCOOH and CH3COOH, and the pmfs show a small barrier with slightly positive relative G for desolvation, the free energy is negative for butyric acid up to R about 1100 pm. More importantly, the butyric acid pmf runs remarkably below the acetic acid pmf in the R = 600–800 pm range. Thus the pmfs are similar in the intramolecular H-bond formation range but the favorable interactions of the non-polar, aliphatic chains at R \u003e 600 pm help increase the readiness for solute association even with substantially separated carboxylic groups. The derivable calculated association degree for CH3COOH is 37% in a molar solution, close to the results of Nagy above when the first charge set was used. Both theoretical predictions overestimate, however, the upper limit experimental value of 14%, when using pKD from Table I in [126]. In fact, all theoretically predicted pKD values are overestimated but the linear correlation with the upper limit experimental values is good, providing 0.97 for the square of the correlation coefficient.\nChocholoušová et al., [129] concluded that whereas acetic acid takes a doubly H-bonded cyclic dimeric form in the gas phase, the monomeric form prevails when it is dissolved in aqueous solution as found from molecular dynamics simulations. The association state is still a doubly H-bonded cyclic dimeric form in chloroform. The presumably Amber NpT molecular dynamic simulations were performed in the range of 0.3 to 10 molar concentration in aqueous solution. The applied RESP charges [90] were fitted to the HF/6-31G* wave function. These charges must differ remarkably from those derived by Nagy above, and probably differ also from those utilized by Chen et al. above. The different charge sets may lead to very different conclusions.\nRecently Pašalić et al., [130] carried out a DFTB [131] molecular dynamics simulation for the acetic acid dimer within a box of 200 water molecules (about 0.5 molar). In such calculations it is not necessary to predefine a set of net atomic charges, because the interactions between the solute and solvent molecules are recalculated quantum mechanically in every step. The calculations starting from different dimer geometries were relatively short, lasting only for 300 ps. Nonetheless, the authors found that the elements of all acetic acid dimers started to dissociate after about 50 ps. Although a DFT-based molecular dynamics is a large progress compared with MD simulations utilizing empirical force fields with set atomic charges, these calculations predict energies in the NVT ensemble, and according to Elstner et al., [131] “… in order to compare to experimental situations, free energies rather than potential energies have to be calculated. This would involve molecular dynamic (MD) simulations over rather long time scales, ranging from several hundreds of picoseconds up to milliseconds.” Thus the simulations conducted by Pašalić et al., [130] must be at the lower limit at best.\nOn the experimental side, dimerization constants for acids have been determined by several groups, as shown in [126]. D’Amico et al., [132] performed inelastic UV scattering experiments on aqueous acetic acid solutions at different temperatures and solute concentrations. The author found a crossover temperature, Tc ≈ 325 ± 10 K above which “the energy of hydrogen bonds responsible for water-acetic acid and acetic acid-acetic acid interactions is strongly reduced. This leads to a reduction in the average number of water molecule interacting with acetic acid, as well as to a lower number of acetic acid clusters.” Thus at about 300 K, where the MC and MD simulations were conducted, existence of acetic acid clusters has been concluded by D’Amico et al.\nIn summary, experimental data predict association for acetic acid in dilute aqueous solution, although the degree of association may be only 14% or less. This result has not been successfully reproduced theoretically. Different approaches lead to different results including both contradicting and overestimating of the association.\nClose X…H distances can appear in the 2-OH and 2-SH furan and thiophene in the X–C–Y–H cis conformation and also for 3-OH pyrazole, 3-OH and 5-OH isoxazole. These structures are not considered to have an intramolecular H-bond within their four-member rings, although the conformational preference compared with the X–C–Y–H trans form is interesting and could be affected by the solvent. Old HF/STO-3G calculations by Radom et al., predict OH cis and trans conformations for furan and thiophene rings, respectively, in the gas phase [133]. No recent solvent-effect calculations have been found.\nFor 3-OH and 5-OH isoxazoles, a number of theoretical calculations have been carried out in aqueous solution without uniform conclusions [134,135,136]. Different solvation methods and internal energy calculations indicate that the structural problem is subtle. The systems are subject to oxo-hydroxy tautomeric transformations, and the possible intramolecular H-bond issue was not of interest in the studies. In contrast, the conformational problem was investigated for the hydroxy tautomer. For 3-OH isoxazole [134], the NCOH cis form is more stable than the trans in the gas phase by 18.0 kJ/mol at the MP4/6-31G**//3-21G level. By combination of the relative gas-phase energy with the relative solvation free energy from an MD/FEP calculation in aqueous solution, the cis form still remains the more stable conformer by 10.9 kJ/mol. In the same paper, the cis O–C–O–H conformation of 5-OH isoxazole was found to be more stable than the trans form by 8.4 kJ/mol in the gas phase and by 2.1 kJ/mol in solution. Gould and Hillier [135] also found the cis O–C–O–H form to be more stable than the trans structure by 1.3 kJ/mol in aqueous solution. Thus the solvation by water favors the trans conformer, but the cis structure is still maintained for the hydroxy forms of substituted isoxazoles.\nCramer and Truhlar [136] studied the conformational/tautomeric problem for the 5-OH isoxazole. The free energy difference in the gas phase at T = 298 K is less than 1 kJ/mol in favor of the cis form as determined from high-level ab intio calculations. The aqueous solvation favors the trans form by about 1.7 kJ/mol, thus the trans O–C–O–H conformation was predicted by these authors as the more preferable conformation by up to 1.7 kJ/mol in aqueous solution, depending on the applied models. The trans form also remains the more stable conformer for the 3-methyl and 3,4-dimethyl derivatives by up to 3 kJ/mol."}