Novel Crystalline Salts of 4-Piperidyl- and 4-Pyridylmethylamines Prepared by Catalytic Hydrogenation of 4-Pyridinecarbonitrile: Crystallographic Unit Cells Based on Powder XRD Patterns by Using the DASH Program Package

Abstract

Structures of some hydrogenated products and intermediates, prepared by a heterogeneous Pd/C or Ru/C catalyst starting from 4-pyridinecarbonitrile (4PN), in water and in the presence of an acidic additive (HCl or H₂SO₄), were confirmed in various salt forms of 4-piperidylmethylamine (4PIPA) and 4-pyridylmethylamine (4PA). Crystallographic unit cell structure of the completely hydrogenated product salts (4PIPA·H₂SO₄ and 4PIPA·2HCl) showed a common double-protonated [4PIPA+2H]²⁺ divalent cation structure, also proved by FT-IR, and that of the 4PA·H₂SO₄ intermediate salt was also indexed and modeled by means of powder X-ray diffraction, applying the DASH 4.0 software package and crystal coordinates coming from former single-crystal X-ray structure determination. Formations of the anhydrous and hydrated forms of 4PA·0.5H₂SO₄·xH₂O (x = 0 or x = 0.5, hemisulfates) were also studied by powder XRD and FT-IR spectroscopy for comparing these crystal structures.

1. Introduction

Aminomethyl-substituted pyridine and piperidine constitutional isomers can be synthesized by liquid-phase heterogeneous catalytic hydrogenation of the corresponding pyridinecarbonitriles using a 10% Pd/C catalyst [1]. Both the partially hydrogenated pyridylmethylamines and the completely saturated piperidylmethylamines can be obtained and captured in strongly acidic aqueous medium as hydrochloride or sulfate salts (Figure 1).

These N-heterocyclic compounds are valuable raw materials and intermediates for the preparation of pharmaceuticals, agricultural chemicals, or other products. Piperidines especially have a wide range of biological effects, including analgesic, antihypertensive, central nervous system depressant, antibacterial, or antifungal activities. For example, a novel class of potent and highly selective M₃ muscarinic antagonists [2] or human β₃ adrenoreceptor agonists [3,4] containing 4-piperydylmethylamine pharmacophore have been published recently. Furthermore, new phase-shifting 2-, 3-, or 4-pyridylmethylamine-based solvents with high CO₂ capture capacity (11−20 wt%) were reported, which readily bind CO₂ to form a crystalline salt under both dry and wet conditions [5]. In addition, the active pharmaceutical ingredients (APIs) are often produced and marketed in crystalline forms (e.g., hydrochlorides, sulfates, formates, etc.), therefore revealing their structures are important in both scientific and technological aspects.

In some cases, the solid-state structures of these crystalline salts are already known, and the product salts can also be identified by their powder X-ray diffraction pattern, generated from their atomic coordinates obtained from former single-crystal structure determinations. Checking for similar salts in the single-crystal structural database (CSD) [6], it can be observed that the various aminomethyl-substituted pyridine isomer salts may occur in either single- or double-protonated forms. As sulfate salts, double-protonated monosulfate–monohydrate ones were reported for 2- and 3-pyridylmethylamines under CSD codes LAQQEB [7] and ATUXUJ [8], respectively, while as hydrochloride salts, 2- and 3-pyridylmethylamine dihydrochlorides, under CSD codes PEKCIS [9] and PICAMC01 [10], were also published. Whereas, there are both mono- [11] and dihydrochloride [12] salts of 4-pyridylmethylamine in the CSD, with solved and known single-crystal structures (under CSD codes QANWOS and IGHUU) containing single- and double-protonated cations, respectively.

Among the corresponding piperidylmethylamine salts, whose structures are rather rarely found in the CSD, only that of 4-piperidylmethylamine diperchlorate is solved as a single crystal with a diprotonated cation, but with two modifications under CSD codes VIVLEU and VIVLEU01 [13]. The (R)- and (S)-2-piperidylmethylamine dihydrochloride salts are also known, and the single-crystal atomic coordinates are available for the (R)-enantiomer under CSD code XOMMAO [14].

To our best knowledge, the structures of these 4-piperidyl- and 4-pyridylmethylamine salts prepared by us have never been described in the literature; thus, we report the FT-IR spectra and crystallographic unit cells of 4PIPA·H₂SO₄, 4PIPA·2HCl, 4PA·H₂SO₄, and 4PA·0.5H₂SO₄ salts obtained by the DASH 4.0 software package [15] based on their powder XRD patterns. This program tool is a versatile, graphical, user interface-driven computer program that was distributed earlier within the Cambridge Structural Database System package [6], but now, it is available separately and as an open source [16]. Among others, it was originally planned to be used for the structure solution [17,18,19,20] from powder XRD data collected in high resolution by synchrotron radiation, especially to determine the crystal structures of large-volume commercial pharmaceuticals [21,22]. However, it could be useful for the structural evaluation of powder diffraction data collected by laboratory X-ray tubes as well [23,24].

This work is part of a systematic investigation concerning the favorable cases using the DASH 4.0 program package for the extraction of any approximate but structural information from powder X-ray patterns of crystalline materials. Our purpose was also to find and demonstrate several cases, especially hydrochloride and sulfate salts that contain Cl or S as heavy elements, when reliable conjectures for crystallographic unit cells (parameters and a choice of reasonable space group) and the successful modeling of unit cell contents could be achieved, starting from the corresponding XRD patterns measured by a common laboratory technique. Naturally, the reliability of these trials is lower than that of single-crystal structural determinations, but it could be useful when single crystals are not available at all.

2. Materials and Methods

2.1. Materials

The samples of 4PIPA·H₂SO₄, 4PIPA·2HCl, and 4PA·0.5H₂SO₄ were prepared according to our published Pd-catalyzed hydrogenation method [1], while that of 4PA·H₂SO₄ was synthesized by using our modified process, in which a 5% Ru/C catalyst was applied under very similar conditions (catalyst/substrate ratio = 0.2 g·g^–1, H₂SO₄/4PN molar ratio = 1.0, water/dichloromethane, 60 °C, 6 bar, reaction time: 7 h). Their chemical compositions were analyzed by GC–MS, as well as ¹H and ¹³C NMR measurements in their free base form, prepared just prior to the analyses. Their spectroscopic data were the following: 4PIPA·H₂SO₄ mp. 285–287 °C (decomp.); 4PIPA·2HCl mp. 293–298 °C (decomp.); 4PA·0.5H₂SO₄ mp. 162–168 °C (decomp.); 4PA·H₂SO₄ mp. 144–146 °C (decomp.); 4PIPA GC–MS m/z (rel%) 114(27), 96(20), 84(39), 69(32), 56(100); ¹H NMR (CDCl₃, 500 MHz) δ ppm 1.38–1.53 (m, 5H, CH₂CHCH₂), 2.35 (br s, 3H, NH and NH₂), 2.94 (d, J = 5.0 Hz, 2H, CH₂NH₂), 3.40–3.47 (m, 4H, CH₂NHCH₂); ¹³C NMR (CDCl₃, 125 MHz) δ ppm 25.7 (CH₂CHCH₂), 31.6 (CH₂CHCH₂), 43.4 (CH₂NHCH₂), 43.7 (CH₂NH₂). 4PA GC–MS m/z (rel%) 108(12), 107(28), 80(100), 51(13); ¹H NMR (CDCl₃, 500 MHz) δ ppm 1.79 (br s, 2H, NH₂), 3.88 (s, 2H, CH₂NH₂), 7.24 (d, J = 5.0 Hz, 2H, Pyr-CHCCH), 8.52 (d, J = 5.0 Hz, 2H, Pyr-CHNCH); ¹³C NMR (CDCl₃, 125 MHz) δ ppm 45.4 (CH₂NH₂), 122.0 (Pyr-CHCCH), 149.8 (Pyr-CHNCH), 151.9 (Pyr-CHCCH).

2.2. Characterization Methods

2.2.1. Powder X-Ray Diffraction (XRD)

Powder XRD patterns were recorded with an X’pert Pro MPD (Malvern Panalytical, Malvern, UK) multipurpose X-ray diffractometer using Cu-Kα radiation (λ = 1.5406 Å), with Ni foil as a β-filter, an X’celerator detector, and “zero background” single-crystal silicon or “top-loaded” sample holders in the range of 2θ = 4–52°. The X-ray tube was operating at 40 kV and 30 mA. For purposes of indexing the crystallographic unit cell [25], searching for space group symmetries [26,27], and structural modeling with simulated annealing, originally built-in or invocable program routines of the DASH 4.0 software package [15] and a measuring step size of 0.0167° up to 2θ = 52° were applied.

2.2.2. FT-IR Spectroscopy

Fourier transform infrared (FT-IR) spectra of the solid powder samples were measured by the PE System 2000 (PerkinElmer, Waltham, MA, USA) FT-IR spectrophotometer in a KBr pastille, between 500 and 4000 cm⁻¹, at a resolution of 4 cm⁻¹.

3. Results and Discussion

3.1. FT-IR Investigations

3.1.1. Comparison of the Completely Hydrogenated 4PIPA·H₂SO₄ and 4PIPA·2HCl Product Salts

FT-IR spectra of the two 4-piperidylmethylamine (4PIPA) products isolated in the form of a hydrochloride or sulfate salt are shown in Figure 2. As seen, they were very similar to each other, except the two strong absorption bands peaked at 1125 and 620 cm^–1. Their highly related FT-IR spectral features can be explained by their analogous saltlike structures. This high similarity is most probably due to their common organic cations, while their differences can be elucidated by the diverse vibration opportunities of their different anions (chloride and sulfate, respectively). The completely hydrogenated 4PIPA·H₂SO₄ and 4PIPA·2HCl product salts should have the same type of cation, most probably a double-protonated one on the nitrogen of both the pyridine ring and the methylamine part. It was obvious that the simple chloride counterion had no absorption bands, while the sulfate anion showed two strong IR-active stretching vibration bands (ν₃ and ν₄) at around 1125 and 620 cm^–1 [24]. It can clearly be observed that the common [4PIPA+2H]²⁺ divalent cations took part in the same types of hydrogen bonding systems in both salts, resulting in almost identically sophisticated, broadened, and similarly extended absorption band systems exhibited between 1900 and 3700 cm^–1.

3.1.2. Comparison of the Partially Hydrogenated 4PA·0.5H₂SO₄·xH₂O (x = 0 or x = 0.5) and 4PA·H₂SO₄ Product Salts

FT-IR spectra of the two 4-pyridylmethylamine products isolated in the forms of their hemisulfate and monosulfate salts are shown in Figure 3. These spectra had no similarities, except the two strong absorption bands that peaked at around 1118–1120 and 619–620 cm^–1, which came from the common inorganic sulfate anion [28]. The highly different FT-IR spectral features of these sulfate salts can be explained by their diverse saltlike structures, containing one and two protonated N-containing groups in the hemi- and monosulfate, respectively. These spectral differences indicate that the 4-pyridylmethylamine (4PA) was only protonated to the methylammonium cation in the case of hemisulfate, while it was protonated to pyridinium- and ammonium-type divalent cations in the case of monosulfate salt. The diverse absorption band structures occurred both in the fingerprint regions and in the wide hydrogen bonding regions. The different degrees of protonation of pyridine parts can also be responsible for the various aromatic ring vibration modes/bands of the obtained mono- and divalent cations observed in the range of 1580–1650 cm^–1. However, the variable degree of hydration of the hemisulfate salt (4PA·0.5H₂SO₄·xH₂O) resulted in two different XRD patterns for the anhydrous (x = 0) and the hemihydrate (x = 0.5) forms (Section 3.2.2.), but this did not significantly affect the measured IR spectra (Figure 4).

3.2. Powder X-Ray Diffraction Examinations

3.2.1. Estimation and Modeling of the Crystallographic Unit Cells of 4PIPA·H₂SO₄ and 4PIPA·2HCl Product Salts

Both the final product samples of 4PIPA·2HCl and 4PIPA·H₂SO₄, as prepared, were found to be crystalline ones by powder X-ray diffraction (Figure 5a,b). Their XRD patterns were subjected to powder pattern indexing, also known as Dicvol [25], using the interactive DASH 4.0 program package [15]. In both cases, the indexing algorithms led to definite unit cell parameters of reasonable volume of the crystallographic cell and appropriate cell symmetry. For 4PIPA·2HCl, an orthorhombic space group, s.g. No. 61 (Pcab), while for 4PIPA·H₂SO₄, a triclinic space group, s.g. No. 2 (P-1), were found to be the proper ones. In addition, a built-in ExtSym (Extinction Symbol) program subroutine [26,27], which is an algorithm for helping to choose the extinction symbol/space group based on probability levels, was also used during the indexing procedure. The proposed cell parameters are summarized in

Table 1. Crystallographic unit cell parameters for crystalline 4PIPA·2HCl and 4PIPA·H₂SO₄ salts obtained from their powder XRD patterns ^a.

Salt Samples/Formula Unit Features of Crystallographic Unit Cells	4PIPA $·$2HCl 4-Piperidiniummethyl- ammonium Dichloride C6H14N2·2HCl = C6H16N22+ 2Cl–	4PIPA·H2SO4 4-Piperidiniummethyl- ammonium Monosulfate C6H14N2·H2SO4 = C6H16N22+ SO42–
Crystal system	orthorhombic	triclinic
Space group (s.g. No.)	Pcab (No. 61)	P-1 (No. 2)
a (Å)	17.601	10.431
b (Å)	15.936	8.405
c (Å)	7.188	5.978
α (°)	90	86.70
β (°)	90	106.40
γ (°)	90	104.24
V (Å3)	2016.06	487.30
Z/Z’ (–)	8/1	2/1
Vm (Å3)	252.01	243.65
Merit of Pawley refinement fitting (χ2)	26.98	22.2
Estimated zero-point shift (°)	0.0898	0.0378

^a Estimated uncertainty of unit cell parameters is 0.005 Å and 0.03°.

.

A structural skeleton for the diprotonated cation ([4PIPA+2H]²⁺) was borrowed from the formerly solved 4-piperidylmethylamine diperchlorate salt structure (under CSD code VIVLEU [13], room temperature modification), with known bond distances and angles. In both cases, it could be applied as a structural model for further simulations on the variation of the single torsion angle of the cation and the positions of anions using simulated annealing randomization and a final Simplex algorithm built in the DASH 4.0 program package.

In case of the 4PIPA·2HCl = [4PIPA+2H]²⁺ 2Cl^– salt, the received orthorhombic space group, s.g. No. 61 (Pcab), with the Z = 8 formula unit per unit cell volume of 2016.0 ų (Z’ = 1 formula unit per asymmetric unit of 252.0 ų) seemed to be its valid crystallographic unit cell and space group choice, as the structural modeling process in all trials, applying the mentioned room temperature dication structure, led to quite a reasonable arrangement of both cations and anions, where the protonated primary ammonium group was involved in three hydrogen bonds with three chloride anions, while the secondary one was involved in two hydrogen bonds with two chloride anions (Figure 6a). One of the chloride anions had two hydrogen-bridged connections, while the other one had three ones to nitrogen atoms of neighboring dications ([4PIPA+2H]²⁺), without any voids in the formed lattice (Figure 6b). Since each modeling trial was ended in a significant Simplex optimization, almost the same structural feature/picture was achieved.

In case of the 4PIPA·H₂SO₄ = [4PIPA+2H]²⁺SO₄^2– salt, the obtained triclinic space group, s.g. No. 2 (P-1), with a Z = 2 formula unit per unit cell volume of 487.3 ų (Z’ = 1 formula unit per asymmetric unit of 243.65 ų) seemed to be quite the valid crystallographic unit cell and space group choice because the structural modeling process in most of the trials, applying the abovementioned room temperature dication structure, led to quite a reasonable arrangement of cations and anions. It meant that the protonated primary ammonium group was involved in four hydrogen bonds (one hydrogen in a bifurcated way, as well), while the secondary one was involved in two hydrogen bonds with oxygen atoms of two sulfate anions (Figure 7a). Each sulfate anion had six hydrogen-bridged connections to nitrogen atoms of five neighboring dications ([4PIPA+2H]²⁺), without any voids in the formed lattice (Figure 7a,b).

3.2.2. Estimation of the Crystallographic Unit Cell of 4PA·0.5H₂SO₄·xH₂O (x = 0.5 or x = 0) Intermediate Salts

The synthesized pyridyl hemisulfate intermediate (4PA·0.5H₂SO₄·xH₂O) samples were obtained in hemihydrate form (x = 0.5), but after a longer period of aging (1–1.5 years), they turned into the anhydrous (x = 0) form and exhibited different XRD patterns (Figure 8a,b). This latter one was also confirmed by a thermal treatment of the fresh hemihydrate sample (4PA·0.5H₂SO₄·0.5H₂O) at 120 °C (Figure 8c). All of them were also subjected to powder pattern indexing by Dicvol [25] using the interactive DASH 4.0 program [15]. The pattern of fresh, hydrated hemisulfate (4PA·0.5H₂SO₄·0.5H₂O) could be indexed in the monoclinic crystal system, and a space group, P2₁/n (s.g. No. 14), was found to be an appropriate choice. For its aged and anhydrous form (4PA·0.5H₂SO₄), a triclinic crystal system with the P-1 (No. 2) space group was determined by using the built-in ExtSym algorithm [27]. The proposed cell parameters are summarized in

Table 2. Proposed crystallographic unit cell parameters of hydrated and anhydrous forms of crystalline 4PA·0.5H₂SO₄·xH₂O (x = 0.5 or x = 0) hemisulfate salts obtained from the measured powder XRD patterns ^a.

Salt Samples/Formula Unit Features of Crystallographic Unit Cell	4PA·0.5H2SO4·0.5H2O (Fresh, Hydrated) 4-Pyridylmethyl- ammonium Hemisulfate Hemihydrate C6H8N2·0.5H2SO4·0.5H2O	4PA·0.5H2SO4 (Aged, Anhydrous) 4-Pyridylmethyl- ammonium Hemisulfate C6H8N2·0.5H2SO4
Crystal system	monoclinic	triclinic
Space group (s.g. No.)	P21/n (No. 14)	P-1 (No. 2)
a (Å)	17.194	10.273
b (Å)	5.874	11.403
c (Å)	15.393	16.134
α (°)	90	53.65
β (°)	101.43	107.86
γ (°)	90	106.71
V (Å3)	1523.83	1434.96
Z/Z’ (–)	8/2	8/4
Vm (Å3)	190.48	179.37
Merit of Pawley refinement fitting (χ2)	234	80.4
Estimated zero-point shift (°)	–0.1238	–0.067

^a Estimated uncertainty of unit cell parameters is 0.005 Å and 0.03°.

. It has to be noted that no intermediate compounds were found; only physical mixtures of the hemihydrated and anhydrous forms were observed.

3.2.3. Estimation and Modeling of the Crystallographic Unit Cell of 4PA·H₂SO₄ Intermediate Salt

The intermediate pyridyl monosulfate sample of 4PA·H₂SO₄, as obtained, was found to be crystalline using powder X-ray diffraction (Figure 5c). Its XRD pattern was also subjected to powder pattern indexing by Dicvol [25] and McMaille [29] methods using the interactive DASH 4.0 program package [15]. At the beginning, neither of the indexing algorithms led to definite unit cell parameters without an assumption of the reasonably high volume (about 1900 ų) of the crystallographic cell and an appropriate cell symmetry. Therefore, some indications were gathered about the related constitutional isomer pyridylmethylamine sulfate salts, where the double-protonated monosulfate–monohydrate salt of 2- and 3-(aminomethyl)pyridine (LAQQEB [7] and ATUXUJ [8]) had Z’ = 223 and 221 ų values, respectively. Using a rough estimation of volume per formula unit, assuming general density, it resulted in approx. 251 ų [30]. Finally, the 4PA·H₂SO₄ salt could be indexed in an orthorhombic crystal system, and a space group, s.g. No. 61 (Pbca), was found to be an appropriate choice by applying the built-in ExtSym algorithm [27]. The proposed cell parameters are shown in

Table 3. Crystallographic unit cell parameters for crystalline 4PA·H₂SO₄ salt obtained from the measured powder XRD patterns ^a.

Salt Samples/Formula Unit Features of Crystallographic Unit Cell	4PA·H2SO4 4-Pyridylmethyl- ammonium Monosulfate C6H8N2·H2SO4 = C6H10N22+ SO42–
Crystal system	orthorhombic
Space group (s.g. No.)	Pbca (No. 61)
a (Å)	17.101
b (Å)	14.372
c (Å)	7.819
α (°)	90
β (°)	90
γ (°)	90
V (Å3)	1921.64
Z/Z’ (–)	8/1
Vm (Å3)	240.21
Merit of Pawley refinement fitting (χ2)	44.65
Estimated zero-point shift (°)	0.144

^a Estimated uncertainty of unit cell parameters is 0.005 Å and 0.03°.

.

Thus, in case of the 4PA·H₂SO₄ = [4PA+2H]²⁺·SO₄^2– salt, the obtained orthorhombic space group, s.g. No. 61 (Pbca), with a Z = 8 formula unit per unit cell volume of 1921.6 ų (Z’ = 1 formula unit per asymmetric unit of 240.2 ų) seemed to be quite a valid crystallographic unit cell and space group choice. Since the structural modeling process, applying a former room-temperature dication structure (under CSD code IGAHUU [12]) led to a quite reasonable arrangement of cations and anions, where both the protonated primary and secondary ammonium groups of the dication were involved in hydrogen bonding with one oxygen atom of two separate sulfate anions (Figure 9). Each sulfate anion had two hydrogen-bridged connections to nitrogen atoms of two neighboring dications ([4PA+2H]²⁺), without any voids in the formed lattice.

4. Conclusions

Structures of N-heterocylic amines (products and intermediates) prepared by heterogeneous catalytic hydrogenations over a Pd/C or Ru/C catalyst, starting from 4-pyridinecarbonitrile, in an aqueous acidic (HCl or H₂SO₄) medium were also confirmed to be 4-piperidylmethylamine (4PIPA) and 4-pyridylmethylamine (4PA) in crystalline forms of their novel salts by powder X-ray diffraction (XRD) structure predictions.

Crystallographic unit cell structure of the completely hydrogenated 4PIPA·2HCl and 4PIPA·H₂SO₄ product salts containing the same double-protonated [4PIPA+2H]²⁺ divalent cation, whose presence was proved by FT-IR spectroscopy, and that of 4PA·H₂SO₄ intermediate salt were definitely indexed and modeled based on their powder X-ray diffraction profiles, applying both the tools of the DASH 4.0 software package and atomic coordinates taken from former single-crystal X-ray structure determinations of related compounds.

Formations of both the anhydrous and hydrated forms of 4-pyridylmethylamine hemisulfate (4PA·0.5H₂SO₄·xH₂O, x = 0 or x = 0.5) were also studied by powder XRD and FT-IR spectroscopy. It was found that the fresh, hydrated hemisulfate (4PA·0.5H₂SO₄·0.5H₂O) had a different crystal system (monoclinic) than that of the anhydrous form (4PA·0.5H₂SO₄, triclinic), i.e., a spontaneous transformation took place, resulting in diverse crystalline forms of this 4-pyridylmethylamine salt.

It was demonstrated that in some favorable cases, such as hydrochloride and sulfate salts, reliable conjectures for crystallographic unit cell parameters and modeling the unit cell contents could be achieved starting from the corresponding XRD patterns measured using a common laboratory technique and by using the DASH 4.0 program package. Obviously, the reliability of this method is lower than that of single-crystal structural determinations, but it could be a useful one when single crystals are not available at all.

Further investigations to propose the different salt structures of other N-heterocyclic amino compounds are in progress.