Gaëlle
Ramon
*,
Kate
Davies
and
Luigi R.
Nassimbeni
Supramolecular Chemistry Group, Department of Chemistry, University of Cape Town, Rondebosch, 7701, South Africa. E-mail: gaelle.ramon@uct.ac.za; Fax: +27 21 650 5768; Tel: +27 21 650 5184
First published on 13th January 2014
A series of five substituted benzoic acids with 10 substituted pyridines and quinolines have been crystallized so that their ΔpKa, defined as pKa base–pKa 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 ΔpKa ≈ 2, we report here a structure that does not follow the general rule and serves as a cautionary tale.
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 ΔpKa (pKa base–pKa acid) is greater than 2–3, the product will be a salt.1 This is not an absolute rule, because the pKa 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 ΔpKa 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 Ka1 and Ka2 respectively:
RCOOH ↔ RCOO− + H+ |
R′PyH+ ↔ R′Py + H+ |
RCOOH + R′Py → RCOO− + R′PyH+ |
If ΔpKa > 0, the ionic species will predominate and vice versa.
For example, if pKa1 = 5 and pKa2 = 3, ΔpKa = +2 so Keq ≈ Ka2/Ka1 = 10−3/10−5 ≈ 100. Thus the concentration of the ionized species is in excess, giving a greater likelihood of the salt being formed.
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 ≈1.0 Å, the movement of the H atom is small, approximately 0.7 Å.
Fig. 1, however displays schematically the extreme, either–or situation. It has been pointed out by Childs, Stahly and Park2 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 (d CO ≈ 1.2 Å, d C–OH ≈ 1.30 Å) but tend to equalize in the carboxylate anion (d C–O ≈ 1.26 Å).
Recently, Cruz-Cabeza3 carried out a survey of over 6000 structures comprising ionised and non-ionised acid-base pairs. She found a linear relationship between ΔpKa and the probability of proton transfer, in the pKa range of −1 to +4. The cross-over point occurs at ΔpKa = 1.3, beyond which there is a greater than 50% probability of the product being a salt. Gilli & Gilli4 have devised a slide rule which predicts the strength of a Donor–Acceptor hydrogen bond based on the ΔpKa of the system. It is noteworthy that their device predicts salts if ΔpKa > 3, co-crystals when ΔpKa < −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 ΔpKa 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 pKa values,6 while the pKa values of the substituted bases varied from 3.63 to 7.62.
The ΔpKa 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 ΔpKa due to some bases having two pKa values. In Table 3 we label these 1 to 26. Eight structures8–23 were taken from the CSD7 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.
Co-crystal | A5·B2 | A3·B2 | A5·B5 | 2A4·B3 | A1·B4 |
---|---|---|---|---|---|
I(1) | II(4) | III(5) | IV(6) | VI(12) | |
ΔpKa = −0.72 | ΔpKa = −0.03 | ΔpKa = 0.02 | ΔpKa = 0.07 | ΔpKa = 2.46 | |
Molecular formula | C7H7NO2· | C7H6O2· | C7H7NO2· | 2(C8H8O3)· | C7H5NO4· |
C7H8N2O | C7H8N2O | C8H10N2O | C10H8N2 | C9H7N | |
Molecular mass | 273.29 | 258.27 | 287.32 | 460.47 | 296.28 |
Crystal system | Orthorhombic | Monoclinic | Monoclinic | Monoclinic | Monoclinic |
Space group | Pna21 | P21/n | P21/c | P21/c | P21 |
a, Å | 14.864(1) | 12.776(3) | 8.435(2) | 9.0319(1) | 3.759(1) |
b, Å | 18.554(2) | 5.184(1) | 23.547(5) | 10.860(1) | 27.082(9) |
c, Å | 4.709(1) | 19.547(4) | 7.127(1) | 23.561(2) | 6.551(2) |
α, deg | 90 | 90 | 90 | 90 | 90 |
β, deg | 90 | 103.08(3) | 90.22(3) | 97.950(2) | 90.735(8) |
γ, deg | 90 | 90 | 90 | 90 | 90 |
V, Å3 | 1298.8(2) | 1261.1(5) | 1415.5(5) | 2288.8(3) | 666.9(4) |
Z | 4 | 4 | 4 | 4 | 2 |
D c, Mg m−3 | 1.398 | 1.360 | 1.348 | 1.336 | 1.475 |
μ, mm−1 | 0.101 | 0.097 | 0.096 | 0.096 | 0.108 |
F(000) | 576 | 544 | 608 | 968 | 308 |
θ min–θmax, deg | 1.8–25.2 | 4.1–27.8 | 3.5–27.9 | 1.8–28.3 | 1.5–26.5 |
Index ranges min./max. h,k,l | −17:17 | −16:16 | −11:11 | −7:12 | −4:4 |
−22:22 | −6:6 | −30:23 | −14:14 | −33:34 | |
−5:5 | −25:25 | −9:6 | −31:31 | −8:8 | |
Reflections collected | 12991 | 4851 | 7340 | 31250 | 5055 |
Independent reflections | 2330 | 2852 | 3315 | 5695 | 2702 |
R int | 0.047 | 0.027 | 0.075 | 0.040 | 0.039 |
Data/parameters refined | 2330/198 | 2852/182 | 3315/208 | 5695/317 | 2702/204 |
No. of reflections with I > 2σ(I) | 2032 | 1873 | 1563 | 4225 | 1894 |
Goodness of fit, S | 1.04 | 0.97 | 0.99 | 1.03 | 0.99 |
R (F) [I > 2σ(I)] | 0.0329 | 0.0401 | 0.0583 | 0.0398 | 0.0470 |
Final wR2 (all data) | 0.0788 | 0.1076 | 0.1566 | 0.1133 | 0.1029 |
Largest diff. peak and hole, e Å−3 | −0.19, 0.12 | −0.23, 0.25 | −0.29, 0.25 | −0.22, 0.25 | −0.21, 0.16 |
Salts | A5·B6 | A3·B8 | A2·B8 | A5·B10 | A4·B9 |
---|---|---|---|---|---|
V(8) | VII(16) | VIII(17) | IX(18) | X(19) | |
ΔpKa = 0.38 | ΔpKa = 2.76 | ΔpKa = 2.80 | ΔpKa = 2.85 | ΔpKa = 3.23 | |
Molecular formula | C7H6NO2· | C7H5O2· | C7H4BrO2· | C7H6NO2· | C8H7O3· |
C9H9N2 | C5H7N2 | C5H7N2 | C6H9N2 | C6H9N2 | |
Molecular mass | 281.31 | 216.24 | 295.13 | 245.28 | 260.29 |
Crystal system | Monoclinic | Orthorhombic | Monoclinic | Orthorhombic | Monoclinic |
Space group | P21/c | Pbca | P21/c | P212121 | P21/n |
a, Å | 7.335(2) | 11.500(2) | 9.686(1) | 5.554(1) | 9.440(2) |
b, Å | 9.187(2) | 15.191(3) | 10.333(1) | 8.553(2) | 11.509(2) |
c, Å | 21.307(4) | 12.228(2) | 12.002(1) | 25.380(5) | 12.690(3) |
α, deg | 90 | 90 | 90 | 90 | 90 |
β, deg | 93.30(3) | 90 | 97.765(2) | 90 | 110.77(3) |
γ, deg | 90 | 90 | 90 | 90 | 90 |
V, Å3 | 1433.3(5) | 2136.2(7) | 1190.2(1) | 1205.7(4) | 1289.2(5) |
Z | 4 | 8 | 4 | 4 | 4 |
D c, Mg m−3 | 1.304 | 1.345 | 1.647 | 1.351 | 1.341 |
μ, mm−1 | 0.089 | 0.094 | 3.444 | 0.094 | 0.095 |
F(000) | 592 | 912 | 592 | 520 | 552 |
θ min–θmax, deg | 2.4–27.5 | 3.8–27.9 | 2.1–26.4 | 2.9–25.3 | 2.9–25.4 |
Index ranges min./max. h,k,l | −9:9 | −14:14 | −12:12 | −6:6 | −11:11 |
−11:11 | −19:19 | −12:12 | −10:10 | −13:13 | |
−27:27 | −14:15 | −15:15 | −30:30 | −15:15 | |
Reflections collected | 6289 | 4451 | 18549 | 2199 | 4578 |
Independent reflections | 3266 | 2433 | 2439 | 2199 | 2355 |
R int | 0.014 | 0.050 | 0.032 | 0 | 0.036 |
Data/parameters refined | 3266/210 | 2433/157 | 2439/198 | 2199/184 | 2355/186 |
No. of reflections with I > 2σ(I) | 2867 | 1432 | 2182 | 1468 | 1445 |
Goodness of fit, S | 1.06 | 0.95 | 1.04 | 0.94 | 0.96 |
R (F) [I > 2σ(I)] | 0.0363 | 0.0443 | 0.0208 | 0.0389 | 0.0423 |
Final wR2 (all data) | 0.1032 | 0.1106 | 0.0540 | 0.0796 | 0.0972 |
Largest diff. peak and hole, e Å−3 | −0.19, 0.28 | −0.25, 0.22 | −0.39, 0.26 | −0.22, 0.16 | −0.24, 0.19 |
Salts | A4·B10 | A3·B9 | A2·B9·2(H2O) | A2·B10 |
---|---|---|---|---|
XI(20) | XII(22) | XIII(23) | XIV(24) | |
ΔpKa = 3.25 | ΔpKa = 3.52 | ΔpKa = 3.56 | ΔpKa = 3.58 | |
Molecular formula | C8H7O3· | C7H5O2· | C7H4BrO2· | C7H4BrO2· |
C6H9N2 | C6H9N2 | C6H9N2·2(H2O) | C6H9N2 | |
Molecular mass | 260.29 | 230.26 | 345.15 | 309.15 |
Crystal system | Monoclinic | Orthorhombic | Monoclinic | Monoclinic |
Space group | P21/c | Pca21 | P21/n | P21/c |
a, Å | 10.337(2) | 11.888(2) | 17.124(2) | 9.579(2) |
b, Å | 11.727(2) | 12.313(3) | 4.132(1) | 11.539(2) |
c, Å | 11.031(2) | 16.815(3) | 22.882(2) | 11.311(2) |
α, deg | 90 | 90 | 90 | 90 |
β, deg | 105.53(3) | 90 | 111.762(2) | 100.45(3) |
γ, deg | 90 | 90 | 90 | 90 |
V, Å3 | 1288.4(4) | 2461.3(9) | 1503.5(2) | 1229.4(4) |
Z | 4 | 8 | 4 | 4 |
D c, Mg m−3 | 1.342 | 1.243 | 1.525 | 1.670 |
μ, mm−1 | 0.096 | 0.085 | 2.748 | 3.339 |
F(000) | 552 | 976 | 704 | 624 |
θ min–θmax, deg | 3.5–27.9 | 2.9–28.0 | 1.9–26.4 | 4.1–27.9 |
Index ranges min./max. h,k,l | −13:12 | −13:13 | −19:21 | −10:12 |
−11:14 | −15:15 | −5:5 | −11:14 | |
−13:13 | −21:21 | −28:19 | −14:12 | |
Reflections collected | 5041 | 4641 | 8753 | 6862 |
Independent reflections | 2887 | 4641 | 3036 | 2789 |
R int | 0.036 | 0 | 0.028 | 0.027 |
Data/parameters refined | 2887/186 | 4641/333 | 3036/204 | 2789/176 |
No. of reflections with I > 2σ(I) | 1640 | 3081 | 2400 | 2326 |
Goodness of fit, S | 0.94 | 1.02 | 1.00 | 1.05 |
R (F) [I > 2σ(I)] | 0.0462 | 0.0525 | 0.0303 | 0.0242 |
Final wR2 (all data) | 0.1205 | 0.1297 | 0.0821 | 0.0556 |
Largest diff. peak and hole, e Å−3 | −0.29, 0.26 | −0.24, 0.21 | −0.40, 0.59 | −0.53, 0.49 |
Crystal 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 literature15–17 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 F2. The program X-Seed27 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.
Fig. 4 Packing of structure I displaying anti-parallel ribbons running along [100]. The ribbons are weakly connected via (Acid)–N–H⋯N–(Acid) displayed in blue. |
Structure II consists of benzoic acid and 2-acetaminopyridine, A3·B2, in the space group P21/n with Z = 4. The structure is made of acid-base pairs which are hydrogen bonded with R22(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 P21/c with Z = 4. The structure is similar to that of 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, C22(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.
Structure IV arose from a mixture of 4-methoxybenzoic acid and 4,4′-bipyridine, 2A4·B3 and crystallises in P21/c with Z = 4. The bipyridine is di-basic and therefore has two distinct pKa values, giving rise to two points on the co-crystal/salt versus ΔpKa diagram reported in Fig. 3. The asymmetric unit consists of the bipyridine moiety hydrogen bonded to two 4-methoxybenzoic acids which may be represented by D22(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 P21 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.
Structure VII is derived from benzoic acid and 2-aminopyridine, A3·B8. It crystallises in Pbca with Z = 8 and its packing is characterised by infinite chains which may be described as C22(6) R22(8) which run parallel to [100] (Fig. 7).
Structure VIII arose from 4-bromobenzoic acid and 2-aminopyridine, A2·B8 and crystallises in the space group P21/c with Z = 4. The hydrogen bonding is comparable to that of structure VII with the infinite chains running parallel to [001].
Structure IX derives from 4-aminobenzoic acid and 2-amino-4-methylpyridine, A5·B10. The packing is characterised by a chain of hydrogen bonds, C33(14) R22(8) running along [001] which cross a spiral of hydrogen bonds C24(8) which extend along [110] (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]. |
Structure X is derived from 4-methoxybenzoic acid and 2-amino-6-methylpyridine, A4·B9. It crystallises in P21/n and the packing displays C22(6) R22(8) similar to that of structure VII.
Structure XI crystallises from 4-methoxybenzoic acid and 2-amino-4-methylpyridine, A4·B10, in space group P21/c with Z = 4 and displays the same hydrogen bond motif as structure VII.
Structure XII was derived from benzoic acid and 2-amino-6-methylpyridine, A3·B9. It crystallises in the space group Pca21 with Z = 8. The packing is characterised by two crystallographically independent chains of hydrogen bonded ions. These C22(6) R22(8) chains run parallel to [100].
Structure XIII arose from 4-bromobenzoic acid and 2-amino-6-methylpyridine, A2·B9·2(H2O). This compound crystallises as a di-hydrate in the space group P21/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: C12(4) R46(12). The second water molecule links ladders together, giving rise to hydrogen bonded sheets which run along [010] (Fig. 9).
Structure XIV arose from 4-bromobenzoic acid and 2-amino-4-methylpyridine, A2·B10, crystallising in space group P21/c with Z = 4. The packing motif is again C22(6) R22(8) similar to that of structure VII.
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.
Footnote |
† The structures were deposited at the Cambridge Crystallographic Data Centre and allocated the numbers: CCDC 963007–963012, 963014–963021. CIF files have been submitted as ESI. For crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ce41963k |
This journal is © The Royal Society of Chemistry 2014 |