Reaction of Picolinamides with Ketones Producing a New Type of Heterocyclic Salts with an Imidazolidin-4-One Ring

Reactions of picolinamides with 1,3-propanesultone in methanol followed by the treatment with ketones led to a series of previously unknown chemical transformations, yielding first pyridinium salts (2a–f), with a protonated endocyclic nitrogen atom, and then heterocyclic salts (3a–j) containing an imidazolidin-4-one ring. The structures of intermediate and final products were determined by IR and 1H, 13C NMR spectroscopy, and X-ray study. The effects of the ketone and alcohol structures on the product yield were studied by quantum-chemical calculations. The stability of salts 3a–j towards hydrolysis and alcoholysis makes them excellent candidates for the search for new types of biologically active compounds.

In our previous works, traditional synthetic approaches [9] were used for the preparation of novel pyridinecarboxamides (A) containing a homotaurin fragment [10].Typically, the reactions proceeded through the opening of the sultone ring, as shown in Scheme 1.For the reactions of 3-and 4-pyridinecarboxamides with sultones in boiling methanol, the position of the amido group has little effect on the yield of the final sulfobetaine A. In contrast, 2-pyridinecarboxamides (picolinamides) under similar conditions produce pyridinium salts B (Scheme 2).
A Scheme 1.General synthetic route to compound A.
For the reactions of 3-and 4-pyridinecarboxamides with sultones in boiling methanol, the position of the amido group has little effect on the yield of the final sulfobetaine A. In contrast, 2-pyridinecarboxamides (picolinamides) under similar conditions produce pyridinium salts B (Scheme 2).The low yield of product A in the case of picolinamides and the formation of salt B at high temperatures are likely to be a result of intramolecular bonding in the substrate involving the amido group and endocyclic nitrogen atom [10].
In this study, the synthesis, structure and properties of new types of imidazolidin-4ones with novel organic anions are reported.The low yield of product A in the case of picolinamides and the formation of salt B at high temperatures are likely to be a result of intramolecular bonding in the substrate involving the amido group and endocyclic nitrogen atom [10].
A Scheme 1.General synthetic route to compound A.
For the reactions of 3-and 4-pyridinecarboxamides with sultones in boiling methanol, the position of the amido group has little effect on the yield of the final sulfobetaine A. In contrast, 2-pyridinecarboxamides (picolinamides) under similar conditions produce pyridinium salts B (Scheme 2).The low yield of product A in the case of picolinamides and the formation of salt B at high temperatures are likely to be a result of intramolecular bonding in the substrate involving the amido group and endocyclic nitrogen atom [10].
In this study, the synthesis, structure and properties of new types of imidazolidin-4ones with novel organic anions are reported.Scheme 3. A typical route involves the synthesis of a linear α-aminoamide followed by cyclisation.
In this study, the synthesis, structure and properties of new types of imidazolidin-4-ones with novel organic anions are reported.

Synthesis
In the present work, the reactions of picolinamide 1a with various alcohols and ketones were explored.Under similar conditions, these reactions produced a broad range of pyridinium (2a-g) and imidazolidin-4-ones (3a-j) salts (Scheme 4, Tables 1 and 2, see also Experimental Part).

Synthesis
In the present work, the reactions of picolinamide 1a with various alcohols and ketones were explored.Under similar conditions, these reactions produced a broad range of pyridinium (2a-g) and imidazolidin-4-ones (3a-j) salts (Scheme 4, Tables 1 and 2, see also Experimental Part).
Scheme 4. General synthetic route to compounds 2a-g and 3a-j.

Synthesis
In the present work, the reactions of picolinamide 1a with various alcohols and ketones were explored.Under similar conditions, these reactions produced a broad range of pyridinium (2a-g) and imidazolidin-4-ones (3a-j) salts (Scheme 4, Tables 1 and 2, see also Experimental Part).
Scheme 4. General synthetic route to compounds 2a-g and 3a-j.

Synthesis
In the present work, the reactions of picolinamide 1a with various alcohols and ketones were explored.Under similar conditions, these reactions produced a broad range of pyridinium (2a-g) and imidazolidin-4-ones (3a-j) salts (Scheme 4, Tables 1 and 2, see also Experimental Part).
Scheme 4. General synthetic route to compounds 2a-g and 3a-j.

Synthesis
In the present work, the reactions of picolinamide 1a with various alcohols and ketones were explored.Under similar conditions, these reactions produced a broad range of pyridinium (2a-g) and imidazolidin-4-ones (3a-j) salts (Scheme 4, Tables 1 and 2, see also Experimental Part).
Scheme 4. General synthetic route to compounds 2a-g and 3a-j.

Synthesis
In the present work, the reactions of picolinamide 1a with various alcohols and ketones were explored.Under similar conditions, these reactions produced a broad range of pyridinium (2a-g) and imidazolidin-4-ones (3a-j) salts (Scheme 4, Tables 1 and 2, see also Experimental Part).
Scheme 4. General synthetic route to compounds 2a-g and 3a-j.

Synthesis
In the present work, the reactions of picolinamide 1a with various alcohols and ketones were explored.Under similar conditions, these reactions produced a broad range of pyridinium (2a-g) and imidazolidin-4-ones (3a-j) salts (Scheme 4, Tables 1 and 2, see also Experimental Part).

Synthesis
In the present work, the reactions of picolinamide 1a with various alcohols and ketones were explored.Under similar conditions, these reactions produced a broad range of pyridinium (2a-g) and imidazolidin-4-ones (3a-j) salts (Scheme 4, Tables 1 and 2, see also Experimental Part).

Synthesis
In the present work, the reactions of picolinamide 1a with various alcohols and ketones were explored.Under similar conditions, these reactions produced a broad range of pyridinium (2a-g) and imidazolidin-4-ones (3a-j) salts (Scheme 4, Tables 1 and 2, see also Experimental Part).

Synthesis
In the present work, the reactions of picolinamide 1a with various alcohols and ketones were explored.Under similar conditions, these reactions produced a broad range of pyridinium (2a-g) and imidazolidin-4-ones (3a-j) salts (Scheme 4, Tables 1 and 2, see also Experimental Part).2. Results

Synthesis
In the present work, the reactions of picolinamide 1a with various alcohols and ketones were explored.Under similar conditions, these reactions produced a broad range of pyridinium (2a-g) and imidazolidin-4-ones (3a-j) salts (Scheme 4, Tables 1 and 2, see also Experimental Part).

Synthesis
In the present work, the reactions of picolinamide 1a with various alcohols and ketones were explored.Under similar conditions, these reactions produced a broad range of pyridinium (2a-g) and imidazolidin-4-ones (3a-j) salts (Scheme 4, Tables 1 and 2, see also Experimental Part).

Synthesis
In the present work, the reactions of picolinamide 1a with various alcohols and ketones were explored.Under similar conditions, these reactions produced a broad range of pyridinium (2a-g) and imidazolidin-4-ones (3a-j) salts (Scheme 4, Tables 1 and 2, see also Experimental Part).

Synthesis
In the present work, the reactions of picolinamide 1a with various alcohols and ketones were explored.Under similar conditions, these reactions produced a broad range of pyridinium (2a-g) and imidazolidin-4-ones (3a-j) salts (Scheme 4, Tables 1 and 2, see also Experimental Part).
Scheme 4. General synthetic route to compounds 2a-g and 3a-j.

Synthesis
In the present work, the reactions of picolinamide 1a with various alcohols and ketones were explored.Under similar conditions, these reactions produced a broad range of pyridinium (2a-g) and imidazolidin-4-ones (3a-j) salts (Scheme 4, Tables 1 and 2, see also Experimental Part).

Synthesis
In the present work, the reactions of picolinamide 1a with various alcohols and ketones were explored.Under similar conditions, these reactions produced a broad range of pyridinium (2a-g) and imidazolidin-4-ones (3a-j) salts (Scheme 4, Tables 1 and 2, see also Experimental Part).
Scheme 4. General synthetic route to compounds 2a-g and 3a-j.In the case of N-substituted amide 1b, the intermediate pyridinium salt 2g was found to be unreactive towards acetone under studied reaction conditions, and the formation of the corresponding imidazolidin-4-one derivative was not observed.
Our attempt to prepare compound 3a by refluxing salt 2a (which was isolated by the evaporation of the solvent and used without further purification from the traces of methanol) in acetone for 3 h was only partially successful, as the yield was impractically low (12%).However, when a hot solution of 2a in methanol was treated with acetone, the yield increased to 80%.These results suggest that the formation of 3a in the second case could involve the reaction of 2a with a hemiketal intermediate (Scheme 5).Our attempt to prepare compound 3a by refluxing salt 2a (which was isolated by the evaporation of the solvent and used without further purification from the traces of methanol) in acetone for 3 h was only partially successful, as the yield was impractically low (12%).However, when a hot solution of 2a in methanol was treated with acetone, the yield increased to 80%.These results suggest that the formation of 3a in the second case could involve the reaction of 2a with a hemiketal intermediate (Scheme 5).Scheme 5. A possible scheme of salt 3a formation.
Most compounds 3a-j were obtained with high yields (75-94%, Table 2).The lower yields of compounds 3g (43%) and 3i (23%) could be caused by elimination reactions of alcohols used for the preparation of pyridinium salts 2c and 2e, respectively.The separation of 3i and 2e was very problematic, so the 1 H NMR spectrum of the final mixture in D2O showed very broad signals of both compounds in 4:1 ratio, respectively (see Experimental Part).The IR spectrum of the mixture also showed the characteristic absorptions of both salts (see Experimental Part).
Our attempts to carry out the condensation of 2a with methyl tert-butyl ketone, acetophenone and benzaldehyde were unsuccessful-in all cases, only the original salt was isolated.

X-ray Study
According to the results of the X-ray study, the values of all bond lengths and angles in salts 2a and 3a (Figure 1) fall within the ranges typical for pyridinium salts of alkylsulfonic acids.Crystallographic data for 2a and 3a are summarised in Table 3 (see Experimental Part).The parameters of hydrogen bonds are shown in Tables S6 and S7.Most compounds 3a-j were obtained with high yields (75-94%, Table 2).The lower yields of compounds 3g (43%) and 3i (23%) could be caused by elimination reactions of alcohols used for the preparation of pyridinium salts 2c and 2e, respectively.The separation of 3i and 2e was very problematic, so the 1 H NMR spectrum of the final mixture in D 2 O showed very broad signals of both compounds in 4:1 ratio, respectively (see Experimental Part).The IR spectrum of the mixture also showed the characteristic absorptions of both salts (see Experimental Part).
Our attempts to carry out the condensation of 2a with methyl tert-butyl ketone, acetophenone and benzaldehyde were unsuccessful-in all cases, only the original salt was isolated.

X-ray Study
According to the results of the X-ray study, the values of all bond lengths and angles in salts 2a and 3a (Figure 1) fall within the ranges typical for pyridinium salts of alkylsulfonic acids.Crystallographic data for 2a and 3a are summarised in Table 3 (see Experimental Part).The parameters of hydrogen bonds are shown in Tables S6 and S7.
Our attempt to prepare compound 3a by refluxing salt 2a (which was isolated by the evaporation of the solvent and used without further purification from the traces of methanol) in acetone for 3 h was only partially successful, as the yield was impractically low (12%).However, when a hot solution of 2a in methanol was treated with acetone, the yield increased to 80%.These results suggest that the formation of 3a in the second case could involve the reaction of 2a with a hemiketal intermediate (Scheme 5).Scheme 5. A possible scheme of salt 3a formation.
Most compounds 3a-j were obtained with high yields (75-94%, Table 2).The lower yields of compounds 3g (43%) and 3i (23%) could be caused by elimination reactions of alcohols used for the preparation of pyridinium salts 2c and 2e, respectively.The separation of 3i and 2e was very problematic, so the 1 H NMR spectrum of the final mixture in D2O showed very broad signals of both compounds in 4:1 ratio, respectively (see Experimental Part).The IR spectrum of the mixture also showed the characteristic absorptions of both salts (see Experimental Part).
Our attempts to carry out the condensation of 2a with methyl tert-butyl ketone, acetophenone and benzaldehyde were unsuccessful-in all cases, only the original salt was isolated.

X-ray Study
According to the results of the X-ray study, the values of all bond lengths and angles in salts 2a and 3a (Figure 1) fall within the ranges typical for pyridinium salts of alkylsulfonic acids.Crystallographic data for 2a and 3a are summarised in Table 3 (see Experimental Part).The parameters of hydrogen bonds are shown in Tables S6 and S7.Salt 2a crystallised in a monoclinic system and chiral space group P2 1 .The unique part of the unit cell contained four crystallographically independent cations and anions linked by strong hydrogen bonds between sulfo groups of anions and amido or pyridinium moieties of cations (Figure 2, left).The supramolecular structure formed by hydrogen bonds can be described as a double layer, with ether groups of anions residing inside the layers, while sulfo groups of anions and pyridinium moieties of cations form the outer shell.In turn, the double layers are held together by weak interactions between sulfo groups and ipso-carbon atoms of pyridinium moieties.The supramolecular structure formed by hydrogen bonds can be described as a double layer, with ether groups of anions residing inside the layers, while sulfo groups of anions and pyridinium moieties of cations form the outer shell.In turn, the double layers are held together by weak interactions between sulfo groups and ipso-carbon atoms of pyridinium moieties.
In the crystal packing of 3a, cations and anions form dimers via hydrogen bonds between the sulfo group of the anion and the imidazolidin-4-one ring of the cation.In turn, these dimers are assembled into a 3-D framework via weak C-H. . .O interactions (Figure 2, right).

Reactions of Hydrolysis of Compounds 3a, 3d and 3e
Many derivatives of imidazolidin-4-one are unstable in acidic and neutral aqueous environments.For example, the half-life of the antibacterial drug hetacillin in aqueous solutions at pH 3-8 is approximately 30 min [34].The main hydrolysis product, ampicillin, is responsible for over 90% of the biological activity of hetacillin [35].The N'-alkylation improves the hydrolytic stability of imidazolidin-4-ones both in human plasma and aqueous buffer with pH 7.4 [19].
In order to evaluate the applicability of salts 3a-j as potential drug candidates, we have studied the stability of compounds 3a, 3d and 3e towards water.
In contrast to hetacillin, compound 3a was stable in water at room temperature (no hydrolysis was observed over a period of seven days).The reflux of compound 3a in water for 5 h led to the elimination of acetone and the formation of salt 2a with a yield of 32% (Scheme 2).The hydrolysis of the same compound at moderate temperatures (70-80 • C) increased the yield of 2a to 63%.
A similar behaviour was observed for compounds 3d and 3e.For example, the reaction of 3d with water at 70-80 • C for 5 h produced a mixture of 2a and 3d, with the IR spectrum showing two ν(C=O) bands at 1708 and 1727 cm −1 , respectively.

Theoretical Study
Thermodynamic parameters of the chemical reactions shown in Scheme 4 were estimated using quantum-chemical calculations.

Thermodynamic Parameters of Formation for Compounds 2a-f
The first step of the reaction leading to salts 2a-f (Scheme 3) is the nucleophilic addition of an alcohol to 1,3-propanesultone, which produces 3-alkoxypropanesulfonic acids 1-IIa-f (Scheme 6): The first step of the reaction leading to salts 2a-f (Scheme 3) is the nucleophilic addition of an alcohol to 1,3-propanesultone, which produces 3-alkoxypropanesulfonic acids 1-IIa-f (Scheme 6): 1-IIa-f Scheme 6. Representative synthetic route for compound 1-IIa-f.
With the exception of R = i-Bu, the thermal effect of this step decreases when the size of the R substituent increases (Figure 3, Table S1).With the exception of R = i-Bu, the thermal effect of this step decreases when the size of the R substituent increases (Figure 3, Table S1).
Therefore, sterical hindrance is likely to be the major factor affecting the concentrations of 3-alkoxypropanesulfonic acids 1-IIa-f in the reaction mixture, which in turn affects the yields of respective salts 2a-f (Scheme 3).
With the exception of R = i-Bu, the thermal effect of this step decreases when the size of the R substituent increases (Figure 3, Table S1).Therefore, sterical hindrance is likely to be the major factor affecting the concentrations of 3-alkoxypropanesulfonic acids 1-IIa-f in the reaction mixture, which in turn affects the yields of respective salts 2a-f (Scheme 3).

Structures of the Cation-Anion Complexes.
The actual thermodynamic parameters of chemical reactions shown in Scheme 3 depend on the mutual orientation of cations and anions under experimental conditions (in boiling methanol).Possible structures of salt 2a in the reaction medium could be predicted by analysing electrostatic potential (ESP) maps of the constituent ions (Figure 4A).Thermodynamic parameters (M052X/TZVP) of the formation of 3-alkoxypropanesulfonic acids.

Structures of the Cation-Anion Complexes
The actual thermodynamic parameters of chemical reactions shown in Scheme 3 depend on the mutual orientation of cations and anions under experimental conditions (in boiling methanol).Possible structures of salt 2a in the reaction medium could be predicted by analysing electrostatic potential (ESP) maps of the constituent ions (Figure 4A).The red and blue dots in Figure 4A correspond to regions of ESP maps with low and high electron density, respectively.The lowest electron density for 1-Ia is observed near the nitrogen atom of the pyridinium ring, while the highest electron density is concentrated around the sulfo group of the anion 1-IIa.
The most common mutual positions of ions 1-Ia and 1-IIa were identified by statisti- The red and blue dots in Figure 4A correspond to regions of ESP maps with low and high electron density, respectively.The lowest electron density for 1-Ia is observed near the nitrogen atom of the pyridinium ring, while the highest electron density is concentrated around the sulfo group of the anion 1-IIa.
The most common mutual positions of ions 1-Ia and 1-IIa were identified by statistical analysis of molecular dynamics (MD) simulation for a system containing two ions of opposite charge and a large number of methanol molecules.This allowed us to take into account the solvation of salt 2a by methanol and thus predict the most likely structure of the complex in solution (Figure 4B).
According to our calculations, salt 2a in solution is stabilised by hydrogen bonds involving one of the oxygen atoms in anion 1-IIa and hydrogen atoms at N1 and N2 in cation 1-Ia (Figure 4B).As expected, the calculated geometric parameters of the cation-anion complex in solution differ significantly from those in the solid state obtained by X-ray study (Figure 1).The most obvious difference is the mutual orientation of the acetamide fragment and pyridinium ring in 1-Ia.In solution (Figure 4B), the calculated value of the dihedral angle (φ) N1-C-C-N2 is close to zero while in the solid state (Figure 1) it approaches 180 • .According to quantum-chemical calculations, the most stable conformation of nonprotonated picolinamide 1a is achieved at φ ≈ 0 • [10].However, this is not the case for protonated picolinamide in 2a, where the conformation with φ ≈ 180 • is by ca.20 kJ/mol more stable (Figure 4C).The reason for this difference is the formation of hydrogen bonds: intramolecular in 1a (φ ≈ 0 • ) and interionic in the 2a complex (φ ≈ 180 • ).In the latter case, the AIM analysis reveals critical points of (3; −1) type (for more detail, see Table S2).
The activation energy for the proton migration from sulfonic acid to the pyridine ring is relatively low (4.5 kJ/mol, M052X-D3/TZVP), which suggests that the formation of salt 2a might involve the following transition state C (Scheme 7).

Thermodynamic Parameters of 2a-g Formation
Figure 5 shows a histogram where the yields of salts 2a-f are plotted together with relative differences of the reaction enthalpy and Gibbs free energy, with zero values for ΔΔrH° and ΔΔrG° corresponding to the lowest values of ΔrH° and ΔrG° from Table S2.

Thermodynamic Parameters of 2a-g Formation
Figure 5 shows a histogram where the yields of salts 2a-f are plotted together with relative differences of the reaction enthalpy and Gibbs free energy, with zero values for ∆∆ r H • and ∆∆ r G • corresponding to the lowest values of ∆ r H • and ∆ r G • from Table S2.
According to Figure 5, relative values ∆∆ r H • and ∆∆ r G • generally increase along with the size of the alkyl chain in the alcohol.The only exception is isopropanol, which also has the lowest values of ∆ r H • and ∆ r G • for the reaction with 1,3-propanesultone (Figure 5, Table S1).The least thermodynamically favourable reaction, the formation of salt 2e, proceeds with the lowest yield (25%).At the same time, similar ∆∆ r H • and ∆∆ r G • values are observed for salt 2f, which was obtained with the highest yield (89%).The formation of salt 2g is characterised by positive absolute values of ∆ r H • and ∆ r G • (Table S2).

Thermodynamic Parameters of 2a-g Formation
Figure 5 shows a histogram where the yields of salts 2a-f are plotted together with relative differences of the reaction enthalpy and Gibbs free energy, with zero values for ΔΔrH° and ΔΔrG° corresponding to the lowest values of ΔrH° and ΔrG° from Table S2.According to Figure 5, relative values ΔΔrH° and ΔΔrG° generally increase along with the size of the alkyl chain in the alcohol.The only exception is isopropanol, which also has the lowest values of ΔrH° and ΔrG° for the reaction with 1,3-propanesultone (Figure 5, Table S1).The least thermodynamically favourable reaction, the formation of salt 2e, proceeds with the lowest yield (25%).At the same time, similar ΔΔrH° and ΔΔrG° values are observed for salt 2f, which was obtained with the highest yield (89%).The formation of salt 2g is characterised by positive absolute values of ΔrH° and ΔrG° (Table S2).

Thermodynamic Parameters of 3a-j Formation
Analysis of thermodynamic parameters of salts 3a-j formation suggests that the observed chemical changes could be divided into three groups.The first group includes the formation of salts 3a-c by reactions of 2a with aliphatic ketones (Figure 6A).

Thermodynamic Parameters of 3a-j Formation
Analysis of thermodynamic parameters of salts 3a-j formation suggests that the observed chemical changes could be divided into three groups.The first group includes the formation of salts 3a-c by reactions of 2a with aliphatic ketones (Figure 6A).In this group, an increase in the alkyl substituent size raises the ΔΔrH° and ΔΔrG° values and, therefore, lowers the reaction yield.The absolute values of ΔrH° and ΔrG° are given in Table S4.
The second group includes the reactions of salt 2a with cyclic ketones.In this case, an increase in the Reactions of the third group includes the formation of salts 3a and 3f-j.In these reactions, an increase in the size of the alkoxy substituent in the sulfonic acid raises the ΔΔrH° and ΔΔrG° values and, therefore, lowers the reaction yield (Figure 6B).These results correlate with the data shown in Figure 5. Ring size lowers the ΔΔrH° and ΔΔrG° values and, therefore, raises the reaction yield.

Chemistry
The purities of all compounds were assessed by elemental analysis and NMR and found to be ≥95%.NMR spectra were recorded on a Bruker Avance II 300 spectrometer In this group, an increase in the alkyl substituent size raises the ∆∆ r H • and ∆∆ r G • values and, therefore, lowers the reaction yield.The absolute values of ∆ r H • and ∆ r G • are given in Table S4.
The second group includes the reactions of salt 2a with cyclic ketones.In this case, an increase in the Reactions of the third group includes the formation of salts 3a and 3f-j.In these reactions, an increase in the size of the alkoxy substituent in the sulfonic acid raises the ∆∆ r H • and ∆∆ r G • values and, therefore, lowers the reaction yield (Figure 6B).These results correlate with the data shown in Figure 5. Ring size lowers the ∆∆ r H • and ∆∆ r G • values and, therefore, raises the reaction yield.

Chemistry
The purities of all compounds were assessed by elemental analysis and NMR and found to be ≥95%.NMR spectra were recorded on a Bruker Avance II 300 spectrometer (Bruker BioSpin GMBH, Rheinstetten, Germany) at 300 MHz ( 1 H) and 75 MHz ( 13 C) in D 2 O in the pulse mode, followed by Fourier transformation using Me 4 Si as the internal standard.Spin multiplicities are designated as s (singlet), d (doublet), t (triplet), q (quartet) or m (multiplet).IR spectra in the solid phase were recorded on a Bruker Tensor-27 instrument (Bruker Corporation, Bremen, Germany) with an attenuated total internal reflectance (ATR) module.Refraction parameters were measured using an IRF-454B2M refractometer (KOMZ, Kazan, Russia).Melting points were determined using a Stuart SMP10 instrument (Barloworld Scientific Ltd., Stone, UK).Elemental analyses were carried out at the Laboratory of Organic Microanalysis of INEOS RAS.

Synthesis
Compounds 1a, 1b, 1,3-propanesultone, ketones and alcohols were obtained as commercial reagents from Acros and Sigma-Aldrich and used without further purification.
General synthesis of compounds 2a-g and 3a-i.A mixture of 0.005 mol of compound 1a or 1b and 0.006 mol of 1,3-propanesultone in alcohol was refluxed for 4 h.The solvent was evaporated, and the salt 2a-f obtained was treated with a ketone at reflux in methanol.The crystals of salt 3a-j formed were filtered out and dried.
(a) 0.11 g (0.003 mol) of 3a in 3 mL of water was stirred for 7 days at room temperature.After evaporation, 0.10 g (91%) of 3a was obtained.
(b) 0.36 g (0.011 mmol) of 3a in 4 mL of water was refluxed for 4 h.After evaporation and recrystallisation of the residue from CH 3 CN, 0.10 g (32%) of 2a was obtained.(c) 0.31 g (0.0097 mol) of 3a in 4 mL of water was stirred at 70-80 • C for 5 h.After evaporation, 0.17 g (63%) of 2a was obtained.(d) 0.11 g (0.003 mol) of 3d in 4 mL of water was stirred at 70-80 • C for 5 h.After evaporation, 0.08 g of a mixture of 3a and 3d was obtained.(e) 0.11 g (0.003 mol) of 3e in 4 mL of water was stirred at 70-80 • C for 5 h.After evaporation, 0.08 g (97%) of 3a was obtained.
The above method was used for the full optimisation of the structures of reactants and products (S1 and S2, Supplementary Materials).The calculations were carried out in the approximation of isolated molecules.The solvent effects were taken into account using the integral equation formalism variant of the polarisable continuum model (IEFPCM).
The correspondence of the calculated structures to minima on the potential energy surface was assessed by the absence of negative elements in the diagonalised Hessian matrix.The transition states were identified by the presence of a single negative element in the matrix.
Thermal effects of reactions and activation enthalpies were calculated as the difference between the absolute enthalpies of the final (or transition) and initial states of the process.Absolute enthalpies were calculated as the sum of total energy, zero-point energy and thermal correction for the enthalpy change from zero to 298 K.The latter values were obtained by frequency calculations using common equations of statistical thermodynamics.
The mutual arrangement of the protonated picolinamide cation and the sulfonate anion was determined using electrostatic potential (ESP) maps, which were calculated using MultiWFN software, ver.3.8 [43] and visualised using VMD software (version 1.1) [44].
The structure of the pre-reaction complex was determined using molecular dynamics (MD) modelling of a system containing a protonated picolinamide cation, a sulfonate anion, a molecule of acetone and 2000 solvent (methanol) molecules (Figure S1).MD modelling was performed for a cube-shaped system with periodic boundary conditions (PBC) using the OPLS4 force field [45].
The simulation of the isobaric-isothermal process was carried out using the NPT molecular ensemble.The dynamics simulation was recorded for 10 ns at 337 K (the boiling point of methanol).A total of 5000 frames were used for the statistical analysis.The analysis of the MD trajectory and the construction of volumetric maps for the PBC space were carried out using VMD software [44].

X-ray Crystallographic Studies
Single-crystal X-ray studies of compounds 2a and 3a were carried out in the Center for Molecule Composition Studies of INEOS RAS using APEX3 software [46].The data obtained were then integrated with SAINT.SADABS was used for scaling, empirical absorption corrections and generation of data files for structure solution and refinement.
The structures were solved by a dual-space algorithm and refined in anisotropic approximation for non-hydrogen atoms against F 2 (hkl).The positions of hydrogen atoms in methyl, methylene and aromatic fragments were calculated for idealised geometry and refined with constraints applied to C-H and N-H bond lengths and equivalent displacement parameters (U eq (H) = 1.2U eq (X) for XH 2 groups and U eq (H) = 1.5U eq (Y) for

Figure 4 .
Figure 4. Structures and coordination of ions: (A)-ESP maps (kJ/mol) of 1-Ia and 1-IIa; (B)-calculated structure of 2a in solution and the actual structure of solid 2a determined by X-ray study; (C)possible conformations of 1-Ia.Bond lengths are given in Å; hydrogen bond energies (bold italic) are given in kJ/mol.

Figure 4 .
Figure 4. Structures and coordination of ions: (A)-ESP maps (kJ/mol) of 1-Ia and 1-IIa; (B)-calculated structure of 2a in solution and the actual structure of solid 2a determined by Xray study; (C)-possible conformations of 1-Ia.Bond lengths are given in Å; hydrogen bond energies (bold italic) are given in kJ/mol.

19 Figure 6 .
Figure 6.Thermodynamic parameters of salts 3a-j formation reactions: (A)-includes the formation of salts 3a-c by reactions of 2a with aliphatic ketones; (B)-includes the reactions of salt 2a with cyclic ketones.

1 13 Figure 6 .
Figure 6.Thermodynamic parameters of salts 3a-j formation reactions: (A)-includes the formation of salts 3a-c by reactions of 2a with aliphatic ketones; (B)-includes the reactions of salt 2a with cyclic ketones.

Table 1 .
Structure and yields of salts 2a-g.
. Structure and yields of salts 2a-g.Scheme 4. General synthetic route to compounds 2a-g and 3a-j.

Table 1 .
Structure and yields of salts

Table 1 .
Structure and yields of salts

Table 1 .
Structure and yields of salts

Table 1 .
Structure and yields of salts

Table 1 .
Structure and yields of salts

Table 1 .
Structure and yields of salts

Table 1 .
Structure and yields of salts

Table 1 .
Structure and yields of salts

Table 1 .
Structure and yields of salts 2a-g.

Table 1 .
Structure and yields of salts 2a-g.

Table 2 .
Structure and yields of salts 3a-j.

Table 2 .
Structure and yields of salts 3a-j.

Table 2 .
Structure and yields of salts 3a-j.

Table 2 .
Structure and yields of salts 3a-j.

Table 2 .
Structure and yields of salts 3a-j.

Table 2 .
Structure and yields of salts 3a-j.

Table 2 .
Structure and yields of salts 3a-j.

Table 2 .
Structure and yields of salts 3a-j.

Table 2 .
Structure and yields of salts 3a-j.

Table 2 .
Structure and yields of salts 3a-j.

Table 2 .
Structure and yields of salts 3a-j.

Table 2 .
Structure and yields of salts 3a-j.

Table 2 .
Structure and yields of salts 3a-j.

Table 2 .
Structure and yields of salts 3a-j.

Table 2 .
Structure and yields of salts 3a-j.

Table 2 .
Structure and yields of salts 3a-j.

Table 2 .
Structure and yields of salts 3a-j.

Table 2 .
Structure and yields of salts 3a-j.

Table 2 .
Structure and yields of salts 3a-j.

Table 2 .
Structure and yields of salts 3a-j.

Table 2 .
Structure and yields of salts 3a-j.