Exploring the hydrogen-bond preference of N–H moieties in co-crystals assembled via O–H(acid)⋯N(py) intermolecular interactions

Abstract

In order to establish the hydrogen-bond preference of an amide based N–H moiety faced with different C=O or –OH hydrogen-bond acceptors, the crystal structures of several new co-crystals and salts were examined: 3-acetaminopyridine fumaric acid (2 : 1) 1, 4-(acetaminomethyl)pyridine fumaric acid (2 : 1) 2, 4-acetaminopyridine decanedioic (sebacic) acid (2 : 1) 3, 4-(acetaminomethyl)pyridine adipic acid (2 : 1) 4, 4-(acetaminomethyl)pyridine isophthalic acid (2 : 1) 5, 4-(acetaminomethyl)pyridinium 5-nitro-hydrogen isophthalate hydrate 6, 4-acetaminopyridinium hydrogenglutarate (1 : 1) 7. All co-crystals, 1–5, are constructed from an O–H(acid)⋯N(py) hydrogen bond and for the salts, 6–7, the primary synthon is the corresponding charge-assisted N–H⁺⋯⁻O interaction. The remaining N–H donor (on the amide moiety) shows a preference (4 out of 5) for the amide C=O over the acid C=O.

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Introduction

The design and synthesis of co-crystals is currently receiving considerable attention¹ partly because of fundamental interest in molecular-recognition driven assembly processes,² and partly because of potential applications of co-crystals in all areas of functional solids, notably pharmaceuticals.³ Most supramolecular synthetic strategies employed in the deliberate design of binary co-crystals^4,5 are based upon combinations of functional groups located on different molecules that prefer to interact with each other rather than with themselves,^6–8 such that heteromeric recognition and binding (required for co-crystal formation) are favored over homomeric hydrogen bonds (which will lead to a simple recrystallization of the reactants). In this context, it is often helpful to utilize the Etter “rules”⁹ which suggest that the best hydrogen-bond donor will preferentially interact with the best hydrogen-bond acceptor and the second-best acceptor with the second-best donor etc. Empirically based guidelines like these have facilitated the deliberate construction of families of co-crystals with desired connectivity incorporating a wide range of acids, amides, and heterocycles.¹⁰

In this particular study, we have employed a combination of two well-known and robust synthons, the heteromeric carboxylic acid⋯pyridine interaction and the N–H⋯O (amide⋯carbonyl) interaction in an attempt to prepare binary co-crystals. The initial assembly of the co-crystal will be achieved by locating a carboxylic acid and a pyridyl moiety on different molecular fragments. Once this interaction is locked into place, the resulting binary aggregates can be further organized through N–H⋯O interactions. However, since the N–H donor has a choice of three different potential hydrogen-bond acceptors, it is not obvious how the competition between those three oxygen atoms will play out, Scheme 1.

Scheme 1 Expected primary acid⋯pyridine synthon (I). Three possible interactions involving the N–H hydrogen-bond donor: with the amide C=O (II), with the acid C=O (III), with the acid O–H (IV).

The goal of this study is to determine patterns of molecular recognition preferences of the N–H moiety based upon an analysis of several new co-crystals as well as of relevant data obtained from the CSD.¹¹

Experimental

All chemicals were purchased from Aldrich and used without further purification. Melting points were determined on a Fisher-Johns melting point apparatus and are uncorrected.

Preparations

Synthesis of 3-acetaminopyridine. 3-Acetaminopyridine was prepared by the previously reported method.¹² 3-Aminopyridine (1.882 g, 20.0 mmol) was dissolved in a mixture of pyridine (10 mL) and acetic anhydride (10 mL) and the resulting solution was kept at room temperature for 24 h. Water (10 mL) was added and the solution was evaporated in vacuo to dryness. The precipitates thus obtained were washed thoroughly with diethyl ether and recrystallized from methanol. Mp 133–134 °C. IR (KBr pellet) v 1695 cm⁻¹ (C=O, s), 1533 cm⁻¹ (Amide II, s).

Synthesis of 4-acetaminopyridine. 4-Aminopyridine (1.882 g, 20 mmol) was dissolved in a mixture of pyridine (10 mL) and acetic anhydride (10.8 g, 106 mmol, 10 mL). The mixture was left to stir at room temperature for 24 h under a nitrogen atmosphere. Water (10 mL) was added and the solution was evaporated in a rotary evaporator to dryness. The precipitate obtained was washed thoroughly with diethyl ether and recrystallized from methanol. The product isolated was a light yellow solid (1.76 g, 65%), mp 144–146 °C. ¹H NMR (CDCl₃) δ 8.49 (d, 1H), 8.46 (d, 1H), 7.76 (s, 1H), 7.52 (d, 1H), 7.48 (d, 1H), 2.23 (s, 3H). IR (KBr pellet) ν 1689 cm⁻¹ (C=O), 1515 cm⁻¹ (Amide II, s).

Synthesis of 4-(acetaminomethyl)pyridine. 4-(Acetaminomethyl)pyridine was prepared by employing a modification of the previously reported procedure.¹³ Acetic anhydride (10 mL) was added very slowly into 4-(aminomethyl)pyridine (5.0 mL, 50.0 mmol) with continuous stirring and the resulting solution was refluxed for 1 h. Excess of acetic anhydride and acetic acid produced during the reaction were evaporated and the product thus obtained was recrystallized from diethyl ether. Mp 88–89 °C. IR (KBr pellet) v 1653 cm⁻¹ (C=O, s), 1558 cm⁻¹ (Amide II, s).

Synthesis of 3-acetaminopyridine fumaric acid (2 : 1), 1. 3-Acetaminopyridine (0.027 g, 0.20 mmol) was dissolved in 7 mL of ethanol. To this solution was added fumaric acid (0.012 g, 0.10 mmol) in 5 mL of ethanol. The resulting solution was boiled and allowed to stand for slow evaporation. Colorless prisms were obtained after seven days. Mp 162–163 °C ; IR (KBr pellet) v 2410 cm⁻¹, 1895 cm⁻¹ (O–H⋯N, br), 1717 cm⁻¹ (C=O acid, s), 1672 cm⁻¹ (C=O amide I, s), 1558 cm⁻¹ (Amide II, s).

Synthesis of 4-(acetaminomethyl)pyridine fumaric acid (2 : 1), 2. 4-(Acetaminomethyl)pyridine (0.030 g, 0.20 mmol) was dissolved in 5 mL of acetonitrile and mixed with a solution of fumaric acid (0.012 g, 0.10 mmol) in 6 mL of acetonitrile. The solution was boiled and allowed to stand at ambient temperature for slow evaporation. Colorless prisms were afforded after 6 d. Mp 120 °C; IR (KBr pellet) v 2426 cm⁻¹, 1900 cm⁻¹ (O–H⋯N, br), 1688 cm⁻¹ (C=O acid, s), 1656 cm⁻¹ (C=O amide I, s), 1560 cm⁻¹ (Amide II, s).

Synthesis of 4-acetaminopyridine decanedioic (sebacic) acid (2 : 1), 3. 4-Acetaminopyridine (0.03 g, 0.22 mmol) was dissolved in 4 mL of acetonitrile. To this solution was added sebacic acid (0.022 g, 0.11 mmol) in 4 mL of acetonitrile. The resulting solution was allowed to stand at room temperature for slow evaporation. Colorless prisms were obtained after 6 d. Mp 120–123 °C; IR (KBr pellet) ν 2499 cm⁻¹, 1920 cm⁻¹ (O–H⋯N, br), 1711 cm⁻¹ (C=O acid, s), 1597 cm⁻¹ (C=O amide I, s), 1507 cm⁻¹ (Amide II, s).

Synthesis of 4-(acetaminomethyl)pyridine adipic acid (2 : 1), 4. 4-(Acetaminomethyl)pyridine (0.030 g, 0.20 mmol) was dissolved in 5 mL of ethanol. To this solution was added adipic acid (0.015 g, 0.10 mmol) in 7 mL of ethanol. The resulting solution was boiled and allowed to stand. Colorless needles were obtained upon slow evaporation of the solvent. Mp 118–120 °C; IR (KBr pellet) v 2500 cm⁻¹, 1950 cm⁻¹ (O–H⋯N, br), 1695 cm⁻¹ (C=O acid, s), 1652 cm⁻¹ (C=O amide I, s), 1554 cm⁻¹ (Amide II, s).

Synthesis of 4-(acetaminomethyl)pyridine isophthalic acid (2 : 1), 5. 4-(Acetaminomethyl)pyridine (0.030 g, 0.20 mmol) was dissolved in 5 mL of ethanol. To this solution was added isophthalic acid (0.017 g, 0.10 mmol) in 5 mL of ethanol. The resulting solution was boiled and allowed to stand for slow evaporation. Colorless prisms were obtained after 4 d. Mp 125–126 °C ; IR (KBr pellet) v 2453 cm⁻¹, 1917 cm⁻¹ (O–H⋯N, br), 1700 cm⁻¹ (C=O acid, s), 1652 cm⁻¹ (C=O amide I, s), 1558 cm⁻¹ (Amide II, s).

Synthesis of 4-(acetaminomethyl)pyridinium 5-nitro-hydrogenisophthalate hydrate, 6. A solution of 4-(acetaminomethyl)pyridine (0.030 g, 0.20 mmol) in 5 mL of ethanol was mixed with a solution of 5-nitro-isophthalic acid (0.021 g, 0.10 mmol) in 8 mL of ethanol and was allowed to stand for slow evaporation. Colorless prisms were obtained after 9 d. Mp 148–150 °C; IR (KBr pellet) v 2515 cm⁻¹, 2158 cm⁻¹ (O–H…O and N–H⋯O, br), 1700 cm⁻¹ (C=O acid, s), 1652 cm⁻¹ (C=O amide I, s), 1534 cm⁻¹ (Amide II, s).

Synthesis of 4-acetaminopyridinium hydrogenglutarate, 7. 4-Acetaminopyridine (0.03 g, 0.22 mmol) was dissolved in 4 mL of acetonitrile. To this solution was added glutaric acid (0.015 g, 0.11 mmol) in 4 mL of acetonitrile. The resulting solution was allowed to stand at room temperature for slow evaporation. Colorless prisms were obtained after 5d. Mp 119–121 °C; IR (KBr pellet) ν 2500 cm⁻¹, 2150 cm⁻¹ and 1850 cm⁻¹ (O–H⋯O and N–H⋯O, br), 1718 cm⁻¹ (C=O acid, s), 1652 cm⁻¹ (C=O amide I, s), 1555 cm⁻¹ (Amide II, s).

Synthesis of 3-acetaminopyridine succinic acid (2 : 1), 8. A solution of 3-acetaminopyridine (0.027 g, 0.20 mmol) and succinic acid (0.012 g, 0.10 mmol) in 12 mL of ethanol was boiled and allowed to stand. Colorless prisms were afforded after one week of slow evaporation of solvent. Mp 133–135 °C; IR (KBr pellet) v 2450 cm⁻¹, 1861 cm⁻¹ (O–H⋯N, br), 1717 cm⁻¹ (C=O acid, s), 1699 cm⁻¹ (C=O amide I, s), 1557 cm⁻¹ (Amide II, s).

X-Ray crystallography

X-Ray data were collected on a Bruker SMART 1000 four-circle CCD diffractometer at 173 K (2, 4, 5, 6, and 7) or a SMART APEX CCD diffractometer at 100 K (1 and 3) using a fine-focus molybdenum Kα tube. Data were collected using SMART.¹⁴ Initial cell constants were found by small widely separated “matrix” runs. Generally, an entire hemisphere of reciprocal space was collected regardless of Laué symmetry. Scan speed and scan width were chosen based on scattering power and peak rocking curves.

Unit cell constants and orientation matrix were improved by least-squares refinement of reflections thresholded from the entire dataset. Integration was performed with SAINT,¹⁵ using this improved unit cell as a starting point. Precise unit cell constants were calculated in SAINT from the final merged dataset. Lorenz and polarization corrections were applied. Laué symmetry, space group, and unit cell contents were found with XPREP.

Data were reduced with SHELXTL.¹⁶ The structures were solved in all cases by direct methods without incident, Table 1. In general, hydrogen atoms were assigned to idealized positions and were allowed to ride. Where possible, the coordinates of the amide hydrogen atoms were allowed to refine. Heavy atoms were refined with anisotropic thermal parameters. Unless otherwise noted, data were corrected for absorption.

Table 1 X-Ray data for 1–7

	1	2	3	4	5	6	7
Formula moiety	(C7H8N2O)2	(C8H10N2O)2	(C7H8N2O)2	(C8H10N2O)2	(C8H10N2O)2	(C8H10N2O)	(C7H8N2O)
	(C4H4O4)	(C4H4O4)	(C10H18O4)	(C6H10O4)	(C8H6O4)	(C8H5NO6)	(C5H8O4)
						(H2O)
Empirical formula	C18H20N4O6	C20H24N4O6	C24H34N4O6	C22H30N4O6	C24H26N4O6	C16H17N3O8	C12H16N2O5
Molecular weight	388.38	416.43	474.55	446.50	466.49	379.33	268.27
Color, habit	Colorless, plate	Colorless, plate	Colorless, irregular	Colorless, plate	Colorless, prism	Amber, prism	Colorless, prism
Crystal system	Orthorhombic	Triclinic	Monoclinic	Monoclinic	Orthorhombic	Monoclinic	Triclinic
Space group, Z	Pca2(1), 4	P1̄, 1	C2/c, 4	P2(1)/c, 2	Fdd2, 16	P2(1)/c, 4	P1̄, 2
a/Å	17.930(4)	4.9718(10)	28.532(3)	4.7523(7)	34.784(6)	18.5868(12)	7.1730(8)
b/Å	3.9380(10)	7.0047(11)	8.2965(8)	24.295(3)	57.476(12)	6.8213(5)	7.6117(8)
c/Å	25.723(6)	15.101(2)	10.6120(10)	10.0355(12)	4.7674(9)	14.0335(10)	11.9194(13)
α/		77.032(10)					80.462(7)
β/°		89.414(12)	101.987(2)	97.944(10)		103.406(4)	75.807(7)
γ/°		82.324(12)					87.896(7)
Volume/Å^3	1816.2(8)	507.80(15)	2457.2(4)	1147.6(3)	9531(3)	1730.8(2)	622.19(12)
Density/g cm^−3	1.420	1.362	1.283	1.292	1.300	1.456	1.432
T/K	100(2)	173(2)	100(2)	173(2)	153(2)	173(2)	173(2)
X-Ray wavelength	0.71073	0.71073	0.71073	0.71073	0.71073	0.71073	0.71073
μ/m^−1	0.109	0.102	0.093	0.095	0.095	0.119	0.112
Θ min/°	1.58	1.38	2.56	1.68	1.37	2.25	1.79
Θ max/°	28.22	28.23	30.53	28.24	28.43	28.30	26.37
Reflections collected	11419	3376	14481	8215	16779	21273	3381
independent	2172	2078	3740	2669	3203	4088	2213
observed	1612	1054	3007	1557	1325	2360	1710
Threshold expression	>2σ(I)	>2σ(I)	>2σ(I)	>2σ(I)	>2σ(I)	>2σ(I)	>2σ(I)
R 1 (observed)	0.0861	0.0883	0.0555	0.0620	0.0699	0.0683	0.0542
wR 2 (all)	0.2264	0.2920	0.1600	0.1486	0.1904	0.2112	0.1483
GooF	1.110	0.941	1.066	0.963	0.823	1.032	1.000

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Compound 1. The two unique amides and the one dicarboxylic acid all sit on general positions. The two amide hydrogens (H13 and H23) and the two carboxylic acid hydrogens (H31 and H34) were inserted in calculated positions and were allowed to ride.

Compound 2. The unique amide sits on a general position. The dicarboxylic acid sits on a crystallographic inversion center. The amide hydrogen (H17) and carboxylic acid hydrogen (H31) were inserted in calculated positions and were allowed to ride.

Compound 3. The unique amide sits on a general position. The dicarboxylic acid sits on a crystallographic inversion center. Positional coordinates for the amide hydrogen (H17) and the carboxylic acid hydrogen (H21) were allowed to refine.

Compound 4. The unique amide sits on a general position. The dicarboxylic acid sits on a crystallographic inversion center. Positional coordinates for the amide hydrogen (H21) and the carboxylic acid hydrogen (H31) were allowed to refine. The pyridine ring exhibited paddlewheel disorder and was modelled as two species. Occupancy of the two species refined to a nearly 50 : 50 ratio. The geometries of the species were constrained by the SHELXL “SAME” command, and the thermal parameters of the superimposable N11A/N11B and C11A/C11B atoms were pairwise constrained to the same values. An extinction parameter was added based on a SHELXL recommendation, and this parameter refined to an acceptably small value.

Compound 5. The two unique amides and the one dicarboxylic acid all sit on general positions. The two amide hydrogen atoms (H17 and H27) and the two carboxylic acid hydrogen atoms (H31 and H33) were inserted in calculated positions and were allowed to ride. Friedel opposites were merged.

Compound 6. The unique amide and unique carboxylic acid both sit on general positions. The difference Fourier map indicated the presence of water of hydration, which was modeled as two superimposed molecules (at a 50 : 50 ratio) differing only in the location of their hydrogen atoms. The two water species were restrained to an idealized geometry. Positional coordinates for the pyridinium hydrogen atom H11, amide hydrogen atom H17, and carboxylic acid hydrogen H23 were allowed to refine.

Compound 7. The unique amide and unique carboxylic acid both sit on general positions. Positional coordinates for the pyridinium hydrogen H11, amide hydrogen H14, and carboxylic acid hydrogen H25 were allowed to refine.

CCDC reference numbers 624060–624066. For crystallographic data in CIF or other electronic format see DOI: 10.1039/b614984g

Results

The crystal structure of 1 contains two molecules of 3-acetaminopyridine and one molecule of fumaric acid in the asymmetric unit. The two unique hydrogen bonds O–H⋯N are formed by the O–H group, from each end of the dicarboxylic acid and the pyridine N atom of the 3-acetaminopyridine molecules, (O31⋯N21, 2.597(7) Å and O34⋯N11, 2.625(7) Å), Table 2. Each trimeric unit resulting from primary hydrogen bonding is coplanar and the two pyridine moieties are arranged in an up–down manner with respect to each other Fig. 1.

Fig. 1 Thermal ellipsoids (50%) and labeling scheme of the supramolecular 2 : 1 trimer in 1.

Table 2 Hydrogen parameters for 1–7

Compound	D–H⋯A	d(D–H)/Å	d(H⋯A)/Å	d(D⋯A)/Å	<(DHA)/°
Symmetry codes: #1 1 − x, 1 − y, −0.5 + z; #2 1.5 − x, −2 + y, 0.5 + z; #3 1 + x, y, z; #4 −1 + x, y, z; #5 x, y, −1 + z; #6 x, y, 1 + z; #7 x, 0.5 − y, 0.5 + z; #8 x, −0.5 − y, −0.5 + z; #9 −x, −y, 2 − z; #10 1 + x, 1 + y, −1 + z.
1	O(31)–H(31)⋯N(21)	0.84	1.76	2.597(7)	173.8
	N(23)–H(23)⋯O(17)#1	0.88	2.02	2.847(7)	157.0
	O(34)–H(34)⋯N(11)	0.84	1.79	2.623(7)	174.7
	N(13)–H(13)⋯O(27)#2	0.88	2.02	2.872(7)	163.2
2	O(31)–H(31)⋯N(11)	0.84	1.78	2.614(5)	176.0
	N(17)–H(17)⋯O(21)#3	0.88	2.04	2.869(4)	157.2
3	O(21)–H(21)⋯N(11)	1.136(19)	1.421(19)	2.5516(15)	172.5(17)
	N(17)–H(17)⋯O(22)	0.845(19)	2.012(19)	2.8494(15)	170.8(17)
4	O(31)–H(31)⋯N(11A)	0.95(2)	1.78(2)	2.731(11)	172(2)
	O(31)–H(31)⋯N(11B)	0.95(2)	1.66(2)	2.610(9)	175(2)
	N(21)–H(21)⋯O(22)#4	0.90(2)	1.86(2)	2.759(2)	173.1(19)
5	O(31)–H(31)⋯N(11)	0.84	1.79	2.632(6)	176.9
	N(17)–H(17)⋯O(18)#5	0.88	1.89	2.762(6)	172.3
	O(33)–H(33)⋯N(21)	0.84	1.76	2.582(6)	164.7
	N(27)–H(27)⋯O(28)#6	0.88	1.88	2.740(6)	165.7
6	O(23)–H(23)⋯O(22)	0.87(3)	1.74(3)	2.602(3)	171(3)
	N(11)–H(11)⋯O(22)	1.09(3)	1.55(3)	2.635(3)	173(3)
	O(1A)–H(1)⋯O(21)	1.09(4)	2.48(7)	2.743(3)	92(4)
	N(17)–H(17)⋯O(1A)#7	0.88(3)	2.01(3)	2.833(4)	156(3)
	O(1A)–H(1)⋯O(18)#8	1.12(4)	1.80(5)	2.790(3)	145(5)
7	O(25)–H(25)⋯O(21)#9	0.96(3)	1.58(3)	2.5309(19)	170(2)
	N(11)–H(11)⋯O(21)	0.88(3)	1.79(3)	2.677(2)	177(2)
	N(14)–H(14)⋯O(26)#10	0.86(2)	1.97(2)	2.822(2)	177(2)

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In addition to the hydrogen bonding within the trimer, each N–H donor (amide) forms a hydrogen bond with an adjacent amide C=O moiety (mode II, Scheme 1), N13⋯O27(#1), 2.874(7) Å and N23⋯O17(#2), 2.851(7) Å, Fig. 2.

Fig. 2 Alignment of trimers by N–H⋯O (amide) hydrogen bonds in 1.

The asymmetric unit of 2 contains one molecule of 4-acetaminomethylpyridine and half a molecule of fumaric acid. Two symmetry related O–H⋯N hydrogen bonds are formed by the two O–H groups of the dicarboxylic acid and pyridine nitrogen atoms (O31⋯N11, 2.611(5) Å), Table 2. The two pyridine rings in the trimer are coplanar with respect to one another as well as with the plane of fumaric acid but the amide groups at both ends are positioned in an up–down arrangement, Fig. 3.

Fig. 3 Thermal ellipsoids (50%) and labeling scheme of the supramolecular 2 : 1 trimer in 2.

Adjacent trimeric supermolecules produced from the primary hydrogen bonds are connected to one another via symmetry related hydrogen bonds involving H17 from the amide N–H group of one molecule and O21(#2) to an adjacent amide C=O group, N17⋯O21(#2), 2.868(4) Å (mode II, Scheme 1). The overall result is an infinite 1-D ladder of trimers, Fig. 4.

Fig. 4 Alignment of trimers by N–H⋯O hydrogen bonds resulting in infinite 1-D ladders in 2.

The crystal structure of 3 has one molecule of 4-acetaminopyridine and half a molecule of sebacic acid in the asymmetric unit. The trimeric supermolecule is constructed from symmetry related O–H⋯N hydrogen bonds between the O–H of the dicarboxylic acid and the pyridine nitrogen atom (O21⋯N11, 2.5516(15) Å), Fig. 5, Table 2.

Fig. 5 Thermal ellipsoids (50%) and labeling scheme of the supramolecular 2 : 1 trimer in 3.

Adjacent trimers are interconnected via an amide–carbonyl hydrogen bond but this time the acceptor moiety is the C=O moiety located on the carboxylic acid (mode III, Scheme 1). The result of this interaction is an infinite 2-D layer of orthogonal supermolecules, Fig. 6.

Fig. 6 Orientation of adjacent supramolecular trimers in 3.

The crystal structure of 4 contains one molecule of 4-acetaminomethylpyridine and half a molecule of adipic acid in the asymmetric unit. A trimeric supermolecule is constructed from the two O–H groups of the dicarboxylic acid and pyridine nitrogen atoms, O31⋯N(11A), 2.731(11) Å (Table 2; for a description of the disorder of the pyridine ring, see the Experimental section). Both pyridine rings in the trimeric unit are coplanar with respect to each other but perpendicular to the plane of the COOH groups, and the two amide groups are organized in an up–down manner, Fig. 7.

Fig. 7 Thermal ellipsoids (50%) and labeling scheme of the supramolecular 2 : 1 trimer in 4.

Each 4-acetaminomethylpyridine molecule forms an N–H hydrogen bond with a neighboring C=O (amide) moiety, N21⋯O22(#2), 2.759(2) Å (mode II, Scheme 1) resulting in infinite 1-D ribbons of trimers, Fig. 8.

Fig. 8 Orientation of adjacent supramolecular trimers in 4 affected by N–H⋯O=C (amide) hydrogen bonds (pyridine moieties are disordered).

In the crystal structure of 5, the asymmetric unit comprises two molecules of 4-acetaminomethylpyridine and one molecule of isophthalic acid. The primary synthons in this structure are the two unique O–H⋯N hydrogen bonds resulting from the interactions between the diacid and two 4-acetaminomethylpyridine molecules (O31⋯N11, 2.620(6) Å; and O33⋯N21, 2.580(6) Å), Fig. 9, Table 2.

Fig. 9 Thermal ellipsoids (50%) and labeling scheme of the supramolecular 2 : 1 trimer in 5.

Adjacent trimeric supermolecules produced from the primary hydrogen bonds are further connected with one another (mode II, Scheme 1) via two unique hydrogen bonds, involving H17 from the amide N–H group and O18 on the amide C=O group and H27 from the amide N–H group and O28 on the amide carbonyl group (N17⋯O18(#1), 2.760(6) Å and N27(#1)⋯O28, 2.739(6) Å), resulting in an infinite 1-D ladder, Fig. 10.

Fig. 10 Orientation of adjacent supramolecular trimers in 5 affected by N–H⋯O=C (amide) hydrogen bonds.

The crystal structure of 6 contains one 4-acetaminomethylpyridinium cation, one monoanion of 5-nitro-isophthalic acid and one disordered water molecule in the asymmetric unit. A charge-assisted N–H⋯O interaction forms as a consequence of proton transfer between one of the carboxyl moieties in 5-nitro-isophthalic acid and the nitrogen atom in the pyridine ring (N11⋯O22, 2.635(3) Å), Fig. 11, Table 2.

Fig. 11 Thermal ellipsoids (50%) and labeling scheme for 6.

The same oxygen atom of the carboxylate group (O22) is bifurcated as it also engages in an O–H⋯O hydrogen bond with the hydroxyl group of the remaining carboxylic acid moiety of the anion, O23#1⋯O22, 2.602(3) Å, producing an infinite 1-D helical chain, Fig. 12.

Fig. 12 1-D helical chain of 6 obtained through the formation of hydrogen bonds between the carboxylate groups and carboxylic acid groups of neighboring asymmetric units (water molecules left out for clarity).

The second oxygen atom of the carboxylate group forms an O–H⋯O hydrogen bond with a water molecule (O1A⋯O21, 2.744 Å). This disordered water molecule further forms hydrogen bonds with a neighboring amide C=O group (O1A⋯O18#2, 2.790(3) Å) and an N–H donor from a second cation (O1A⋯N17#1, 2.834(3) Å), Table 2; the combination of these interactions produce an infinite 1-D chain parallel to that of the 1-D helical backbone.

The crystal structure determination of 7 showed that a salt had formed resulting from proton transfer from one of acid moieties of glutaric acid to the pyridine ring leading to a charge assisted N–H⁺⋯O⁻ hydrogen bond as the driving force for the formation of the salt, Fig. 13.

Fig. 13 Thermal ellipsoids (50%) and labeling scheme for 7.

As was the case in 6, one oxygen atom is bifurcated and is participating in an O–H⋯O hydrogen bond with the remaining neutral carboxylic acid moiety resulting in a tetrameric pair of ions, Fig. 14.

Fig. 14 Two ion pairs connected into a tetramer in 7.

The N–H amide moiety forms a hydrogen bond with a C=O moiety at the neutral end of the anion (N14–H14⋯O26, 2.823 Å) corresponding to mode III, Scheme 1. These interactions connect adjacent tetramers into an infinite chain.

Discussion

The infrared spectra for compounds 1–8 reported in the present study indicate that reactions between acetaminopyridines and dicarboxylic acids produced molecular co-crystals in six (1–5, and 8) of the eight cases. Broad stretches near 2450 cm⁻¹ and 1900 cm⁻¹, which are characteristic of O–H⋯N(py) hydrogen bonds, appeared in the vibrational spectra of all of these six compounds suggesting the presence of neutral COOH⋯py intermolecular interactions thus eliminating the possibility of salt formation by conversion to the carboxylate anion (COO⁻). In the vibrational spectra of compounds 6–7, however, the 1900 cm⁻¹ band is shifted considerably towards higher wavenumbers, about 2150 cm⁻¹, suggesting the presence of COO⁻ moieties.

The single-crystal structure determinations carried out on 1–7 confirmed the assignments made on the basis of the vibrational spectroscopy. Structures 1–5 contain similar primary trimeric supermolecules constructed through the expected intermolecular O–H⋯N synthon between the dicarboxylic acid and pyridine. No proton transfer from acid to the base was observed in any of these five structures confirming the formation of co-crystals. The distinction between salt and co-crystal can also be made based upon select intermolecular distances and angles.

In the crystal structures of compounds 1–5 each carboxylic acid contains distinctly different C–O bond distances corresponding to the C=O (1.187–1.216 Å) and C–O(H) (1.300–1.323 Å) covalent bonds, and the C–N–C endocyclic bond angle of the heterocyclic moieties fall in the range 114.4–119.6° which is indicative of a non-ionized pyridine unit. In contrast, in the structures of 6 and 7 the carboxylate C–O bond distances are more similar (1.27/1.23 Å, and 1.29/1.22 for 6 and 7, respectively). Furthermore, the C–N–C endocyclic bond angles of the heterocyclic moieties in 6 and 7 are 121.8° and 121.1°, respectively, which is typical for a pyridinium cation.¹⁷

In addition to the primary hydrogen bonding within each trimer, the N–H moiety in each acetamino group is further involved in the formation of hydrogen bonds with a neighboring molecule; in four out of these five cases, the amide C=O moiety acts as the hydrogen-bond acceptor and only in 3 is this motif broken in favor of a C=O acid site. There is no obvious reason as to why the acid–based C=O is the preferred binding site for the N–H donor is this case since the ladder-type arrangement seen in 2, 4, and 5, would seem attainable even with a longer dicarboxylic acid such as sebacic acid (which is present in 3).

It is difficult to make direct comparisons between the co-crystals 1–5, and the salts, 6–7, but both salts display charge assisted carboxylate⋯pyridinium interactions. The N–H moiety in 6 forms a hydrogen bond with a water molecule (not a predictable option) and in 7 the acid C=O moiety is the acceptor.

A search for relevant acetaminopyridine⋯carboxylic acid co-crystals in the CSD produced 46 hits. Eighteen of those hits contained an amide moiety adjacent to the nitrogen atom of the heterocycle, whereas the remaining 28 structures contain pyridine substituted in the 3- or 4 position; we will only discuss structures in the latter category, as they are most relevant to this study.

First of all, every one of the 28 structures contains an O–H(acid)⋯N(py) hydrogen bond; this is undoubtedly the primary driving force for the formation of the co-crystals in this family of compounds. In 18 out of 28 hits, the amide N–H donor is forming a hydrogen bond with a C=O amide moiety (mode II, Scheme 1). In 8 out of 28 hits, the N–H donor is, instead, interacting with the C=O group from a carboxylic acid (mode III, Scheme 1). In the remaining two structures, the amide N–H donor is (a) structurally inactive, (b) using another py nitrogen atom as an acceptor, respectively.

The self-complementarity of monoacetylated amides is, generally, a reliable motif with the combination of functionalities present in 1–5, despite the potential competition from a C=O moiety located on a carboxylic acid. This intermolecular compatibility of the amide N–H and the amide C=O may therefore be employed in subsequent supramolecular synthetic strategies based upon a hierarchy of hydrogen-bond interactions even in the presence of potentially competitive hydrogen-bond acceptors. Furthermore, the carbonyl moiety located on the neutral carboxylic acid is not utilized as a hydrogen-bond acceptor in 1–5, and it may therefore provide a binding site for a third molecular component in the design of ternary co-crystals.

Acknowledgements

We are grateful for financial support from NSF (CHE-0316479), the Terry C. Johnson Center for Basic Cancer Research, and for a Fulbright Fellowship (to I.H.) by the U.S. Department of State Bureau of Educational and Cultural Affairs and the Council for International Exchange of Scholars.

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