Structures of benzoic acids with substituted pyridines and quinolines: salt versus co-crystal formation

A series of five substituted benzoic acids with 10 substituted pyridines and quinolines have been crystallized so that their Δ p K a , defined as p K a base – p K a acid , varied from − 1.14 to +4.16. This spans the ‘ uncertainty ’ region for the formation of salt versus co-crystals. Although most of our results confirmed that structure formation of co-crystal versus salt parts at Δ p K a ≈ 2, we report here a structure that does not follow the general rule and serves as a cautionary tale.


Introduction
The question of pH control in the formation of salts versus co-crystals is a topic of current research interest.This is particularly important in the pharmaceutical industry which is continually seeking Active Pharmaceutical Ingredients (APIs) with desirable properties such as stability and taste.
When an acid is reacted with a base, the ensuing product will be a salt or a co-crystal, and the general rule is that if ΔpK a (pK a base -pK a acid ) is greater than 2-3, the product will be a salt. 1 This is not an absolute rule, because the pK a is an acid dissociation constant measured in water at a fixed temperature.However, the product of the reaction depends upon the solvent or mixture of solvents, the temperature and, if the product is a crystalline solid, on the packing forces impinging on the molecules or ions in the crystal structure.
However the ΔpK a can be used as a guideline and may be justified by a simplified analysis of the equilibria between a carboxylic acid RCOOH and a substituted pyridine base R′Py.
If the equilibrium constants of the base and the acid are K a1 and K a2 respectively: Here we have approximated concentration with activities.For the reaction: If ΔpK a > 0, the ionic species will predominate and vice versa.
In the crystalline solid state, the difference between a salt and a co-crystal is subtle, being dependent in the unambiguous location of a hydrogen atom as shown in Fig. 1.
Thus if the O⋯N distance is typically ≈2.7 Å and O-H and N + -H distances are ≈1.0Å, the movement of the H atom is small, approximately 0.7 Å.
Fig. 1, however displays schematically the extreme, eitheror situation.It has been pointed out by Childs, Stahly and Park 2 that there are cases where the location of the proton is ambiguous and is not clearly covalently bonded to either the oxygen or the nitrogen atom.The proton transfer should thus be regarded as a continuum and can, in addition, be traced by the difference in bond lengths in the carboxyl group.
These are distinctly different in the acid Recently, Cruz-Cabeza 3 carried out a survey of over 6 000 structures comprising ionised and non-ionised acid-base pairs.She found a linear relationship between ΔpK a and the probability of proton transfer, in the pK a range of −1 to +4.The cross-over point occurs at ΔpK a = 1.3, beyond which there is a greater than 50% probability of the product being a salt.Gilli & Gilli 4 have devised a slide rule which predicts the strength of a Donor-Acceptor hydrogen bond based on the ΔpK a of the system.It is noteworthy that their device predicts salts if ΔpK a > 3, co-crystals when ΔpK a < −3 and the uncertainty region which contains the strong hydrogen bonds is pictured as D⋯H⋯A, which may be regarded as the true three-centre-four-electron system.
The Gilli & Gilli review points out that the interval of ΔpK a matching should be shifted by 1.5 units when interpreting crystal structures, 5 which agrees with the findings in the survey by Cruz-Cabeza.
Based on the above, we have crystallized a series of five substituted benzoic acids with 10 substituted pyridines and quinolines as shown in Fig. 2.
The acids were selected to have different Hammett substituent constants varying from p-amino (σ = −0.66) to p-nitro (σ = +0.78),yielding different pK a values, 6 while the pK a values of the substituted bases varied from 3.63 to 7.62.
The ΔpK a values of our chosen compounds varied from −1.14 to +4.16, thus spanning the 'uncertainty' region identified by both Cruz-Cabeza and Gilli & Gilli.
In this work we discuss the bonding of 22 structures made up of acid-base pairs which either form salts or co-crystals.They give rise to 26 ΔpK a due to some bases having two pK a values.In Table 3 we label these 1 to 26.Eight structures [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] Fig. 2 List of acids and bases used in this project and their pK a .were taken from the CSD 7 while the remainder were newly elucidated and are labelled I to XIV as shown in Fig. 3.
Table 1 for the co-crystals and Table 2 & 3 for the salts report the crystal data, structure and refinement parameters for I to XIV.

Crystal growth
The acid and base to be combined were selected and equal molar amounts were weighed accurately.The compounds were dissolved in separate vials in ethanol with gentle stirring and heating.The solutions were filtered and combined.The acid-base mixtures were allowed to crystallise at room temperature upon slow evaporation of the solvent to afford crystals suitable for single crystal structure determination.

Crystal structure
For structures II, III, VII, X, XI, XII and XIV, the intensity data measured on a Bruker KAPPA CCD diffractometer using graphite-monochromated Mo-Kα radiation (λ = 0.71073 Å) were used to determine the cell dimensions.The strategy for the data collections was evaluated using COLLECT software. 23r these structures, the intensity data were collected by the standard φ scan and omega scan techniques, scaled and reduced using the program DENZO-SMN. 24rystal structure determinations for I, IV, V, VI, VIII, IX and XIII were performed by single crystal X-ray diffraction using a Bruker KAPPA APEX II DUO diffractometer with graphite monochoromated Mo-Kα radiation.Unit cell refinement and data reduction were performed using the program SAINT. 25 All structures were determined at low temperature (173 K) and the refinement parameters are presented in Tables 1-3.
Structures VII and IX were previously reported in the literature [15][16][17] but for data collections at room temperature (VII and IX) and 208 K (for VII).
The structures were solved using direct methods and refined by full-matrix least squares with SHELX-97, 26 refining on F 2 .The program X-Seed 27 was used as a graphical interface.For all the structures the non-hydrogen atoms were found in the difference electron density map.The aromatic and methyl hydrogen atoms were placed in calculated positions and refined isotropically using a riding model.The hydrogen atoms belonging to amine, protonated pyridyl or hydroxyl groups were placed using the electron density map and refined isotropically.At times, the N-H distance in  amines was restricted to an acceptable value using DFIX.
We were careful to establish whether the compound was a co-crystal or a salt.In the case of co-crystals, the hydroxyl hydrogen atom was located in a difference density map and refined freely.In the case of salts, we located the hydrogen atom as being bonded to the N + of the base and in addition we noted the equalisation of the C-O bond length of the carboxyl moiety.The structures were deposited at the Cambridge Crystallographic Data Centre and allocated the numbers: CCDC 963007-963012, 963014-963021.I with the only difference arising from the 6-methyl group substitution on the base.The packing is still characterised by a chain of hydrogen bonds, C 2 2 (12) , running along [010], as well as the ring formed by the interaction of the carboxylic moiety with the amino-pyridine nitrogens of the base.

Crystal structures of the co-crystals
Structure IV arose from a mixture of 4-methoxybenzoic acid and 4,4′-bipyridine, 2A4•B3 and crystallises in P2 1 /c with Z = 4.The bipyridine is di-basic and therefore has two distinct pK a values, giving rise to two points on the co-crystal/ salt versus ΔpK a diagram reported in Fig. 3.The asymmetric unit consists of the bipyridine moiety hydrogen bonded to Table 4 Metrics of the hydrogen bonds in structure I to XIV two 4-methoxybenzoic acids which may be represented by D 2 2 (10) bonds (Fig. 5).
The packing is characterised by columns of 4-methoxybenzoic acids and bipyridine running in the [108] direction.
Structure VI comprising 4-nitrobenzoic acid and quinoline, A1•B4, crystallises in space group P2 1 with Z = 2, the asymmetric unit displays the acid hydrogen bonded to the quinoline base via (Acid)O-H⋯N(Base).The packing is characterised by layers approximately parallel to the bc face, and stacked perpendicular to the [104] direction.

Crystal structures of the salts
Structure V from 4-aminobenzoic acid and 6-aminoquinoline, A5•B6, crystallises in space group P2 1 /c with Z = 4.The asymmetric unit comprises one aminoquinolinium hydrogen bonded to an aminobenzoate.An inspection of Fig. 3 makes structure V appear as an outlier.However, the ΔpK a value of +0.38 yields a probability of salt formation of 34% as proposed by the Cruz-Cabeza assessment.In addition, this system is further stabilised by a complex hydrogen bonding network.In Fig. 6a, we show a central aminobenzoate anion which is hydrogen bonded to four neighbouring aminobenzoates and three aminoquinolinium cations.We note that there are five unique additional hydrogen bonds stabilising the structure as listed in Table 4.The packing shown in Fig. 6b displays alternate chains of anti-parallel aminobenzoates interleaved with aminoquinolates.
Structure VIII arose from 4-bromobenzoic acid and 2-aminopyridine, A2•B8 and crystallises in the space group P2 ).This compound crystallises as a di-hydrate in the space group P2 1 /n with Z = 4.One of the waters of crystallisation acts as a hydrogen bonding bridge creating a spiral of O-H⋯O bonds about the 2-fold screw axis at Wyckoff position e.In addition, the amino groups are hydrogen bonded to the oxygen of this water molecule.We again have the synthon of hydrogen bonds between the carboxylate moiety and the aminopyridinium cation.We may therefore describe this as two parallel chains running along [010] linked by ring systems.The motif resembles a ladder: C 1 2 (4) R 4 6 (12).The second water molecule links ladders together, giving rise to hydrogen bonded sheets which run along [010] (Fig. 9).

Conclusions
Fig. 3 shows that the break from co-crystal to salt occurs at ΔpK a ≈ 2. Structure 8(V), obtained from combining 4-aminobenzoic acid and 6-aminoquinoline, forms a salt.Its value of ΔpK a is +0.38, and is clearly an outlier (Fig. 3).However, according to the Cruz-Cabeza survey, there is a 34% chance of the compound being a salt at this value of ΔpK a , and the survey points out that secondary hydrogen bonds can influence the stabilisation of the ionic structure. 29This is the case with structure 8(V) in which, in addition to the (quinolinium)-N + -H⋯O − -CO-(benzoate) hydrogen bond, the amino-benzoate anion is further stabilised by six other N-H⋯O-CO hydrogen bonds, the metrics of which are given in Table 4.
The hydrogen-bonding table is arranged so that each of the structures I to XIV displays the main H-bond (Acid)-O1-H⋯N1-(Base) in blue for the co-crystals or as (Protonated Base)-N1-H⋯O1-(Anion) in red for a salt.One notes that most of the structures listed in Table 4 display additional hydrogen bonds, a feature which is obviously common on the systems under study.

If
ΔpK a = 0 there are equal quantities of ions and neutral molecules in the solution.
Structure I, derived from 4-aminobenzoic acid and 2-acetaminopyridine, A5•B2, crystallises in the space group Pna2 1 with Z = 4.Each 4-aminobenzoic acid is stabilised by three hydrogen bonds as shown in Fig. 4, comprising a closed ring and an infinite chain running along [100].In all figures, the same nomenclature has been employed whereby the acid molecules are always represented in orange while the base molecules display the conventional colours.Employing the graph nomenclature of Etter and Bernstein 28 these may be designated as R 2 2 (8) and C 2 2 (12) respectively.In this packing the chains are anti-parallel running along [100] and are hydrogen bonded via a weak (Acid)-N-H⋯N-(Acid) displayed in blue in Fig. 4. The metrics of the hydrogen bonding for this and the remaining structures are reported in Table 4. Structure II consists of benzoic acid and 2-acetaminopyridine, A3•B2, in the space group P2 1 /n with Z = 4.The structure is made of acid-base pairs which are hydrogen bonded with R 2 2 (8) motif similar to that of the previous structure.Structure III of 4-aminobenzoic acid and 2-acetamido-6-methylpyridine, A5•B5, crystallises in space group P2 1 /c with Z = 4.The structure is similar to that of

Fig. 6
Fig. 6 Motif in structure V: a) a central aminobenzoate ion (in orange) is hydrogen bonded to seven ions-four aminobenzoates and three aminoquinoliniums, b) anti-parallel chains of aminobenzoate ions (in orange and pink) in the packing of V.

Fig. 7
Fig. 7 Hydrogen bond motifs in structure VII displaying chains which run along [100].

Fig. 8
Fig. 8 Structure IX displaying the different hydrogen bond motifs with two types of chains running a) along [001] and b) along [110].

Fig. 9
Fig. 9 Packing of the only solvated structure (XIII) obtained during this study: a) Packing of XIII viewed down [010] displaying sheets of hydrogen bonded molecules and solvents which run along [101].b) Schematic representation of the ladders where only the moieties involved in hydrogen bonding are displayed.The ladders are connected through ribbons of hydrogen bonded water molecules running along [010].