CrystEngComm View Article Online PAPER View Journal | View Issue Virtual assessment achieved two binary cocrystals This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Cite this: CrystEngComm, 2023, 25, based on a liquid and a solid pyridine derivative Open Access Article. Published on 04 August 2023. Downloaded on 8/30/2023 9:15:18 AM. 4798 with modulated thermal stabilities† a Daniel Ejarque, Teresa Calvet,b Mercè Font-Bardiac and Josefina Pons *a The rational design of cocrystals triggered by the control of recurrent H-bonded patterns referred to as supramolecular synthons enabled the correlation between their structure and properties, which has been a topic of interest owing to the possibility to modulate them depending on the selected components. Accordingly, melting point has been one of the most studied properties, providing materials with enhanced thermal stability for specific applications. Within this frame, in this work we have selected a liquid and a solid pyridine derivative (dPy), namely 4-acetylpyridine (4-Acpy) and 2-hydroxypyridine (2-OHpy) to combine with carboxylic acids to obtain a pair of cocrystals. An initial virtual screening of some carboxylic acids based on the positive and negative critical points of the molecular electrostatic potential (MEP) surfaces was performed to evaluate the feasibility of cocrystal formation. This enabled us to select 1,3-benzodioxole-5-carboxylic acid (piperonylic acid, HPip) to combine with 4-Acpy and α-acetamidocinnamic acid (HACA) with 2-OHpy. Then, we have obtained the corresponding cocrystal experimentally by means of liquid-assisted grinding (LAG), and their crystal structures were elucidated, revealing the formation of (HPip)(4-Acpy) (1) and (HACA)(Pdon) (2) (Pdon = 2-pyridone), observing the tautomerization of 2-OHpy to Pdon. Both cocrystals were characterized by analytical and spectroscopic Received 16th June 2023, techniques. In addition, a Cambridge Structural Database (CSD) survey of 4-Acpy and Pdon in cocrystal Accepted 21st July 2023 systems was performed and the observed preferences regarding their preferable synthons and DOI: 10.1039/d3ce00608e dimensionalities were shown. Finally, their melting points have been determined, and the resulting values have been correlated with the crystal packing of the compounds, supported by Hirshfeld surface analysis rsc.li/crystengcomm and energy frameworks. Introduction (APIs)9,10 as well as their opportunities to overcome patent protection of existing APIs.11 Interestingly, recent studies used Over the past decades, the study of organic multicomponent this approach to stabilize liquid molecules in the solid crystalline materials has attracted the attention of researchers state,12,13 providing a better handling of pesticides14 or owing to their promising applications in the fields of medicines.15 We emphasize herein that these materials medicine,1,2 agriculture,3,4 and explosives,5,6 among others.7,8 should also be regarded as cocrystals despite one of their In particular, the design of cocrystals has been a hot topic former components being a liquid at room temperature, due to their ability to improve the physicochemical properties which has been subjected to debate during the past two of pharmaceuticals without altering the pharmacological decades.16 Therefore, researchers have focused their efforts properties of the selected active pharmaceutical ingredients on the control of intermolecular interactions towards the rational design of these materials. Accordingly, the emergence of the concept of supramolecular synthon17 not only led the a way to the preparation of cocrystals based on predictable Departament de Química, Universitat Autònoma de Barcelona, 08193-Bellaterra, Barcelona, Spain. E-mail: josefina.pons@uab.es H-bonded patterns (i.e. acid⋯pyridine,18 acid⋯amide,19 and b Departament de Mineralogia, Petrologia i Geologia Aplicada, Universitat de alcohol⋯pyridine,20 among others21) but also permitted the Barcelona, Martí i Franquès s/n, 08028 Barcelona, Spain understanding of their structure–property relationships.22,23 c Unitat de Difracció de Raig-X, Centres Científics i Tecnològics de la Universitat de Within this frame, melting point has been an extensively Barcelona (CCiTUB), Universitat de Barcelona, Solé i Sabarís, 1-3, 08028 studied physical property of solids.24–26 Its modulation has Barcelona, Spain † Electronic supplementary information (ESI) available. CCDC 2267801 and enabled the enhancement of the thermal stability and 2267802. For ESI and crystallographic data in CIF or other electronic format see processability of the determined molecules through the DOI: https://doi.org/10.1039/d3ce00608e formation of cocrystals.27–29 Indeed, our group has previously 4798 | CrystEngComm, 2023, 25, 4798–4811 This journal is © The Royal Society of Chemistry 2023 View Article Online CrystEngComm Paper studied the formation of cocrystals based on the acid⋯amide30 (CD3OD) was used for the NMR experiments and was and acid⋯pyridine heterosynthons31 and the correlation of the purchased from Eurisotop. All of them were used without crystal packing with their melting point values.31 Therefore, further purification. All the reactions and manipulations were aiming to extend our knowledge on the structure–property carried out in air at room temperature (RT). Powder X-ray relationship of cocrystals focusing on the melting point, we diffraction (PXRD) patterns were measured with a Panalytical have selected a liquid and a solid pyridine derivative (dPy), X'Pert PRO MPD apparatus using monochromatic CuKα namely 4-acetylpyridine (4-Acpy) and 2-hydroxypyridine radiation with λ = 1.5406 Å. All of them were recorded from (2-OHpy), respectively. It should be noted that 2-OHpy exists in 2θ = 5° to 30° with a step scan of 0.01671°. Melting point (m. equilibrium with its keto form (2-pyridone, Pdon), which in the p.) was measured on a Stuart melting point apparatus SMP30 This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. solid state is preferentially shifted to Pdon.32 Then, we evaluated using a 2.0 °C min−1 step rate from RT to 200 °C. Elemental Open Access Article. Published on 04 August 2023. Downloaded on 8/30/2023 9:15:18 AM. the most promising carboxylic acids over a group of available analyses (EAs) were carried out on a Thermo Scientific Flash components in our laboratory as well as the feasibility of 2000 CHNS analyzer. FTIR-ATR spectra were recorded on a cocrystal formation of the chosen combinations using a virtual Perkin Elmer spectrometer equipped with an attenuated total assessment based on the maximum and minimum critical reflectance (ATR) accessory model MKII Golden Gate with a points from their corresponding MEP surfaces. This enabled us diamond window in the range 4000–500 cm−1. 1H, 13C{1H} to select the combinations of 4-Acpy with 1,3-benzodioxole-5- and DEPT-135 NMR spectra were recorded on a Bruker carboxylic acid (piperonylic acid, HPip), and 2-hydroxypyridine Ascend 300 MHz spectrometer in CD3OD solution at RT. All (2-OHpy) with α-acetamidocinnamic acid (HACA), which led us the chemical shifts (δ) are given in ppm relative to to successfully obtain a pair of cocrystals by means of liquid- tetramethylsilane (Me4Si) as internal standard. Simultaneous assisted grinding (LAG) (Scheme 1). The elucidation of their thermogravimetric/differential thermal analysis (TG/DTA) crystal structures showing the formulas (HPip)(4-Acpy) (1) and determinations were carried out using 69.30 mg (1) and 52.30 (HACA)(Pdon) (2) enabled an exhaustive study of their mg (2), in a Netzsch STA 409 instrument with an aluminium intermolecular interactions and their resulting crystal packings oxide powder (Al2O3) crucible and heating at 5 °C min−1 from supported by Hirshfeld surface analysis and energy frameworks. 25 to 350 °C, under a nitrogen atmosphere with a flow rate of Moreover, a Cambridge Structural Database (CSD)33 survey of 80 mL min−1. Al2O3 (Perkin-Elmer 0419-0197) was used as the selected dPy in cocrystal systems was performed and their standard. preferable synthons and dimensionalities have been compiled. Finally, the structural features of both cocrystals have been correlated with their melting point values. Synthesis of cocrystal 1 Cocrystal 1 was prepared by placing in an agate mortar 200 Experimental section mg (1.20 mmol) of HPip and 268 μL (2.42 mmol) of 4-Acpy and then grinding for about 15 minutes until a homogeneous Materials and general methods powder was obtained. Then, the phase purity of the sample 1,3-Benzodioxole-5-carboxylic acid (piperonylic acid, HPip), was verified by PXRD (ESI,† Fig. S1). Single crystals suitable α-acetamidocinnamic acid (HACA), 4-acetylpyridine (4-Acpy), for X-ray diffraction were obtained by recrystallization of the 2-hydroxypyridine (2-OHpy), and methanol (MeOH) as solvent powder in MeOH and allowing the resulting solution to were purchased from Sigma-Aldrich. Deuterated methanol evaporate at RT for seven days. Scheme 1 Outline of the preparation of cocrystals 1 and 2. This journal is © The Royal Society of Chemistry 2023 CrystEngComm, 2023, 25, 4798–4811 | 4799 View Article Online Paper CrystEngComm 1. Isolated yield: 293 mg (84.6%). M.p. 110–111 °C. 136.0 [HN–CHPdon], 135.5 [HOOC–C–CHHACA], 135.0 [HOOC– Elemental analysis calc (%) for C15H13NO5 (287.27): C 62.71; C–CH–CHACA], 130.9 [o-CHACA], 130.6 [p-CHACA], 129.7 [m- H 4.56; N 4.88; found: C 62.48; H 4.39; N 4.62. FTIR-ATR CHACA], 127.0 [HOOC–CHACA], 120.8 [OC–CHPdon], 108.5 [HN– (wavenumber, cm−1): 3078–3040(w) [ν(C–H)ar+alk], 2993– CH–CHPdon], 22.5 [CH3,HACA]. DEPT-135 NMR (75 MHz, CD3- 2799(w) [ν(C–H)al], 2691–2156(br) [ν(O–H)]HPip, 2135–1757(w) OD; Me4Si; 298 K): δ = 143.7 [OC–CH–CHPdon], 136.0 [HN– [ν(O–H⋯N)], 1693(br) [ν(CO)]4-Acpy + [ν(COOH)]HPip, 1605(w) CHPdon], 135.5 [HOOC–C–CHHACA], 130.8 [o-CHACA], 130.6 [p- [ν(CC/CN)], 1560(w), 1502(w), 1493(w), 1439(m), 1412(m) CHACA], 129.6 [m-CHACA], 120.8 [OC–CHPdon], 108.5 [HN–CH– [δ(CC/CN)], 1364(w), 1286(m), 1257(s), 1232(s), 1213(m), CHPdon], 22.5 [CH3,HACA]. 1165(m) [ν(C–O–C)], 1119(m), 1086(m), 1063(m), 1032(s), This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. 1013(s), 959(w), 930(m), 916(m) [δip(C–H)], 883(m), 845(w), X-ray crystallographic data Open Access Article. Published on 04 August 2023. Downloaded on 8/30/2023 9:15:18 AM. 822(s), 768(s) [δoop(C–H)], 748(w), 719(w), 667(w), 658(w), 588(s), 532(m). 1H NMR (300 MHz, CD3OD; Me4Si; 298 K): δ = Yellowish prism-like (1) and colorless needle-like (2) 9.99 [2H, d, 3J = 5.9 Hz, o-H4-Acpy], 9.08 [2H, dd, 3J = 4.5 Hz, 4J specimens were used for the X-ray crystallographic analysis. = 1.7 Hz, m-H4-Acpy], 8.86 [1H, dd, 3J = 8.2 Hz, 4J = 1.7 Hz, The X-ray intensity data were measured on a D8 Venture HOOC–C–CH–CHHPip], 8.63 [1H, d, 4J = 1.7 Hz, HOOC–C–CH– system equipped with a multilayer monochromator (λ = COHPip], 8.12 [1H, d, 3J = 8.2 Hz, HOOC–C–CH–CHHPip], 5.71 0.71073 Å). For both compounds, the frames were integrated [2H, s, O–CH2–OHPip], 3.86 [3H, s, CH3,4-Acpy]. 13C{1H} NMR using the Bruker SAINT software package (version-2018/3). (75 MHz, CD3OD; Me4Si; 298 K): δ = 198.8 [CO4-Acpy], 168.4 The integration of the data with 0.70 Å (1) and 0.73 Å (2) [COOHHPip], 152.9 [HOOC–C–CH–CH–CHPip], 151.5 [o-C4-Acpy], resolution, of which 3980 (1) and 3952 (2) reflections were 149.0 [HOOC–C–CH–CHPip], 144.6 [H3C–CO–C4-Acpy], 128.8 independent, gave an average redundancy of 8.677 (1) and [HOOC–CHPip], 126.4 [HOOC–C–CH–CHHPip], 122.8 [m-C4-Acpy], 9.327 (2), completeness of 99.8% (1) and 99.7% (2), Rsig of 110.2 [HOOC–C–CH–COHPip], 108.9 [HOOC–C–CH–CHHPip], 1.85% (1) and 3.35% (2), presenting 3380 (84.92%) (1) and 103.2 [O–CH2–OHPip], 26.9 [CH3,4-Acpy]. DEPT-135 NMR (75 3010 (76.16%) (2) reflections greater than 2σ(|F|2). MHz, CD3OD; Me4Si; 298 K): δ = 151.5 [o-C4-Acpy], 126.4 For 1 and 2, the final cell constants and volumes are [HOOC–C–CH–CHHPip], 122.9 [m-C4-Acpy], 110.2 [HOOC–C– based upon refinement of the XYZ-centroids of reflections CH–COHPip], 108.9 [HOOC–C–CH–CHHPip], 103.2 [O–CH2– above 20σ(I). Data were corrected for absorption effects using OHPip], 26.9 [CH3,4-Acpy]. the Multi-Scan method (SADABS). Crystal data and additional details of structure refinement for 1 and 2 are reported in Table 1. Complete information about the crystal structure Synthesis of cocrystal 2 and molecular geometry is available in CIF format via CCDC Cocrystal 2 was prepared using the same methodology as for 2267801 (1), and 2267802 (2). Molecular graphics were the synthesis of 1 with 200 mg (0.975 mmol) of HACA, 92.7 generated using Mercury 4.3.1 software34 with the POV-Ray mg (0.975 mmol) of 2-OHpy, and 100 μL of MeOH. The phase image package.35 The color codes for all the molecular purity of the sample was verified by PXRD (ESI† Fig. S2). graphics are as follows: red (O), light blue (N), gray (C), and Single crystals suitable for X-ray diffraction were obtained by white (H). The topological analysis was done using the recrystallization of the powder in MeOH and allowing the ToposPro 5.3.3.4 program.36 resulting solution to evaporate at RT for five days. 2. Isolated yield: 278 mg (95.1%). M.p. 156–157 °C. Elemental analysis calc (%) for C16H16N2O4 (300.31): C 63.99; Computational details H 5.37; N 9.33; found: C 63.74; H 5.18; N 9.12. FTIR-ATR The virtual screening method proposed by Hunter et al.37,38 (wavenumber, cm−1): 3263(m) [ν(N–H)]HACA, 3167–2604(br) was used to evaluate if the combinations of the available [ν(N–H)]Pdon + [ν(C–H)ar+alk+al], 2556–2075(br) [ν(O–H)]HACA, carboxylic acids and the selected dPy are likely to overcome 2029–1746(br) [ν(O–H⋯O)], 1703(w) [ν(CO)]Pdon, 1636(br) the energy of the packings of the single components. The [ν(COOH)]HACA + [ν(CO)]HACA, 1609(s) [ν(CC/CN)], carboxylic acids used for the virtual screening were 1518(m), 1492(w), 1475(w), 1424(m) [δ(CC/CN)], 1368(m), 1,3-benzodioxole-5-carboxylic acid (piperonylic acid, HPip), 1333(w), 1319(w), 1309(w), 1286(w), 1265(m), 1237(s), 1215(s), α-acetamidocinnamic acid (HACA), trans-cinnamic acid 1156(m), 1138(m), 1072(w), 1038(w), 1021(w), 991(m), 985(m), (HCinn), and 2-furoic acid (2-FA), which were available in our 917(m) [δip(C–H)], 889(w), 863(w), 851(w), 791(s) [δoop(C–H)], laboratory. This methodology utilized the local maxima and 761(m), 735(w), 712(w), 683(s), 619(w), 606(m), 577(s), 550(w), minima of the molecular electrostatic potential (MEP) 521(s), 511(s). 1H NMR (300 MHz, CD3OD; Me4Si; 298 K): δ = surfaces of the initial components of the cocrystals to identify 7.58 [3H, m, OC–CH–CHPdon + o-HHACA], 7.48 [1H, s, HOOC– surface site interaction points (SSIPs), which are used to C–CHHACA], 7.39 [4H, m, HN–CHPdon + m-HHACA + p-HHACA], extract the corresponding hydrogen bond donor and acceptor 6.54 [1H, m, HN–CH–CHPdon], 6.41 [1H, td, 3J = 6.6 Hz, 4J = interaction site parameter (α and β) values.37 These 1.1 Hz, OC–CHPdon], 2.10 [3H, s, CH3,HACA]. 13C{1H} NMR (75 parameters were used to calculate the interaction site pairing MHz, CD3OD; Me4Si; 298 K): δ = 173.2 [HN–COHACA], 168.2 energies (E) from eqn (1), which were used to obtain ΔE [COOHHACA], 165.8 [HN–COPdon], 143.8 [OC–CH–CHPdon], values from eqn (2), 4800 | CrystEngComm, 2023, 25, 4798–4811 This journal is © The Royal Society of Chemistry 2023 View Article Online CrystEngComm Paper Table 1 Crystal data and structure refinement for 1 and 2 Studio.39,40 Then, geometry optimizations were done using 1 2 density functional theory (DFT) with the B3LYP/6-31G(+) theory level with Gaussian09 software version D.01.41 Since it Empirical formula C15H13NO5 C16H16N2O4 has been shown that different conformations of the same Formula weight 287.26 300.31 T (K) 100(2) 100(2) components do not change significantly the α and β values Wavelength (Å) 0.71073 0.71073 unless intramolecular interactions are possible to occur,42 System, space group Triclinic, P1̄ Monoclinic, P21/c only the most stable conformation in the gas phase has been Unit cell dimensions a (Å) 7.4176(5) 17.3245(7) considered for each component. The local minima and maxima from the MEP surfaces were extracted using This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. b (Å) 7.5344(5) 4.8311(2) c (Å) 13.4049(9) 18.3867(8) Multiwfn software,43 while their visualization and rendering α (°) Open Access Article. Published on 04 August 2023. Downloaded on 8/30/2023 9:15:18 AM. 94.585(2) 90 were done in the VMD program.44 β (°) 101.837(2) 107.778(2) γ (°) 115.880(2) 90 Hirshfeld surface analysis and energy frameworks of 1 and 2 V (Å3) 647.36(8) 1465.41(11) have been performed with CrystalExplorer 17.5.45 The Hirshfeld Z 2 4 surfaces of each component of the cocrystals have been Dcalc (g cm−3) 1.474 1.361 calculated independently using an isovalue of 0.5 e au−3. μ (mm−1) 0.112 0.099 F (000) 300 632 Moreover, both cocrystals have been analyzed with energy Crystal size (mm) 0.362 × 0.158 × 0.078 0.180 × 0.060 × frameworks with TONTO,46 using a scale factor of 150, and the 0.040 CE-B3LYP/6-31G(d,p) energy model, starting from the .cif files hkl ranges −10 ≤ h ≤ 10, −23 ≤ h ≤ 23, obtained from the single-crystal X-ray diffraction data. Each of −10 ≤ k ≤ 10, −6 ≤ k ≤ 6, −19 ≤ l ≤ 19 −25 ≤ l ≤ 25 the molecules of the cocrystals has been confined in a cluster of θ range (°) 3.062 to 30.571 2.277 to 29.154 20 Å in the unit cell, including those that are Reflections 34 534/3980/0.0319 36 859/3952/0.0664 crystallographically independent. The contribution of all the collected/unique/[Rint] molecular pairs around the selected cluster has been considered Completeness to θ (%) 99.9 99.7 Absorption correction Semi-empirical Semi-empirical following a previously reported methodology.44 In addition, the from equivalents from equivalents calculation of the total energy for each interaction has been Max. and min. 0.7461 and 0.7246 0.7458 and 0.6929 done using eqn (3),47,48 while the obtention of the lattice energy transmission Refinement method Full-matrix Full-matrix least- (Elatt) has been done with eqn (4).49 least-squares on |F|2 squares on |F|2 Data/restrains/parameters 3980/0/191 3952/0/202 Etot ¼ Eele þ Epol þ Edis þ Erep Goodness of fit on F 2 1.045 1.058 ¼ 1:057E′ele þ 0:740E′pol þ 0:871E′dis þ 0:618E′rep (3) Final R indices [I > 2σ(I)] R1 = 0.0392 R1 = 0.0412 wR2 = 0.1092 wR2 = 0.0896 R indices (all data) R1 = 0.0484 R1 = 0.0646 1X n Elatt ¼ ðN i × Ei Þ (4) wR2 = 0.1154 wR2 = 0.1035 2 i¼1 Extinction coefficient n/a n/a Largest diff. peak and 0.492 and −0.278 0.295 and −0.247 hole (e Å−3) Results and discussion Synthesis of cocrystals 1 and 2 X E¼ − α i βj (1) Before starting the experimental trials with the selected dPy, ij we performed a virtual screening considering the carboxylic acids available in our laboratory to determine the ΔE = ECC − nE1 − mE2 (2) probabilities of success. From the ΔE extracted using the potential combinations, it is shown that the formation of where E1, E2, and ECC are the interaction site pairing energies cocrystals with 4-Acpy is generally more favorable than the of the initial components and the cocrystal, and n and m formation of cocrystals with Pdon, which should be stand for the proportion of initial components, which has attributed to the stronger crystal packing of Pdon with been considered as 1 : 1 for all the combinations owing to the respect to 4-Acpy (Table 2). In addition, combinations with use of monopyridines and monocarboxylic acids which only similar ΔE values to those proposed by us have been allow the formation of a single main synthon. ΔE < 0 successfully found experimentally.38,50 The screening using indicates the feasibility of cocrystal formation, while ΔE > 0 4-Acpy showed the HPip : 4-Acpy combination as the more suggests that the formation of the cocrystal is unlikely to favorable, and thus it was selected for the experimental trials occur. Noteworthily, Pdon has been considered as the initial obtaining cocrystal 1. Otherwise, all the combinations using component for the formation of cocrystal 2 owing to its Pdon displayed similar ΔE values, and therefore we envisage strong preference over 2-OHpy in the solid state as stated in the potential feasibility to successfully achieve all of them. the Introduction section.32 All the structures were energy- However, we have focused the study on the combination of minimized using the COMPASS II force field in Materials HACA : Pdon, leading to cocrystal 2. This journal is © The Royal Society of Chemistry 2023 CrystEngComm, 2023, 25, 4798–4811 | 4801 View Article Online Paper CrystEngComm Table 2 Calculated energies and energetic differences in interaction site grinding (LAG), improves significantly the kinetics of the pairing energies (kJ mol−1) of the screened components and their reactions, allowing a better molecular diffusion, while potential cocrystal outcome considering a 1 : 1 molar ratio keeping the high yields commonly achieved through Component mechanochemical methods.53 Hence, we selected this combinations E (acid) E (dPy) E (cocrystal) ΔE methodology for the preparation of both cocrystals. Cocrystal HPip + 4-Acpy −24.5 −12.7 −40.4 −3.2 1 was afforded using a 1 : 2 (HPip : 4-Acpy) molar ratio, where 2-FA + 4-Acpy −23.2 −37.8 −1.9 the excess of 4-Acpy served as the medium for the LAG HCinn + 4-Acpy −21.4 −35.0 −0.9 synthesis. Instead, for cocrystal 2 a small amount of MeOH HACA + 4-Acpy −39.0 −52.0 −0.3 promoting a more displaced shifting towards Pdon formation This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. HPip + Pdon −24.5 −24.6 −50.1 −1.0 2-FA + Pdon −23.1 −48.7 −1.0 was employed (Scheme 2),54 using a 1 : 1 (HACA : 2-OHpy) Open Access Article. Published on 04 August 2023. Downloaded on 8/30/2023 9:15:18 AM. HACA + Pdon −39.0 −64.1 −0.5 molar ratio. HCinn + Pdon −21.4 −46.5 −0.5 Characterization of cocrystals 1 and 2 51,52 According to Etter's rule, it is expected that for the Cocrystals 1 and 2 were characterized by powder X-ray HPip : 4-Acpy combination, the acid⋯pyridine heterosynthon diffraction (PXRD), elemental analysis (EA), FTIR-ATR, 1H, 13 stands out as its main synthon (Fig. 1a). In addition, for C{1H}, and DEPT-135 NMR spectroscopies, and single HACA : Pdon, the carboxylic and amide moieties presented crystal X-ray diffraction. The phase purity of the ground similar α values (Fig. 1b), which should compete or cooperate samples was verified by PXRD (ESI† Fig. S1 and S2). The EA towards H-bond formation with the carbonyl moiety from agrees with the proposed formulas. The FTIR-ATR spectra of Pdon, which presents the highest β value. both cocrystals displayed broad bands attributable to ν(O–H) Neat grinding has been established as an efficient and of the carboxylic acids in the 2691–2156 cm−1 (1) and 2556– greener approach to obtain cocrystals compared with 2075 cm−1 (2) regions. These bands are shifted to lower conventional solution methods. However, it has been wavenumbers compared with the free carboxylic acids due to demonstrated that the addition of small quantities of solvent the formation of the acid⋯pyridine heterosynthons (Fig. 2). during the grinding process, referred to as liquid-assisted Additional broad bands at 2135–1757 cm−1 (1) and 2029–1746 Fig. 1 MEP representations for the components of cocrystals (a) 1 and (b) 2 with their corresponding α (red) and β (blue) values. 4802 | CrystEngComm, 2023, 25, 4798–4811 This journal is © The Royal Society of Chemistry 2023 View Article Online CrystEngComm Paper carbon assignations are provided in the Experimental section and the ESI† (Fig. S5 and S8). Crystal and extended structure of cocrystal 1 Cocrystal 1 belongs to the triclinic P1̄ space group. It consists of Scheme 2 Tautomeric equilibrium between 2-OHpy and Pdon in the a binary cocrystal formed by one HPip and one 4-Acpy presence of MeOH. molecules held together by an acid⋯pyridine heterosynthon (O(1)–H(1O)⋯N(1)) (Fig. 3a), in line with the MEP surface prediction. This synthon represents 3.9% of the HPip and 6.5% This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. cm−1 (2) have also been assigned to the ν(O–H⋯N/O) of the 4-Acpy area in their 2D fingerprint plots with distances Open Access Article. Published on 04 August 2023. Downloaded on 8/30/2023 9:15:18 AM. vibrations of the acid⋯pyridine (1) and acid⋯amide (2) notably shorter compared with the rest of the interactions heterosynthons, while the ν(CO) (1693 cm−1 (1); 1703 cm−1 (Table 3), standing out as the main interaction of the basic (2)), and ν(COOH) (1693 cm−1 (1); 1636 cm−1 (2)) vibrations structural motif (BSM) (ESI† Fig. S9 and S10),56 which is also have also been identified. In addition, the spectrum of shown in its Hirshfeld surfaces as well as its associated cocrystal 2 also presents two additional bands in the upper interaction energy (Table 3). In addition, the presence of the region, displaying a sharp signal at 3263 cm−1 and another C(4)–H(4)⋯O(2) association completes the construction of a broad band between 3167 and 2604 cm−1, which are assigned supramolecular ring with R44(20) as the graph-set descriptor to ν(N–H) from HACA and Pdon, respectively. Accordingly, (Table 3 and Fig. 3a). Then, the C(11)–H(11)⋯O(4), C(12)–H(12) these bands suggest that for cocrystal 2 various synthons are ⋯O(5) and C(6)–H(6A)⋯O(5) interactions lead to the formation responsible for the assembly of the cocrystal, showing the of a R23(8) ring, while the latter interaction is also involved in the strongest strength for the interactions involving the H donors formation of a R22(7) ring conjointly with the C(16)–H(16A) in the order NHHACA > NHPdon > COOHHACA, respectively ⋯O(3) association (Fig. 3b). The 2D expansion along the (44̄0) (Fig. 2).19,55 The complete assignation is provided in the plane is completed by a R33(16) motif formed by the C(11)–H(11) Experimental section and the ESI† (Fig. S3 and S4). ⋯O(4), C(16)–H(16A)⋯O(3) and C(4)–H(4)⋯O(2) interactions The 1H, 13C{1H} and DEPT-135 NMR spectra of cocrystals (Fig. 3b). These associations define two orthogonal layers 1 and 2 have been recorded in CD3OD solution. The spectra connected by C–H⋯π interactions between a methyl H atom show the signals attributable to the corresponding ligands from 4-Acpy and a HPip ring (C(16)–H(16C)⋯Cg(1)), assembling with an acid : dPy ratio of 1 : 1 for both compounds (ESI† Fig. a 2D bilayer with 56.22° of slippage. Furthermore, reciprocal C– S5 and S6). Furthermore, the 13C{1H} NMR spectra present all H⋯O associations between a dioxole H atom and the carbonyl the bands of the corresponding ligands (ESI† Fig. S7 and S8). oxygen atoms from HPip (C(6)–H(6B)⋯O(2)) supported the Both 1H and 13C{1H} spectra of cocrystal 2 do not show bilayer formation, shaping an R22(17) ring (Fig. 3b). Finally, the signals corresponding to 2-OHPy, which combined with the bilayers interact between them by weak π⋯π forces between presence of three signals in the carbonyl region of its 13C{1H} 4-Acpy ligands, forming a 3D network presenting a {39·422·55} NMR spectrum (173.2–165.8 ppm) suggest the full conversion point symbol corresponding to a nci underlying topology of 2-OHpy to Pdon. Further details about the proton and (Fig. 3c). Detailed information on the intermolecular Fig. 2 Comparative FTIR-ATR spectra of the former components and the resulting cocrystal in (a) 1 and (b) 2. This journal is © The Royal Society of Chemistry 2023 CrystEngComm, 2023, 25, 4798–4811 | 4803 View Article Online Paper CrystEngComm This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Open Access Article. Published on 04 August 2023. Downloaded on 8/30/2023 9:15:18 AM. Fig. 3 (a) General view of the 2D layers along the (44̄0) plane in 1. (b) View of the 3D expansion of cocrystal 1 by weak interactions highlighted in green. (c) Schematic representation of the topology of cocrystal 1. Table 3 Selected intermolecular interactions for cocrystal 1 Associated energy Number D–H⋯A (Å) D–H (Å) H⋯A (Å) D⋯A (Å) >D–H⋯A (°) (kJ mol−1) of interactionsa O(1)–H(1O) ⋯N(1) 0.84 1.78 2.622(1) 174 −46.2 1 C(4)–H(4)⋯O(2) 0.95 2.38 3.324(1) 173 −9.1 1 C(11)–H(11)⋯O(4) 0.95 2.48 3.393(1) 162 −11.7 1 C(12)–H(12)⋯O(5) 0.95 2.58 3.521(1) 171 −7.8 1 C(16)–H(16A)⋯O(3) 0.98 2.51 3.449(1) 160 −13.8 1 C(6)–H(6A)⋯O(5) 0.99 2.61 3.409(1) 138 C(6)–H(6B)⋯O(2) 0.99 2.54 3.380(1) 143 −28.6 2 Associated energy Number X–H⋯Cg(J) H⋯Cg(J) (Å) H-Perpb (Å) γc (°) X⋯Cg(J) (Å) X–H, Pid (°) (kJ mol−1) of interactionsa C(16)–H(16C)⋯Cg(1) 2.77 2.76 4.80 3.5418(13) 50 −29.4 1 Cg(I)⋯Cg(J) dCg⋯Cge (Å) α f (°) β, γg (°) dplane⋯planeh (Å) doffseti (Å) Associated energy (kJ mol−1) Number of interactionsa Cg(2)⋯Cg(2) 3.9732(7) 0.00(5) 30.0 3.4423(5) 1.984 −11.1 1 a Number of interactions encompassed in each associated total energy. b Perpendicular distance of H to ring plane J. c Angle between Cg(J)–H vector and ring J normal. d Angle of the X–H bond with the Pi plane (Pi stands for plane of the aromatic ring; perpendicular = 90°, parallel = 0°). e Cg⋯Cg = distance between ring centroids. f α = dihedral angle between planes I and J. g Offset angles: β = angle Cg(I)–Cg(J) and normal to plane I and γ = angle Cg(I)–Cg(J) and normal to plane J (β = γ, when α = 0°). h Perpendicular distance of Cg(I) on plane J and perpendicular distance of Cg(J) on plane I (equal when α = 0°). i Slippage = horizontal displacement between Cg(I) and Cg(J) (equal for both centroids when α = 0°). Cg(1) = C(2) C(3) C(4) C(5) C(7) C(8); Cg(2) = N(1) C(10) C(11) C(12) C(14) C(15). interactions and their associated interaction energies is triacids (1 hit),69 all of them presenting similar bond lengths provided in Table 3. The complete topological analysis is and angles of their H-bonds compared with cocrystal 1. supplied in the ESI† (Fig. S13). Analysis of the dimensionality of these structures showed 3 A search in the CSD33 of multicomponent solids hits with layered arrangements connected by weak containing 4-Acpy revealed a total of 5 salts57–61 and 10 interactions leading to 3D nets,67–69 while the remaining 3 cocrystals.62–69 Details about the components forming the hits consisted of different types of 3D networks,70,71 probably cocrystals as well as their dimensionalities are provided in attributed to the presence of bidirectional H-donor groups the ESI† (Table S1). Within the 10 cocrystal structures, their (e.g. amine groups) able to tilt neighboring molecules BSMs were held together by alcohol⋯pyridine (2 hits),62,63 towards the formation of recurrent synthons such as the halogen⋯pyridine (2 hits),64 and acid⋯pyridine (6 hits) amine⋯acid or the amine⋯amine. Thomas et al. found that heterosynthons.65–69 Focusing on the latter type of cocrystals, in the 4-Acpy : 3-fluorobenzoic acid system, the ability to form they contained monoacids (4 hits),65–67 diacids (1 hit),68 and layered arrays was ascribed to the orientation of the acetyl 4804 | CrystEngComm, 2023, 25, 4798–4811 This journal is © The Royal Society of Chemistry 2023 View Article Online CrystEngComm Paper moiety, showing that small changes completely altered their C(6)–H(6)⋯O(3) association extends the array along the [100] resulting crystal packings.67 Thus, it is important to highlight direction, forming a 3D net with {36·410·511·6} as point symbol the need to incorporate an additional H-acceptor group in (Fig. 4b and c).72 Remarkably, the associated interaction the acid⋯4-Acpy-based cocrystals that orients the molecules energies of the three recurrent synthons driving the packing of in a planar fashion by a recurrent synthon or by a medium/ 2 (Pdon⋯Pdon, acid⋯amide and amide⋯amide) are in line weak interaction unable to tilt the molecules out of the with the order of strengths suggested by its FTIR-ATR spectrum. plane. Detailed information on the intermolecular interactions and In cocrystal 1, the presence of the dioxole group of HPip their associated interaction energies is provided in Table 4. The provides a donor (H6A) and an acceptor (O3) atom that complete topological analysis is supplied in the ESI† (Fig. S14). This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. interact with the nearby 4-Acpy, ordering the molecules in a A search in the CSD33 of cocrystals containing Pdon/2-OHpy Open Access Article. Published on 04 August 2023. Downloaded on 8/30/2023 9:15:18 AM. proper HPip⋯4-Acpy⋯HPip pattern towards the layered molecules showed 73 hits, whose main information is arrangement (Fig. 3a). These interactions leave only one H summarized in Fig. 5 and detailed in the ESI† (Table S2). It was atom from the dioxole unit (H6B) to connect two adjacent observed that the Pdon form promotes the formation of layers that are oppositely aligned in a way that both dispose cocrystals (65 hits), while the 2-OHpy form resulted in molecular their free H atom towards the formation of a slipped bilayer salts (8 hits). Within the cocrystal arrangements, the through the formation of an R22(17) ring (Fig. 3b), bringing Pdon⋯Pdon homosynthon stands out as the most abundant this combination of acid⋯pyridine synthons and weak primary synthon, appearing in 81.54% of the hits, while in the interactions of 1 as an adequate example for the formation of rest of the dispositions it is disrupted by heterosynthons layered arrangements. involving carboxylic acids (10.77%), or even combinations of various sulfonamides (3.08%), amides (1.54%), alcohols and pyridines (1.54%), or amides and thiadiazoles (1.54%) Crystal and extended structure of cocrystal 2 (Fig. 5a and c). In addition, the disposition of the carbonyl Cocrystal 2 belongs to the monoclinic P21/c space group. It group in the Pdon⋯Pdon motif allows the presence of a consists of a binary cocrystal formed by two HACA and two secondary synthon able to stabilize a tetrameric array through Pdon molecules. The BSM of the cocrystal is held together by an carboxylic acids (43.40%), alcohols (30.19%), halogens (13.21%), R22(8) ring between Pdon molecules forming a reciprocal amines (5.66%), amides (3.77%), or sulfonamides (3.77%) amide⋯amide homosynthon (N(2)–H(2)⋯O(4)), being the (Fig. 5b and d). This supramolecular motif brings the potential strongest contribution, as the Hirshfeld surface of Pdon and its possibility to form ternary cocrystals where different associated interaction energy indicate (Table 4 and Fig. S11 and components could be located forming asymmetric secondary S12, ESI†). Moreover, this motif is supported by two H-bonds synthons with Pdon. However, to the best of our knowledge they between two carboxylic acid moieties with two carbonyl groups have not been found so far, and thus, only the 1 : 1 proportion from Pdon (O(1)–H(1)⋯O(4)), forming two acid⋯amide is expected in this type of cocrystal arrays. The overall packing heterosynthons, which combined with two C–H⋯O interactions considering the synthons resulted in 0D tetramers (7 hits), 1D between the carboxylate oxygen atoms and a H atom from Pdon chains (12 hits), 2D layers (2 hits) and 3D nets (2 hits), whose (C(16)–H(16)⋯O(2)) lead to a robustly connected tetrameric scaffolds are extended by weak interactions (i.e. C–H⋯O, C– array (Fig. 4a). This arrangement is in line with the observed α H⋯π, and π⋯π interactions) leading to 1D chains (5 hits), 2D and β values of the MEP predictions, which also follows Etter's layers (8 hits), and 3D nets (10 hits) (Fig. 5e and Table S2, ESI†). rule.51,52 The tetramers are ordered along the [001] direction in Among them, the family of aliphatic diacids has been a crossed fashion with a torsion angle of 84.60° between BSMs extensively studied showing 13 of the hits, leading to tetrameric owing to the C(14)–H(14)⋯O(3) interaction (Fig. 4a). Finally, the arrays forming 1D chains assisted by primary Pdon⋯Pdon and amide⋯amide homosynthons between HACA molecules (N(1)– secondary Pdon⋯acid synthons in most of the examples,73–78 H(1N)⋯O(3)), supported by the C(11)–H(11A)⋯O(3) interactions while in a few cases there is a competition between the propagate the structure along the [010] direction, while the Pdon⋯Pdon and the acid⋯acid interactions as primary Table 4 Selected intermolecular interactions for cocrystal 2a Associated energy Number D–H⋯A (Å) D–H (Å) H⋯A (Å) D⋯A (Å) >D–H⋯A (°) (kJ mol−1) of interactionsa N(2)–H(2)⋯O(4) 0.88 1.88 2.754(1) 175 −91.6 2 O(1)–H(1)⋯O(4) 0.920(19) 1.657(19) 2.561(1) 166.7(13) −44.7 1 C(16)–H(16)⋯O(2) 0.95 2.49 3.344(2) 150 −12.1 1 C(14)–H(14)⋯O(3) 0.95 2.60 3.445(1) 148 −22.6 1 N(1)–H(1 N)⋯O(3) 0.88 2.00 2.866(1) 169 −53.6 1 C(11)–H(11A)⋯O(3) 0.98 2.55 3.412(2) 147 C(6)–H(6)⋯O(3) 0.95 2.82 3.592(2) 139 −30.5 2 a Number of interactions encompassed in each associated total energy. This journal is © The Royal Society of Chemistry 2023 CrystEngComm, 2023, 25, 4798–4811 | 4805 View Article Online Paper CrystEngComm This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Open Access Article. Published on 04 August 2023. Downloaded on 8/30/2023 9:15:18 AM. Fig. 4 Propagation of the BSMs of cocrystal 2 along the (a) [001] direction and (b) (110) plane. (c) Schematic representation of the topology of cocrystal 2. synthons.78 Remarkably, the obtention of 2D/3D arrangements with the pyridine component followed by carboxylic acid. using recurrent synthons has been achieved only with Otherwise, for cocrystal 2 the melting point appeared at a sulfonamides,79,80 alcohols,74 or cocrystallized water higher temperature, displaying a Tonset = 152.1 °C and a 73 molecules. Nevertheless, these examples evinced the low Tpeak = 157.4 °C, followed again by the continuous loss of reliability of these groups, which presented different behaviors mass of all its components and its further decomposition at within the same crystal structure. However, in cocrystal 2 the 303.2 °C (Fig. 6b). Likewise, the DTA curve revealed a different orientations of the acid and amide from HACA change around 210.0 °C, which could be associated with the moieties combined with the synthon reliability between the mass of Pdon (exp. 33.8%; calc. 31.7%) and could indicate amide moieties of Pdon lead to the formation of strongly that the loss of mass followed the same trend as in 1. In arranged 2D layers, being the first example of this kind of addition, the values obtained using the melting point disposition through consistent supramolecular synthons, which apparatus (110–111 °C, 1; 156–157 °C, 2) were in line with defines this combination of carboxylic acid and amide moieties those observed in the thermograms and lie in between the with this specific disposition as a promising system to be melting point values of their former molecules, as obtained further applied to the design of cocrystals of higher complexity. in most of the reported examples.81 However, the formation of cocrystal 1 represents an interesting example of how a liquid (4-Acpy) can be stabilized in the solid state using the Thermal properties of cocrystals 1 and 2 cocrystal approach, which is pursued in terms of stability The thermal behavior of cocrystals 1 and 2 was studied by and processability.12,15 TG-DTA. For both cocrystals a single endothermic event is observed involving melt degradation of the products. The melting point peak of cocrystal 1 presents a Tonset = 95.7 °C Structure–property relationship in cocrystals 1 and 2 and a Tpeak = 104.0 °C followed by the continuous loss of The relationship between the crystal packing of cocrystals 1 mass of all its components and its further decomposition at and 2 and their melting points was investigated using energy 297.9 °C (Fig. 6a). However, the DTA curve showed a change framework calculations.82 To this aim, the different in the thermal events around 215.0 °C, which approximately contribution energies for both cocrystals were analyzed, fits with the mass of 4-Acpy (exp. 43.0%; calc. 42.2%) and observing a higher influence of the electrostatic factors rather could indicate that the loss of mass in cocrystal 1 started than the dispersion effects (ESI† Fig. S15). Detailed values of 4806 | CrystEngComm, 2023, 25, 4798–4811 This journal is © The Royal Society of Chemistry 2023 View Article Online CrystEngComm Paper This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Open Access Article. Published on 04 August 2023. Downloaded on 8/30/2023 9:15:18 AM. Fig. 5 (a) Types of primary supramolecular synthons involving Pdon. (b) Types of complementary groups involved in the secondary Pdon synthons. Outline of the results of the CSD study regarding (c) types of primary Pdon synthons, (d) complementary groups involved in the secondary Pdon synthons, and (e) dimensionality considering recurrent synthons. the contribution of each energetic type are provided in the acid⋯pyridine heterosynthon was highlighted as the unique ESI† (Table S3). electrostatic component above the cut-off energy, forming To select the more representative interactions between discrete BSM entities (Fig. 7c). Remarkably, the dispersion each molecular pair, the associated total energy of the energy represented in Fig. 7d stands out as the main interactions between each cocrystal molecule have been contributor for the connection of the BSMs mainly through plotted with respect to the radius around a central cocrystal the interactions responsible for the bilayer formation (C(6)– molecule, showing that the main interactions that held H(6B)⋯O(2)) and (C(16)–H(16C)⋯Cg(1)), leading to 2D layers together the crystal packing of 1 and 2 present associated (Fig. 7e). In addition, for cocrystal 2 a strong binding of its interaction energies below −20 kJ mol−1 (Fig. 7a and b). Thus, BSM through the Pdon⋯Pdon and Pdon⋯acid synthons and a cut-off energy of −20 kJ mol−1 was used for the energy the interactions responsible for the expansion along the [010] framework representations of Fig. 7c–h. For cocrystal 1, the direction (N(1)–H(1N)⋯O(3) + C(11)–H(11A)⋯O(3)) are the This journal is © The Royal Society of Chemistry 2023 CrystEngComm, 2023, 25, 4798–4811 | 4807 View Article Online Paper CrystEngComm This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Open Access Article. Published on 04 August 2023. Downloaded on 8/30/2023 9:15:18 AM. Fig. 6 TG/DTA of cocrystal (a) 1 and (b) 2 between 25 °C and 350 °C. The regions marked in green are suggested as the areas where the first change after the melting point event is observed in the DTA curves, which potentially fit with the loss of mass of the corresponding dPy of cocrystals 1 and 2. Fig. 7 Relationship between the molecular pair radius and the associated interaction energies in (a) cocrystal 1 and (b) cocrystal 2. Energy frameworks (Eele, Edis, Etot) for cocrystals (c–e) 1 and (f–h) 2. All the diagrams use the same energy cylinder scale factor of 150 and an energy cut- off of −20 kJ mol−1 within a 2 × 2 × 2 (1) and a 1 × 2 × 2 (2) unit cell. Table 5 Structural parameters and melting point values of cocrystals 1 and 2 Cocrystal Melting point (°C) Crystal density (g cm−3) Elatt (kJ mol−1) 1 104.0 1.474 −211.0 2 157.4 1.361 −274.2 more representative electrostatic contributions (Fig. 7f), while From these data, it is inferred that the 2D layers the dispersion forces do not play a key role such as in 1 assembled by weakly dispersive forces of 1 resulted in a lower (Fig. 7g), leading to 3D nets (Fig. 7h). melting point than the 3D nets connected by strong 4808 | CrystEngComm, 2023, 25, 4798–4811 This journal is © The Royal Society of Chemistry 2023 View Article Online CrystEngComm Paper electrostatic interactions of 2, showing a difference of 53.4 Writing—review and editing, J. P. Visualization, D. E. °C. This is also supported by their corresponding lattice Supervision, J. P. Project administration, J. P. Funding energies, with the packing of 2 being significantly more acquisition, J. P. All authors have read and agreed to the stable than that of 1, which also correlates with their crystal published version of the manuscript. densities (Table 5).83,84 Therefore, the extrapolation of these combinations of interactions to other systems bearing Conflicts of interest relevant molecules could be a useful way to modulate the melting points of either liquid or solid components. There are no conflicts to declare. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. Acknowledgements Conclusions Open Access Article. Published on 04 August 2023. Downloaded on 8/30/2023 9:15:18 AM. J. P. acknowledges financial support from the CB615921 Two binary cocrystals have been successfully predicted using project, the CB616406 project from “Fundació La Caixa”, and the critical points from the MEP surfaces of the initial the 2021SGR00262 project from the Generalitat de Catalunya. components and then prepared by LAG and fully characterized. D. E. acknowledges the PIF pre-doctoral fellowship from the Their compositions include a liquid (4-Acpy) and a solid (Pdon) Universitat Autònoma de Barcelona. dPy combined with two different carboxylic acids (HPip and HACA, respectively). The elucidation of their crystal structures References revealed that their BSMs are constructed from the acid⋯pyridine heterosynthon (1) and the Pdon⋯Pdon 1 N. K. Duggirala, M. L. Perry, Ö. Almarsson and M. J. homosynthon supported by secondary Pdon⋯acid synthons (2), Zaworotko, Chem. Commun., 2016, 52, 640–655. leading to a dimeric (1) and a tetrameric (2) BSMs. The study of 2 M. A. E. Yousef and V. R. 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Rev., 2022, 122, their structures using energy frameworks, observing 2D layers 11514–11603. based on dispersive interactions where the BSMs are connected 11 Ö. Almarsson, M. L. Peterson and M. Zaworotko, Pharm. Pat. by the acid⋯pyridine heterosynthon for 1, and a 3D net Anal., 2012, 1, 313–327. connected by stronger electrostatic interactions for 2, which 12 C. B. Aakeröy, T. K. Wijethunga, J. Benton and J. Desper, results in a remarkably higher melting point of 2 (157.4 °C) Chem. Commun., 2015, 51, 2425–2428. compared with 1 (104.0 °C). This work provides new examples 13 D. Capucci, D. Balestri, P. P. Mazzeo, P. Pelagatti, K. of binary cocrystals and correlates the structural features with Rubini and A. Bacchi, Cryst. Growth Des., 2017, 17, their thermal stability as well as collects some tendencies 4958–4964. regarding the preferred behavior of 4-Acpy and Pdon in the 14 P. P. Mazzeo, C. Carraro, A. Monica, D. Capucci, P. 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