Organic Salts of P-Coumaric Acid and Trans-Ferulic Acid with Aminopicolines

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Article Organic Salts of p-Coumaric Acid and Trans-Ferulic Acid with Aminopicolines

Sosthene Nyomba Kamanda and Ayesha Jacobs * Chemistry Department, Faculty of Applied Sciences, Cape Peninsula University of Technology, PO Box 1906, Bellville 7535, South Africa; [email protected] * Correspondence: [email protected]

Received: 16 October 2019; Accepted: 14 January 2020; Published: 10 February 2020

Abstract: p-Coumaric acid (pCA) and trans-ferulic acid (TFA) were co-crystallised with 2-amino-4-picoline (2A4MP) and 2-amino-6-picoline (2A6MP) producing organic salts of (pCA )(2A4MP+)(1), (pCA )(2A6MP+)(2) and (TFA )(2A4MP+) ( 3 H O) (3). For salt 3, water was − − − · 2 2 included in the crystal structure fulfilling a bridging role. pCA formed a 1:1 salt with 2A4MP (Z’ = 1) and a 4:4 salt with 2A6MP (Z’ = 4). The thermal stability of the salts was determined using differential scanning calorimetry (DSC). Salt 2 had the highest thermal stability followed by salt 1 and salt 3. The salts were also characterised using Fourier transform infrared (FTIR) spectroscopy. Hirshfeld surface analysis was used to study the different intermolecular interactions in the three salts. Solvent-assisted grinding was also investigated in attempts to reproduce the salts.

Keywords: p-coumaric acid; trans-ferulic acid; organic sals; hydroxycinnamic acids; multicomponent crystals

1. Introduction Multicomponent crystals are structurally homogeneous crystalline materials containing two or more building blocks present in definite stoichiometric amounts [1–3]. The design and synthesis of multicomponent crystals have considerable therapeutic and commercial benefits as they often lead to improvement of physicochemical properties like solubility, bioavailability and stability [4,5]. Multicomponent crystals encompass co-crystals, organic salts, hydrates and solvates. Organic salts are multicomponent crystals that can be identified by the transfer of a proton between an acid and a base [6]. An organic salt can improve the physicochemical properties such as solubility of an API 100–1000 times more than co-crystals. Thus, 50% of the drugs on the market are in a salt form [7]. The most studied donor group is the carboxylic acid [8]. The reaction of an acid and a base will produce organic salts or co-crystals depending on the pKa difference between the acid and the base. According to the previous observations on the pKa rule in the literature, if the ∆pKa (pKa base pKa acid) is less than 1, non-ionised acid–base complexes are exclusively observed. Ionised − − acid–base complexes are exclusively expected for ∆pKa 4 and for ∆pKa between 1 and 4, there is a ≥ − probability of either salt or co-crystal formation [9–11]. This study focuses on the formation of organic salts of p-coumaric acid (pCA) and trans-ferulic acid (TFA), both derivatives of hydroxycinnamic acid. They are classified as phytochemical and nutraceutical molecules and are found in various plant species, such as peanuts, carrots and tomatoes [12,13]. They possess antioxidant and anti-inflammatory properties [14–16]. pCA and TFA are the most prevalent hydroxycinnamic acids [17]. They differ structurally due to the substituted methoxy group present in the meta position in TFA. pCA and TFA both contain carboxylic acid (strong hydrogen bond donor) and hydroxyl (hydrogen bond donor and/or acceptor) functional groups. These functional groups compete in the formation of supramolecular synthons in crystalline solids [18]. A CSD search (version 5.40,

Molecules 2020, 25, 751; doi:10.3390/molecules25030751 www.mdpi.com/journal/molecules Molecules 2020, 25, 751 2 of 11

Molecules 2020, 25, x FOR PEER REVIEW 2 of 11 August 2019 update) [19] revealed only ﬁve multicomponent crystal structures of p-coumaric acid (pCA) and seven of trans-ferulic acid (TFA). In this study, 2-amino-4-picoline (2A4MP) and 2-amino-6-picoline (2A6MP)Molecules 2020 were, 25, usedx FOR asPEER co-crystal REVIEW formers (Scheme1). 2 of 11

Scheme 1: Chemical structures of p-coumaric acid (pCA), trans-ferulic acid (TFA), 2-amino-4-picoline (2A4MP) and 2-amino-6-picoline (2A6MP). Scheme 1. Chemical structures of p-coumaric acid (pCA), trans-ferulic acid (TFA), 2-amino-4-picoline Scheme 1: Chemical structures of p-coumaric acid (pCA), trans-ferulic acid (TFA), 2-amino-4-picoline (2A4MP) and 2-amino-6-picoline (2A6MP). 2. Results(2A4MP) and and Discussion 2-amino-6-picoline (2A6MP).

2. ResultsThe Δ andpKa Discussionfor pCA with 2A4MP is 3.61; for pCA with 2A6MP ΔpKa = 3.59, whereas ΔpKa for TFA 2.with Results 2A4MP and is Discussion 4.04 [20]. Thus, a higher probability of salt formation is expected for these compounds The ∆pKa for pCA with 2A4MP is 3.61; for pCA with 2A6MP ∆pKa = 3.59, whereas ∆pKa for TFA withas ΔpThe 2A4MPKa isΔ pbetweenK isa for 4.04 pCA [320 and]. with Thus, 4 [9]. 2A4MP a No higher crystals is 3.61; probability werefor pCA obtained of with salt 2A6MP formation for TFA Δ withp isKa expected = 2A6MP. 3.59, whereas for these Δp compoundsKa for TFA with 2A4MPOrganic is salt 4.04 1, [20]. (pCA Thus,−)(2A4MP a higher+), crystallised probability in of thesalt orthorhombicformation is expected space group for these Pbca compounds with Z = 8. as ∆pKa is between 3 and 4 [9]. No crystals were obtained for TFA with 2A6MP. asThe Δ pOrganicdeprotonatedKa is between salt 1 ,( carboxylic3p andCA 4)(2A4MP [9]. acid No crystalsgroup+), crystallised of were pCA obtained is in linked the orthorhombic for to TFA both with nitrogen space2A6MP. atoms group ofPbca 2A4MPwith viaZ = N-8. − − + TheH···O deprotonatedOrganic interactions salt 1, carboxylic forming (pCA )(2A4MP acid (8) group rings;), crystallised of itp CAis also islinked inhydrogen the toorthorhombic both bonded nitrogen to space atomsthe phenolic group of 2A4MP Pbca OH viawith of N-Hanother Z = O8. − ThepCA deprotonated anion resulting carboxylic2 in 10 acid chains group [21]. of p CAThe is 2-aminopyridinium linked to both nitrogen carboxylate atoms ofheterosynthon 2A4MP via··· N- is interactions forming R2 (8) rings; it is also hydrogen bonded to the phenolic OH of another pCA− anion H···Oknown interactions to be 1a( robust) forming interaction (8) [22],rings; see it Figureis also 1.hydrogen The second bonded amine to hydrogen the phenolic atom OH is involvedof another in resulting in C1 10 chains [21]. The 2-aminopyridinium carboxylate heterosynthon is known to be a a weaker− N-H···O interaction with the carboxylate group of a neighbouring pCA− anion forming robustpCA anion interaction resulting [22], in see Figure 10 1 chains. The second [21]. The amine 2-aminopyridinium hydrogen atom is involvedcarboxylate in aheterosynthon weaker N-H Ois ··· known 6 chains.to be a Theserobust interactions interaction result[22], see in Figurea 2D network 1. The secondalong the amine c axis hydrogen (Figure 2). atom2( ) is involved in interaction with the carboxylate group of a neighbouring pCA− anion forming C2 6 chains. These interactionsa weaker N-H···O result ininteraction a 2D network with along the carboxylate the c axis (Figure group2). of a neighbouring pCA− anion forming 6 chains. These interactions result in a 2D network along the c axis (Figure 2).

Figure 1. Hydrogen bonding with motif ring of organic salt 1.

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b b

0 c 0 c

Figure 2.2. Packing diagram of salt 1 along [100]. Figure 2. Packing diagram of salt 1 along [100]. + Organic saltsalt 22,,( (ppCACA−−)(2A6MP+),), crystallised crystallised in the monoclinic spacespace groupgroupP P2211 withwith ZZ == 8. Again, Again, 2 2( ) thethe 2-aminopyridinium2-aminopyridiniumOrganic salt 2, (pCA carboxylatecarbox−)(2A6MPylate+), heterosynthon crystallised in formsthe monoclinic R2 (8)(8) ringsrings space withwith group aaC 2 P202201 withchain chain Z which= 8.which Again, is is a + resulta result of alternatingof alternatingpCA pCAand− and 2A6MP 2A6MPions+ ions (Figure (Figure3). These 3). interactionsThese interactions form a complexform a 3Dcomplex network. 3D the 2-aminopyridinium− carboxylate heterosynthon forms (8) rings with a 20 chain which is Itnetwork.a isresult interesting ofIt isalternating interesting to note thatp CAto note this− and saltthat 2A6MP hasthis Z’ salt+ =ions 4has unlike (Figure Z’ = 4 the unlike 3). previous These the previousinteractions structure structure which form had whicha complexZ’= had1. The Z3D’= density1.network. The density of thisIt is saltinteresting of isthis lower salt to thanis notelower that that forthan this salt that salt1, thusfor has salt less Z’ =1 close ,4 thus unlike packing less the close isprevious possible packing structure when is possible the which methyl when had group theZ’= changesmethyl1. The densitygroup position changesof in this 2A4MP salt position is ( paralower into the2A4MPthan pyridine that (para for nitrogen) saltto the 1, thuspyridine vs less 2A6MP closenitrogen) (ortho packingto vs the 2A6MPis pyridinepossible (ortho nitrogen).when to thethe Saltpyridinemethyl2 also group nitrogen). displays changes moderateSalt 2position also hydrogen displays in 2A4MP bondsmoderate (para in the hydrogento range the pyridine 2.606(3) bonds to innitrogen) 2.941(3)the range Åvs [2.606(3)232A6MP], compared to(ortho 2.941(3) toto saltthe Å 1[23],pyridine, which compared has nitrogen). three to moderatesalt Salt 1 ,2 which also (2.662(2)–2.893(3) displays has three moderate moderate Å) and hydrogen (2.662(2)–2. one weaker bond893(3) hydrogens in the Å) rangeand bond one 2.606(3) of weaker 3.365(2) to hydrogen2.941(3) Å. Thus, Å thebond[23], lower comparedof 3.365(2) density to Å. for salt Thus, salt 1, 2which isthe accompanied lower has three density moderate by for shorter salt (2.662(2)–2. hydrogen2 is accompanied bonds893(3) comparedÅ) by and shorter one to weakerhydrogen salt 1, and hydrogen bonds this is typicalcomparedbond of for 3.365(2) highto saltZ ’1Å., structures and Thus, this the is [24 typical lower–26]. fordensity high forZ’ structuressalt 2 is accompanied [24–26]. by shorter hydrogen bonds compared to salt 1, and this is typical for high Z’ structures [24–26].

Figure 3. Hydrogen bonding with motif ring of organic salt 2. Figure 3. Hydrogen bonding with motif ring of organic salt 2. + 3 Organic salt 3, (TFA−)(2A4MP )( 2 H2O), was successfully solved in the monoclinic space group Figure 3. Hydrogen bonding with motif ring of organic salt 2. − + 2 C2/c andOrganic again salt the 3,2-aminopyridinium (TFA )(2A4MP ) ( H carboxylate2O), was successfully heterosynthon solved is observedin the monoclinic forming spaceR2 (8) group rings. 4 2 The TFA anions are bridged by water molecules resulting in R (24) rings and C (14) chains. The C2/c andOrganic− again salt the 3, 2-aminopyridinium (TFA−)(2A4MP+) ( Hcarboxylate2O), was successfully heterosynthon solved4 is observed in the monoclinic forming2 space (8) grouprings. TFA anions− are disordered over two positions with the site occupancy of the major component, The −TFA anions are bridged by water molecules resulting in (24) rings and C 14 chains. The C2/c and again the 2-aminopyridinium carboxylate heterosynthon is observed forming (8) rings. 0.80837.− The hydrogen bonding is shown in Figure4 with the major component of the TFA anion TFA anions− are disordered over two positions with the site occupancy of the major component,− The TFA anions are bridged by water molecules resulting in (24) rings and C14 chains. The shown. Both pCA and TFA contain hydroxyl and carboxylic acid groups which compete in synthon− 0.80837.TFA− anions The hydrogenare disordered bonding over is twoshown positions in Figure with 4 withthe sitethe occupancymajor component of the majorof the component,TFA anion formation [18]. For all three structures, the supramolecular heterosynthons were preferred over the shown.0.80837. Both The phydrogenCA and TFA bonding contain is shownhydroxyl in andFigure carboxylic 4 with the acid major groups component which compete of the TFAin synthon− anion homosynthons with the persistence of the 2-aminopyridinium carboxylate heterosynthon. In addition, formationshown. Both [18]. pCA For and all threeTFA containstructures, hydroxyl the supram and carboxylicolecular heterosynthons acid groups which were compete preferred in oversynthon the this synthon was favoured in the presence of the competing hydroxyl group. Furthermore the homosynthonsformation [18]. Forwith all the three persiste structures,nce of the the supram 2-aminopyridiniumolecular heterosynthons carboxylate were heterosynthon.preferred over theIn hydroxyl group participated in this interaction by acting as a hydrogen bond donor to the carboxylate addition,homosynthons this synthon with wasthe favouredpersistence in theof thepresence 2-aminopyridinium of the competing ca hydroxylrboxylate group. heterosynthon. Furthermore In forming a three-centred (bifurcated) hydrogen bond. For salt 3, the hydroxyl group interacts with the theaddition, hydroxyl this groupsynthon participated was favoured in inthis the interact presenceion ofby the acting competing as a hydrogen hydroxyl group.bond donor Furthermore to the carboxylate via the water molecule. TFA also has a methoxy group, which reduces the donating ability carboxylatethe hydroxyl forming group aparticipated three-centred in this(bifurcated) interact ionhydrogen by acting bond. as aFor hydrogen salt 3, the bond hydroxyl donor groupto the carboxylate forming a three-centred (bifurcated) hydrogen bond. For salt 3, the hydroxyl group

Molecules 2020, 25, x FOR PEER REVIEW 4 of 11 MoleculesMolecules2020 ,202025, 751, 25, x FOR PEER REVIEW 4 of 114 of 11 interacts with the carboxylate via the water molecule. TFA also has a methoxy group, which reduces theinteracts donating with ability the of carboxylate the phenolic via OH the group water compar molecuedle. toTFA the also carboxylic has a methoxy acid [27], group, and did which not affectreduces of the phenolic OH group compared to the carboxylic acid [27], and did not aﬀect the formation of thethe formation donating of ability the 2-aminopyridinium of the phenolic OH carboxylategroup compar heterosynthon.ed to the carboxylic In a recent acid [27], article, and thedid crystalnot affect the 2-aminopyridinium carboxylate heterosynthon. In a recent article, the crystal structures of two structuresthe formation of two aminopyridiniumof the 2-aminopyridinium citrate salts carboxylate were reported, heterosynthon. the 3:1 2-aminopyridinium:citrate In a recent article, the crystalsalt aminopyridinium citrate salts were reported, the 3:1 2-aminopyridinium:citrate salt displayed the displayedstructures the of 2-aminopyridinium two aminopyridinium carboxylate citrate salts hetero weresynthon reported, whereas the 3:1 the 2-aminopyridinium:citrate other 1:1 salt did not [28]. salt 2-aminopyridinium carboxylate heterosynthon whereas the other 1:1 salt did not [28]. displayed the 2-aminopyridinium carboxylate heterosynthon whereas the other 1:1 salt did not [28].

FigureFigure 4. 4.Hydrogen Hydrogen bonding bonding with with the the ring ring motif motif of of organic organic salt salt3 .3. Figure 4. Hydrogen bonding with the ring motif of organic salt 3. NoteNote that that neighbouring neighbouring TFA TFA− anions− anions are orientedare oriented parallel parallel to each to other each with other the with distance the betweendistance thebetween ring centroidsNote the ringthat approximatelycentroidsneighbouring approximately 3.856TFA− Å.anions This 3.856 couldare Å. oriented This be due could toparallel thebe due steric to to each hindrancethe stericother hindrance ofwith the methoxythe ofdistance the groupmethoxybetween on thegroup the aromatic ringon the centroids ring,aromatic as forapproximately ring, salt as1 thefor salt adjacent 3.856 1 the Å. padjacent CAThis− anionscould pCA be− are anions due nearly to are the orthogonal. nearly steric orthogonal.hindrance In salt of 3In, the thesalt watermethoxy 3, the molecules water group molecules on act the as aromatic a act space as a ﬁllerspace ring, and asfiller for play and salt a play1 bridging the a adjacent bridging role linkingp roleCA− linkinganions the hydroxyl arethe nearlyhydroxyl group orthogonal. group to the to In 4 − R carboxylatethesalt carboxylate 3, the of water neighbouring of neighbouring molecules TFA act TFA− asanions. a anions.space The filler The 4and (24) (24)play rings rings a bridging form form columns columns role linking that that are theare linked hydroxyllinked by by water groupwater to molecules (Figure5). The water molecule− located on a twofold axis and sandwiched between the moleculesthe carboxylate (Figure of5). neighbouring The water molecule TFA anions. locat Theed on a (24) twofold rings formaxis and columns sandwiched that are linkedbetween by thewater columnscolumnsmolecules is is hydrogen hydrogen (Figure bonded bonded5). The to waterto two two TFAmolecule TFA− −anions anions locat andanded two twoon otheraother twofold water water axis molecules. molecules. and sandwiched between the columns is hydrogen bonded to two TFA− anions and two other water molecules.

0 0

c c

a a

Figure 5. Packing diagram of salt 3 along [010].

2.1. PXRD Analysis Figure 5. Packing diagram of salt 3 along [010]. Figure 5. Packing diagram of salt 3 along [010]. 2.1. Solvent-assistedPXRD Analysis grinding was used in an attempt to reproduce the organic salts, and an equimolar mixture2.1. PXRD of the acidAnalysis and the co-former were placed in a mortar and ground for 20 to 30 min with a few

Molecules 2020, 25, x FOR PEER REVIEW 5 of 11 Molecules 2020, 25, 751 5 of 11 Solvent-assisted grinding was used in an attempt to reproduce the organic salts, and an equimolar mixture of the acid and the co-former were placed in a mortar and ground for 20 to 30 min dropswith a of few the drops solvent of mixture,the solvent 75:25 mixture, (v/v) ethanol 75:25 (v/v and) ethanol 1,2-dichloroethane. and 1,2-dichloroethane. For the grinding For the experiment grinding ofexperiment TFA and 2A4MP,of TFA aand few 2A4MP, drops of a water few drops were alsoof water added. were The also PXRD added. patterns The of PXRD the ground patterns products of the 1gground, 2g and products3g were 1g compared, 2g and with3g were their compared respective with starting their materials respective and starting the calculated materials patterns and the of organiccalculated salts patterns1, 2 and of3 organicfrom LAZY salts PULVERIX1, 2 and 3 [from29]. ForLAZYpCA PULVERIX and 2A4MP, [29]. partial For p reactionCA and occurred 2A4MP, (partial1g, Figure reaction6). For occurredpCA and (1g 2A6MP, Figure partial6). For reactionpCA and was 2A6MP also observedpartial reaction but unidentified was also observed peaks were but alsounidentified found in peaks the PXRD were pattern also found of the in ground the PXRD product pattern (2g of). Thisthe ground grinding product experiment (2g). This was repeatedgrinding forexperiment 60 min and was the repeated PXRD pattern for 60 showedmin and a the better PXRD match pattern to that showed of the calculated a better match one; however, to that of there the werecalculated still unidentified one; however, peaks, there thus were confirming still unidenti the presencefied peaks, of a mixture.thus confirming The corresponding the presence PXRD of a patternsmixture. have The beencorresponding deposited inPXRD the supplementary patterns have data.been Thedeposited ground in product the supplementary3g obtained after data. 20 minThe grindingground product appears 3g to obtained be a mixture after of20 startingmin grinding material, appears salt 3toand be a an mixture unidentified of starting product material, (Figure salt7). 3 Thus,and an the unidentified solvent-assisted product grinding (Figure experiments 7). Thus, were th partiallye solvent-assisted successful ingrinding the preparation experiments of the were salts. Thepartially grinding successful experiment in the of preparation TFA and 2A6MP of the wassalts. also The attempted grinding experiment even though of no TFA single and crystals 2A6MP were was obtained.also attempted A 1:1 even mixture though of TFA no single and 2A6MP crystals was were ground obtained. for 60 A min1:1 mixture using the of sameTFA and solvent 2A6MP mixture was usedground in thefor previous60 min using experiments. the same The solvent PXRD patternmixture of used the resultant in the previous powder showedexperiments. new peaks The PXRD when comparedpattern of the to those resultant of the powder starting showed materials, new indicating peaks when that compared a new compound to those of was the formedstarting (Figurematerials,8). Thereindicating were that also a residual new compound peaks of 2A6MP was formed present, (Figure thus the 8). reactionThere were was also incomplete. residual Mechanochemical peaks of 2A6MP synthesespresent, thus is a popularthe reaction technique was incomplete. for preliminary Mech co-crystallisationanochemical syntheses experiments is a aspopular it gives technique quick results for andpreliminary requires co-crystallisation either no solvent experiments or a minimum as it amount gives quick of solvent results [30 and]. The requires grinding either experiments no solvent ofor thesea minimum hydroxycinnamic amount of solvent acids gave [30]. promising The grinding results experiments even though of these partial hydroxycinnamic reaction occurred, acids possibly gave duepromising to the manualresults grindingeven though technique partial which reaction requires occurred, longer reactionpossibly times due thanto the an manual automatic grinding device. However,technique thesewhich preliminary requires longer experiments reaction could time paves than the wayan forautomatic further studydevice. into However, the structural these landscapepreliminary of experimentspCA and TFA could which pave is underexplored the way for further as shown study by into the fewthe structural crystal structures landscape present of pCA in theand CSD. TFA which is underexplored as shown by the few crystal structures present in the CSD.

13900 pCA 2g 11900 2

9900 1g 1 7900

5900 Relative Intensity Relative 3900

1900

-100 5 15253545 2θ Figure 6. PXRD patterns for pCA, the ground products 1g and 2g after 30 min and the calculated organicFigure 6. salts PXRD1 and patterns2. for pCA, the ground products 1g and 2g after 30 min and the calculated organic salts 1 and 2.

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MoleculesMolecules 20202020, ,2525, ,x 751 FOR PEER REVIEW 66 of of 11 11 11900 TFA 11900 3g 9900 TFA3 3g 9900 7900 3

7900 5900

5900 3900 Relative intensity intensity Relative

3900

Relative intensity intensity Relative 1900

1900 -100 5 15253545 -100 2θ 5 15253545 2θ Figure 7. PXRD pattern for TFA compared with the ground product 3g after 20 min and the calculated Figureorganic 7. saltPXRD 3. pattern for TFA compared with the ground product 3g after 20 min and the calculated organic salt 3. Figure 7. PXRD pattern for TFA compared with the ground product 3g after 20 min and the calculated organic25000 salt 3. TFA2A6MP grinding (60 min) 25000 TFA TFA2A6MP grinding (60 min) 20000 2A6MP TFA 20000 2A6MP 15000

15000 10000

10000 intensity Relative 5000 Relative intensity Relative

5000 0 5 15253545 0 2θ 5 15253545 FigureFigure 8.8: PXRDPXRD analysesanalyses of of the the ground ground product product of of TFA TF andA and 2A6MP 2A6MP after after 60 min60 min (black), (black), TFA TFA (red) (red) and 2θ 2A6MPand 2A6MP (blue). (blue). Figure 8: PXRD analyses of the ground product of TFA and 2A6MP after 60 min (black), TFA (red) 2.2.2.2. and Infrared 2A6MP Spectroscopy (blue). 1 TheThe absenceabsence ofof thethe carboxyliccarboxylic acidacid OHOH stretchingstretchingbroad broad band band of ofp pCACA around around the the 3000 3000 cm cm−−1 region 2.2. Infrared Spectroscopy waswas observedobserved forfor bothboth saltssalts 11 andand 2,, conﬁrmingconfirming thethe protonproton transfertransfer betweenbetween thethe startingstarting materialmaterial andand thethe co-formers.Theco-formers. absence Salt Saltof the1 1shows carboxylicshows two two small acid small peaksOH peaks stretching around around those broad those regions band regions of corresponding pCA corresponding around tothe the 3000 to primary thecm− 1primary region amine was(NHamine observed2) of(NH 2A4MP.2) offor 2A4MP. both For salt salts For2, 1 no saltand primary 22,, noconfirming primary amine peak aminethe proton is shownpeak transfer is but shown a shifted between but a peak shifted the was starting peak observed, was material observed, which and is theassignedwhich co-formers. is assigned to the hydrogenSalt to 1 the shows hydrogen bonding two betweensmall bonding peaks the between phenolicaround the OHthose phenolic of regionspCA OH and ofcorresponding the pCA carbonyl and the oxygen carbonylto the of primary anotheroxygen aminepofCA another in (NH the2 crystal)p ofCA 2A4MP. in structure. the crystalFor salt Similarly, structure. 2, no primary salt Similarly,3 does amine not salt peak show 3 doesis a shown carboxylic not butshow OHa shifteda stretchingcarboxylic peak bandwas OH observed, butstretching a shift whichdue to is the assigned hydrogen to the bonding hydrogen between bonding the phenolicbetween OHthe phenolic of TFA and OH the of p waterCA and molecule, the carbonyl is observed oxygen at 1 ofapproximately another pCA 3000in the to crystal 3700 cm structure.− . The FTIR Similarly, spectra salt of the3 does salts not are show given a in carboxylic the supplementary OH stretching data.

Molecules 2020, 25, x FOR PEER REVIEW 7 of 11

band but a shift due to the hydrogen bonding between the phenolic OH of TFA and the water molecule, is observed at approximately 3000 to 3700 cm−1. The FTIR spectra of the salts are given in Molecules 2020, 25, 751 7 of 11 the supplementary data.

2.3.2.3. Thermal Thermal Analysis Analysis TheThe diﬀ erentialdifferential scanning scanning calorimetry calorimetry (DSC) (DSC) curves ofcurves the organic of the salts organic displayed salts onedisplayed endothermic one endothermic peak which corresponds to the melting points of the compounds. All the salts have peak which corresponds to the melting points of the compounds. All the salts have melting peaks melting peaks occurring at temperatures in between those of the starting materials, Figure 9. The occurring at temperatures in between those of the starting materials, Figure9. The melting point of melting point of salt 1 results in an endothermic peak at 170 °C, which differs from the melting points salt 1 results in an endothermic peak at 170 C, which diﬀers from the melting points of pCA (214.9 C) of pCA (214.9 °C) and 2A4MP (100 °C). The◦ endothermic peak for salt 2 occurs at a slightly higher◦ and 2A4MP (100 ◦C). The endothermic peak for salt 2 occurs at a slightly higher temperature (173 ◦C) temperature (173 °C) compared to salt 1 (Tpeak of 2A6MP = 44.9 °C). Salt 3 has the lowest melting point compared to salt 1 (T of 2A6MP = 44.9 C). Salt 3 has the lowest melting point at 135 C (T for at 135 °C (Tpeak forpeak TFA =174 °C), the inclusion◦ of water could have contributed to the lower◦ meltingpeak TFApoint=174 of◦ C),this the salt. inclusion of water could have contributed to the lower melting point of this salt.

100 pCA TFA 80 1 2 60 3 170 40 173 Heat flow flow (mW) Heat 20 135 0 30 70 110 150 190 230 Temperature (˚C)

Figure 9. Differential scanning calorimetry (DSC) plot of pCA (blue), TFA (brown), salt 1 (black), salt 2 (green)Figure and 9. salt Differential3 (red). scanning calorimetry (DSC) plot of pCA (blue), TFA (brown), salt 1 (black), salt 2 (green) and salt 3 (red). 2.4. Torsion Angles 2.4. Torsion Angles Figure 10 depicts the torsion angles considered in this study for both pCA and TFA. The torsion angles forFigure all four 10 depictspCA− anions the torsion in salt angles2 were considered obtained in and this significant study for dibothfferences pCA and were TFA. found. The torsion For this − salt,anglesτ1 varied for all from four 0.5 pCA to 14.4anions◦ and inτ 2saltvaried 2 were from obtained 5.1 to 26.7and◦ .significant Salt 1 showed differences similar were flexibility found. in For the Molecules 2020 , 25, x FOR PEER REVIEW 8 of 11 rotationthis salt, of the ringvaried (τ 1from) compared 0.5 to 14.4° to saltand2 with variedτ1 = from12.8 5.1◦ and to 26.7°.τ2 = 10.1 Salt◦ 1. showed TFA in saltsimilar3 has flexibility both the in the rotation of the ring ( ) compared to salt 2 with = 12.8° and = 10.1°. TFA in salt 3 has lowest ring twist torsion angle (τ1 = 0.2◦) and the lowest carboxylic acid twist torsion angle (τ2 = 4.9◦). both the lowest ring twist torsion angle ( = 0.2°) and the lowest carboxylic acid twist torsion angle ( = 4.9°).

Figure 10. Torsion angles of pCA and TFA. Figure 10. Torsion angles of pCA and TFA.

2.5. Hirshfeld Surface Analysis For all three salts, the leading interactions are as follows, H···H > O···H > C···H. The π···π stacking represented by C···C has a lower contribution to the stability of the salts, with salt 3 displaying the highest value of 7.5 %. Similar percentage contributions were found for the O···H interactions in the three salts (average 30.8 %). For all three salts, the C···H contacts are shown as “chicken wings”. The H···H contacts (average 40.1 %) are prominent in the molecular packing and appear as scattered points in the middle region of the 2D fingerprint plots [31].

3. Materials and Methods All chemicals were obtained from Sigma Aldrich (Schnelldorf, Germany) and were used without further purification.

3.1. Crystallisation The salts were obtained by dissolving the target compound and co-former (1:1 molar ratio) in a solvent mixture followed by gentle heating on a hot plate and stirring until the solution became clear. The solutions were left at room temperature until crystallisation occurred. For (pCA−)(2A4MP+) (1) and (pCA−)(2A6MP+) (2) a 75:25 (v/v) ethanol and 1,2-dichloroethane solvent mixture was used and crystals were obtained after 1 week. For (TFA−)(2A4MP+)·( H2O) (3) a similar solvent mixture was used; however, a few drops of water were added to give a clear solution. Slow evaporation of this solution gave crystals after 4 days.

3.2. Thermal Analysis Differential scanning calorimetry (DSC) was conducted on a Perkin–Elmer 6000 (PerkinElmer Inc., Waltham, MA, USA) with a nitrogen gas purge at 20 mL min-1. Experiments were performed from 30 to 250 °C at a heating rate of 10 °C min−1.

3.3. Infrared Spectroscopy IR spectra were measured on a PerkinElmer Spectrum Two FTIR spectrometer (PerkinElmer Inc., Waltham, MA, USA) equipped with an ATR Diamond accessory for powder samples. Samples were scanned over a range of 400 to 4000 cm−1.

Molecules 2020, 25, 751 8 of 11

2.5. Hirshfeld Surface Analysis For all three salts, the leading interactions are as follows, H H > O H > C H. The π π stacking ··· ··· ··· ··· represented by C C has a lower contribution to the stability of the salts, with salt 3 displaying the ··· highest value of 7.5%. Similar percentage contributions were found for the O H interactions in the ··· three salts (average 30.8%). For all three salts, the C H contacts are shown as “chicken wings”. The ··· H H contacts (average 40.1%) are prominent in the molecular packing and appear as scattered points ··· in the middle region of the 2D ﬁngerprint plots [31].

3. Materials and Methods All chemicals were obtained from Sigma Aldrich (Schnelldorf, Germany) and were used without further puriﬁcation.

3.1. Crystallisation The salts were obtained by dissolving the target compound and co-former (1:1 molar ratio) in a solvent mixture followed by gentle heating on a hot plate and stirring until the solution became clear. + The solutions were left at room temperature until crystallisation occurred. For (pCA−)(2A4MP )(1) + and (pCA−)(2A6MP )(2) a 75:25 (v/v) ethanol and 1,2-dichloroethane solvent mixture was used and crystals were obtained after 1 week. For (TFA )(2A4MP+) ( 3 H O) (3) a similar solvent mixture was − · 2 2 used; however, a few drops of water were added to give a clear solution. Slow evaporation of this solution gave crystals after 4 days.

3.2. Thermal Analysis Diﬀerential scanning calorimetry (DSC) was conducted on a Perkin–Elmer 6000 (PerkinElmer Inc., 1 Waltham, MA, USA) with a nitrogen gas purge at 20 mL min− . Experiments were performed from 30 1 to 250 ◦C at a heating rate of 10 ◦C min− .

3.4. Powder X-ray Diffraction The powder X-ray diffraction patterns of the samples were recorded with a D2 Phaser Bruker diffractometer (Bruker, Karlsruhe, Germany) with Cu-Kα radiation of 1.54184 Å. The samples were scanned between 4 and 50◦ 2θ and the voltage tube and amperage were at 30 kV and 10 mA max, respectively, with an Xflash detector and a scintillation counter, 1-dim LYNXEYE.

3.5. Crystal Structure Determination Single crystal X-ray diffraction data were recorded on a Bruker KAPPA APEX II DUO diffractometer (Bruker, Karlsruhe, Germany) using graphite monochromated Mo-Kα radiation (λ = 0.71073 Å) at 173 K. Data were corrected for Lorentz-polarization effects and for absorption (SADABS) [32]. The structures were solved by direct methods in SHELXS and refined by full-matrix least-squares on F2 using SHELXL [33] within the interface XSEED [34]. The non-hydrogen atoms were found in the difference electron density map and were refined anisotropically, whereas hydrogen atoms were placed in calculated positions and refined with isotropic temperature factors. Details of the crystal structure refinements are given in Table1. Molecules 2020, 25, 751 9 of 11

Table 1. Crystallographic data for salts 1, 2 and 3.

Organic Salts 1 2 3

Molecular formula C15H16N2O3 C60H64N8O12 C16H21N2O6 Mr (g/mol) 272.30 1089.19 329.35 Temperature (K) 173 173 173 Crystal system Orthorhombic Monoclinic Monoclinic Space group Pbca P21 C2/c a (Å) 12.056(2) 13.930(3) 20.111(4) b (Å) 9.1511(18) 9.948(2) 12.016(2) c (Å) 25.048(5) 20.797(4) 14.226(3) α (◦) 90 90 90 β (◦) 90 94.33(3) 104.96(3) γ (◦) 90 90 90 V (Å3) 2763.4(9) 2873.6(10) 3321.4(12) Z 8 2 8 λ (Å) 0.71073 0.71073 0.71073 ρ (calcd) (g/cm3) 1.309 1.259 1.317 Absorption coefficient µ 1 0.092 0.089 0.100 (mm− ) 2θmax (◦) 56.6 55.8 56.7 Reflections collected 26738 23267 24936 No. data with I > 2σ(I) 3424 13608 4149 No. parameters 198 789 288 Final R (I > 2σ(I)) R1 = 0.0460; wR2 = 0.1049 R1 = 0.0574; wR2 = 0.1372 R1 = 0.0431; wR2 = 0.1072 R indices (all data) R1 = 0.0714; wR2 = 0.1198 R1 = 0.0783; wR2 = 0.1493 R1 = 0.0540; wR2 =0.1153 Goodness-of-fit on F2 1.028 1.052 1.030 Min, max e density (e Å 3) 0.241, 0.199 0.234, 0.239 0.239, 0.297 − − − − −

4. Conclusions

The pKa rule predicted that both pCA and TFA would form salts with the aminopicolines. The salts (pCA )(2A4MP+), (pCA )(2A6MP+) and (TFA )(2A4MP+) ( 3 H O) were analysed using − − − · 2 2 single crystal X-ray diffraction. No suitable crystals were obtained for TFA and 2A6MP however grinding experiments revealed that a new compound was formed. The aminopyridinium carboxylate supramolecular heterosynthon was favoured in the presence of the hydroxyl group in the case of pCA, and it was also preferred in the presence of both hydroxyl and methoxy groups for TFA. For the pCA salts, the phenol OH hydrogen bonds to the carboxylate and in the case of the TFA salt, water forms a bridge between the phenol OH and the carboxyl group. pCA gave a 1:1 salt with 2A4MP and a 4:4 salt with 2A6MP. The change in position of the methyl group in the aminopicolines influenced the packing. Similarly the presence of the methoxy group in TFA compared to pCA also resulted in a different packing arrangement for the salts involving 2A4MP. The thermal stability trend as determined by the melting points for the salts is 2 > 1 > 3.

Supplementary Materials: The following are available online at http://www.mdpi.com/1420-3049/25/3/751/s1: Hydrogen bond data, torsion angles, Hirshfeld surface analysis, PXRD and FTIR spectra. The crystallographic data have been deposited with the CCDC, deposition numbers 1957748-1957750. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Author Contributions: Conceptualization, A.J.; Formal analysis, S.N.K. and A.J.; Investigation, S.N.K.; Supervision, A.J.; Visualization, S.N.K. and A.J.; Writing – original draft preparation, S.N.K.; Writing—review & editing, A.J. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by the National Research Foundation of South Africa, grant number 81245. The APC was funded by the Cape Peninsula University of Technology. Conﬂicts of Interest: The authors declare no conﬂicts of interest. Molecules 2020, 25, 751 10 of 11

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Sample Availability: Samples of the compounds are not available from the authors.

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