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

molecules 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 DpKa (pKa base pKa acid) is less than 1, non-ionised acid–base complexes are exclusively observed. Ionised − − acid–base complexes are exclusively expected for DpKa 4 and for DpKa 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 DpKa for pCA with 2A4MP is 3.61; for pCA with 2A6MP DpKa = 3.59, whereas DpKa 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 inof thesalt orthorhombicformation is expected space group for these Pbca compounds with Z = 8. as DpKa 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 1chains. 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. Figure 1. Hydrogen bonding with motif ring of organic salt 1. Figure 1. Hydrogen bonding with motif ring of organic salt 1. Molecules 2020, 25, x FOR PEER REVIEW 3 of 11 Molecules 2020, 25, 751 3 of 11 Molecules 2020, 25, x FOR PEER REVIEW 3 of 11 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.

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