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Article

Syntheses and Solid-State Characterizations of N-Alkylated Glycine Derivatives

by
Darko Vušak
,
Mia Jurković
,
Neven Smrečki
and
Biserka Prugovečki
*
Division of General and Inorganic Chemistry, Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, 10000 Zagreb, Croatia
*
Author to whom correspondence should be addressed.
Crystals 2023, 13(10), 1438; https://doi.org/10.3390/cryst13101438
Submission received: 5 September 2023 / Revised: 20 September 2023 / Accepted: 26 September 2023 / Published: 27 September 2023
(This article belongs to the Special Issue Pharmaceutical Crystals (Volume III))
Browse Figures
Versions Notes

Abstract

:
Seven N-alkylated glycine derivatives were prepared and characterized using single-crystal X-ray diffraction, infrared spectroscopy and thermal analysis. Chloride salts, H2EtGlyCl, H2(n-PrGly)Cl and H2(i-PrGly)Cl were prepared by aminolysis of chloroacetic acid with respective alkylamine. Nitrate salts, H2EtGlyNO3, H2(i-PrGly)NO3, H2(n-PrGly)NO3 and zwitterionic compound H(n-PrGly)·1/3H2O were prepared using ion exchange reactions from corresponding chloride salts. In all the N-alkylated glycine chloride salts, two N-alkylglycinium cations and two chloride anions were connected into centrosymmetric dimers that were additionally hydrogen bonded into endless chains. In the nitrate salts, 2D networks of different topologies were formed through hydrogen bonds between nitrate anions and N-alkylglycinium cations. In compound H(n-PrGly)·1/3H2O, the zwitterionic N-(n-propyl)glycines and water molecules of crystallization were connected into the 3D hydrogen bond networks. Chloride salts have significantly more H⋯H and O⋯C contacts than nitrate salts. All chloride salts decompose in endothermic, while nitrate salts decompose in exothermic thermal events.

1. Introduction

Amino acids, the building blocks of proteins, can undergo numerous chemical reactions via their various chemical functionalities (carboxyl, amino- and alkyl groups). Glycine is the smallest achiral amino acid that is most easily grouped with nonpolar amino acids, but its side chain makes no real contribution to hydrophobic interaction [1]. N-alkylated-α-amino acid derivatives possess alkyl groups attached to the amino-group nitrogen atom of the corresponding amino acid. They play important roles in biological chemistry, and their biocatalytic properties, as well as chemical syntheses, are widely investigated [2,3,4,5]. N-alkylated-α-amino acids find widespread application as highly valuable building blocks for the synthesis of pharmaceutically active compounds [6], ligands for asymmetric catalysis [7] and biodegradable polymers [8]. Also, they are used in many other special cases, for example as surfactants or when transporting ions across cell membranes [9,10]. The incorporation of N-alkylated amino acids, in place of natural amino acids, is known to have dramatic effects on the bioactive conformation of such mutant proteins [11]. They play an important biological role in metabolic pathways; for instance, N-methylglycine is used as a dietary supplement and as a non-specific glycine transport inhibitor, while N-ethylglycine inhibits pain signalling and is a promising candidate for chronic pain treatment [12]. The size and shape of the alkyl chain in N-alkylated-α-amino acids can significantly affect the dimensionality and topology of hydrogen bond networks [13], as well as the steric effects and stability of various complex compounds [14]. Furthermore, N-alkylated-α-amino acids are very suitable for studying steric effects in chelates with heavy metals, especially copper(II). These chelates are particularly interesting because of pronounced stereoselective effects. In fact, the enantioselectivity effect in that class of compounds was first observed for N-benzylproline and that phenomenon was later used for designing resins for ligand exchange chromatography [15].
The most commonly used traditional methods of synthesis of N-alkylated-α-amino acids are reductive alkylation with aldehydes, using inorganic reducing agents and nucleophilic substitution with alkyl halides. These methods include numerous disadvantages such as limited availability, versatility or stability of the starting compounds, the formation of stoichiometric amounts of by-products and tedious purification procedures. Consequently, more and more investments are being made in the development of sustainable, alternative methods of synthesis, such as the catalytic N-alkylation of amino acids with alcohols and biocatalytic synthesis [3,16].
Among N-alkylated-α-amino acids, N-methylglycine (sarcosine) has been the most investigated, and numerous crystal structures of N-methylglycine salts and complexes, as well as co-crystals, have been reported [17]. In contrast, N-alkylated-α-amino acids with a longer alkyl chain and their salts or complexes have been structurally poorly investigated [13,18,19,20,21,22,23,24,25,26].
Recently, we reported the synthesis, structural and magnetic characterization of the coordination compounds of cobalt, nickel and copper with N-alkylglycinates (N-methylglycinate, N-ethylglycinate and N-(n-propyl)glycinate) [4,27,28]. In a continuation of our studies on N-alkylated glycine derivatives, in this work, we report the synthesis, spectroscopic, thermal and crystallographic investigations of seven new compounds: N-ethylglycinium chloride and nitrate (H2EtGlyCl, H2EtGlyNO3), N-isopropylglycinium chloride and nitrate (H2(i-PrGly)Cl, H2(i-PrGly)NO3), N-(n-propyl)glycinium chloride and nitrate (H2(n-PrGly)Cl, H2(n-PrGly)NO3) and N-(n-propyl)glycine∙hydrate (H(n-PrGly)·1/3H2O). The packing of compounds as well as the dimensionality and topology of hydrogen bond networks, depending on the size and shape of the N-alkyl chain and anion, are investigated. In future research, these new compounds will be the starting compounds for the synthesis of new ternary coordination copper(II) complexes and metal–organic frameworks.

2. Materials and Methods

All chemicals for the syntheses (ethylamine, n-propylamine, isopropylamine, hydrochloric acid, nitric acid, silver nitrate, ethanol) were purchased from commercial sources (Sigma Aldrich, St. Louis, MO, USA; Acros, Verona, Italy; Alfa Aesar, Ward Hill, MA, USA; Alkaloid, Skopje, North Macedonia) and used without further purification. The attenuated total reflectance Fourier transform infrared spectroscopy (FT-IR-ATR) spectra were obtained in the range 4000–400 cm−1 on a PerkinElmer Spectrum Two™ spectrometer equipped with an ATR module.
The thermogravimetric measurements were performed on a Mettler-Toledo TG/DSC3+ instrument (callibrated by indium) at a heating rate of 10 °C min−1 in the temperature range 25–600 °C, under a nitrogen flow of 50 mL min−1. Approximately 10 mg of each sample was placed in a standard alumina crucible (70 µL). Onset temperature in DSC thermogram was used for determination of melting points. Data analysis was performed using Mettler-Toledo STARe Evaluation Software (version 14.00).

2.1. X-ray Diffraction Measurements

Single-crystal X-ray diffraction data of all compounds were collected using ω-scans on an Oxford Diffraction Xcalibur3 CCD diffractometer (H2EtGlyCl, H(n-PrGly)·1/3H2O) with graphite-monochromated MoKα radiation and on a Rigaku Synergy-S diffractometer (H2EtGlyNO3, H2(i-PrGly)Cl, H2(i-PrGly)NO3, H2(n-PrGly)Cl, H2(n-PrGly)NO3) with a Hypix6000 detector and microfocus CuKα radiation. Data reduction was performed using the CrysAlis software package [29]. Solution, refinement and analysis of the structures were performed using the programs integrated in the WinGX system [30]. All structures were solved using direct methods (SHELXS) [31] or dual-space method (SHELXT) [32] and the refinement procedure was performed by the full-matrix least-squares method based on F2 against all reflections using SHELXL [33].
The non-hydrogen atoms were refined anisotropically. All hydrogen atoms were located in the difference Fourier maps. Because of the poor geometry for some of them, they were placed in calculated positions and refined using the riding model. Hydrogen atoms of the crystallization water molecule in compound H(n-PrGly)·1/3H2O were found in a difference Fourier maps and the O–H distances were fixed to 0.85(1) Å, and the H–H distances were fixed to 1.39(2) Å. Geometrical calculations were performed using PLATON [34]. The crystallographic data are summarized in Table 1 and Table 2 [34]. Drawings of the structures were prepared using PLATON, MERCURY and ToposPRO programs [34,35,36]. Based on the crystal structures, the Hirshfeld surface was generated and analysed using program CrystalExplorer21 [37,38]. Additionally, Hirshfeld surface fingerprint plots were generated representing 2D histograms of the di and de distances; di corresponds to the distance from a point on the surface to the nearest nucleus inside the surface and de corresponds to the distance from a point on the surface to the nearest nucleus outside the surface [38].

2.2. Preparation and Thermal Stability of N-Alkylated Glycine Derivatives

2.2.1. Synthesis of the N-Alkylglycinium Chlorides

CAUTION—the experiment should be performed in a fume hood!
N-Ethylglycinium chloride (H2EtGlyCl), N-isopropylglycinium chloride (H2(i-PrGly)Cl) and N-(n-propyl)glycinium chloride (H2(n-PrGly)Cl) were prepared by aminolysis of chloroacetic acid with respective alkylamine (ethylamine, i-propyl amine or n-propylamine) according to the method of E. Fischer (Scheme 1) [39]. In the process of synthesis, solutions were acidified by hydrochloric acid, after which chloride salts were crystallized from solution.
Chloroacetic acid (19.0 g, 0.2 mol) was slowly added to an excess of concentrated aqueous alkylamine (alkyl = ethyl, i-propyl or n-propyl) solution over a half an hour period (the reaction is exothermic). The flask was covered and left to stand for 2 days at room temperature. The reaction mixture was then concentrated at ≈100 °C (the final volume was about 20 mL). The mixture was diluted with water (20 mL) and again concentrated at ≈100 °C and this procedure was repeated once again to completely remove the excess amine. The mixture was finally treated with concentrated hydrochloric acid (50 mL), after which the product started to crystallize. The reaction mixture was left to stand overnight in a refrigerator and the product was filtered off, washed with ice-cold ethanol (50 mL) and air-dried. Additional amount of the product can be obtained through the evaporation of the filtrate at room temperature. When prepared in this manner, the product can be used without any further purification. The single-crystals obtained through the slow evaporation of the filtrate were suitable for X-ray structural analysis.
H2EtGlyCl. From concentrated aqueous ethylamine solution (160 mL, 70% w/w), the yield was 23.2 g (83%); mp = 164.7 °C. IR (ATR)/cm−1: 2976 (m), 2947 (s), 2853 (s), 2789 (s), 2728 (m), 2686 (m), 2657 (w), 2586 (w), 2554 (w), 2489 (w), 2457 (w), 2447 (w), 2379 (w), 2360 (w), 1753 (s), 1472 (w), 1433 (w), 1416 (s), 1353 (m), 1302 (w), 1189 (s), 1125 (m), 1055 (m), 1036 (m), 912 (m), 881 (m), 871 (m), 798 (s), 781 (m), 641 (m), 525 (m).
H2(i-PrGly)Cl. From concentrated aqueous isopropylamine solution (prepared by mixing 85 mL of isopropylamine with 85 mL of water), the yield was 24.1 g (78%); mp = 183.1 °C. IR (ATR)/cm−1: 3399 (m), 3002 (m), 2982 (s), 2937 (s), 2909 (s), 2854 (s), 2799 (s), 2734 (m), 2692 (m), 2608 (m), 2570 (w), 2528 (w), 2502 (m), 2418 (m), 1747 (s), 1612 (m), 1567 (w), 1509 (w), 1473 (m), 1450 (w), 1422 (s), 1409 (s), 1390 (s), 1376 (s), 1332 (w), 1309 (m), 1246 (w), 1212 (s), 1171 (s), 1151 (s), 1059 (m), 1008 (w), 936 (m), 898 (m), 865 (m), 821 (s), 648 (s), 531 (m), 450 (m).
H2(n-PrGly)Cl. From concentrated aqueous n-propylamine solution (prepared by mixing 80 mL of n-propylamine with 80 mL of water), the yield was 26.5 g (86%); mp = 197.4 °C. IR (ATR)/cm−1: 3399 (m), 3008 (m), 2957 (s), 2941 (s), 2902 (s), 2860 (s), 2815 (s), 2786 (s), 2731 (m), 2705 (m), 2683 (m), 2647 (w), 2618 (m), 2583 (m), 2510 (w), 2479 (m), 2408 (m), 1749 (s), 1608 (m), 1511 (w), 1474 (m), 1463 (m), 1417 (s), 1392 (s), 1383 (m), 1324 (w), 1298 (m), 1201 (s), 1138 (m), 1064 (m), 1048 (m), 1001 (m), 927 (m), 906 (m), 886 (m), 847 (s), 807 (s), 759 (m), 655 (s), 538 (m), 509 (w), 472 (w), 412 (m).

2.2.2. Synthesis of the N-Alkylglycinium Nitrates and N-(n-Propyl)glycine Hydrate

CAUTION—the experiment should be performed in a fume hood!
H2EtGlyNO3. N-Ethylglycinium chloride (1.3905 g, 0.01 mol) was dissolved in 10 mL of water. Afterward, silver nitrate solution was prepared by dissolving silver nitrate (1.6977 g, 0.01 mol) in 9 mL of water with the addition of 1 mL of HNO3 (c = 1 mol dm−3). Silver nitrate solution was gradually added to the N-ethylglycinium chloride solution. Mixing of these two prepared solutions resulted in the formation of silver chloride precipitate which was filtered off. The filtrate was slowly evaporated at room temperature for 14 days until colorless single-crystals of the H2EtGlyNO3 were obtained. The yield was 0.6864 g (41%); mp = 143.5 °C. IR (ATR)/cm−1: 3004 (m), 2975 (s), 2948 (s), 2901 (s), 2844 (s), 2790 (s), 2729 (m), 2684 (m), 2656 (w), 2585 (w), 2486 (w), 2460 (w), 2448 (w), 2379 (w), 2359 (w), 2354 (w), 1755 (s), 1472 (w), 1454 (w), 1417 (s), 1353 (m), 1303 (w), 1189 (s), 1125 (m), 1055 (m), 1036 (m), 912 (m), 877 (m), 800 (s), 778 (m), 641 (s), 523 (m).
H2(i-PrGly)NO3. N-isoproylglycinium chloride (0.1539 g, 1 mmol) was dissolved in 10 mL of water and silver nitrate (0.1768 g, 1 mmol), dissolved in 10 mL of water and acidified with a few drops of HNO3 (c = 1 mol dm−3). Silver nitrate solution was gradually added to the N-isopropylglycinium chloride solution. After filtration of silver chloride precipitate and gradual evaporation of filtrate at room temperature, the colorless single-crystals of the H2(i-PrGly)NO3 were obtained. The yield was 0.1422 g (79%). The compound decomposed before melting point was reached. IR (ATR)/cm−1: 3474 (w), 3013 (s), 3003 (s), 2970 (s), 2944 (s), 2882 (s), 2845 (s), 2757 (s), 2683 (w), 2624 (m), 2556 (w), 2525 (w), 2478 (w), 1741 (s), 1620 (m), 1479 (m), 1454 (w), 1415 (s), 1393 (s), 1381 (m), 1366 (m), 1307 (s), 1216 (s), 1173 (w), 1154 (m), 1142 (m), 1060 (m), 1043 (m), 1009 (w), 938 (m), 904 (m), 879 (m), 825 (w), 818 (m), 718 (w), 713 (m), 651 (m), 532 (m), 460 (m), 430 (w).
H2(n-PrGly)NO3. N-(n-propyl)glycinium nitrate was also prepared by the same, already mentioned, method. N-(n-propyl)glycinium chloride (0.1542 g, 1 mmol) was dissolved in 10 mL of water, while silver nitrate (0.1726 g, 1 mmol) was dissolved in 10 mL of HNO3 (c = 1 mol dm−3). After filtration of silver chloride precipitate and gradual evaporation of filtrate at room temperature, the colourless single-crystals of H2(n-PrGly)NO3 were obtained. The yield was 0.1512 g (84%); mp = 111.6 °C.
IR (ATR)/cm−1: 3481 (w), 3064 (s), 3010 (m), 2939 (s), 2904 (s), 2860 (s), 2818 (s), 2787 (s), 2730 (m), 2704 (m), 2647 (w), 2618 (w), 2583 (w), 2510 (w), 2478 (w), 2411 (w), 1752 (s), 1593 (w), 1574 (w), 1513 (w), 1475 (m), 1462 (w), 1418 (s), 1383 (m), 1322 (w), 1297 (w), 1205 (s), 1138 (m), 1064 (m), 1045 (m), 1001 (m), 928 (m), 908 (m), 886 (m), 845 (m), 810 (m), 759 (m), 654 (s), 536 (m), 507 (w), 472 (w).
H(n-PrGly)·1/3H2O. Solution-based synthesis of zwitterionic compound N-(n-propyl)glycine·1/3H2O was performed by using N-(n-propyl)glycinium chloride (1.5350 g, 0.01 mol), dissolved in 10 mL of water, and silver nitrate (1.6910 g, 0.01 mol), dissolved in 10 mL of water and acidified with a few drops of HNO3 (c = 1 mol dm−3). After filtration of silver chloride precipitate and gradual evaporation of filtrate at room temperature, the small amount of colorless crystals of the H(n-PrGly)·1/3H2O occurred. This synthesis is not always reproducible, and due to the high solubility of the compound, only a small amount of crystals form.

3. Results and Discussion

3.1. Synthesis of N-Alkylated Glycine Derivatives

All compounds except H(n-PrGly)·1/3H2O are crystallized as chloride or nitrate salts, containing N-alkylglycinium cation and chloride or nitrate anion. Compound H(n-PrGly)·1/3H2O is crystallized as a hydrate of zwitterionic N-(n-propyl)glycine. N-alkylglycinium chlorides H2EtGlyCl, H2(i-PrGly)Cl and H2(n-PrGly)Cl were synthesized through the aminolysis of chloroacetic acid with respective alkylamin, and crystallized using the evaporation method (Scheme 1).
The synthesis of N-alkylglycinium nitrates H2EtGlyNO3, H2(i-PrGly)NO3 and H2(n-PrGly)NO3 and zwitterionic compound H(n-PrGly)·1/3H2O were performed in aqueous solutions (Scheme 2) using ion exchange reactions from corresponding N-alkylglycinium chloride. Microscopic photographs of the crystals are given in Figure S1.

3.2. Crystal Structures of N-Alkylated Glycine Derivatives

Non-hydrogen atoms in cationic species in chloride salts (H2EtGlyCl and H2(n-PrGly)Cl) and nitrate salt H2EtGlyNO3, as well as in one independent zwitterionic molecule in H(n-PrGly)·1/3H2O, are planar (Table 3, Figure 1). The other two symmetrically independent zwitterions in H(n-PrGly)·1/3H2O are in twisted conformation with C11–C12–N1–C13 and C21–C22–N2–C23 torsion angles of −67.0(3)° and −71.5(3)° (Table 3, Figure 1). In two symmetrically independent cations of H2(n-PrGly)NO3, the non-hydrogen atoms are almost linear with the torsion angles in the range of 174.2(2)–179.6(3)° (Table 3). In isopropyl derivatives H2(i-PrGly)Cl and H2(i-PrGly)NO3, torsion angles C1–C2–N1–C3 deviate from planarity with values between −164.28(17) and −171.05(15)° (Table 3).

3.2.1. Crystal Structures of the N-Alkylglycinium Chlorides

H2EtGlyCl and H2(n-PrGly)Cl crystallize in the centrosymetric orthorhombic space group Pnma, while H2(i-PrGly)NO3, crystallize in the centrosymmetric monoclinic space group P21/n (Table 1). The asymmetric units of H2EtGlyCl and H2(n-PrGly)Cl consist of one N-alkylglycinium cation (N-ethylglycinium in H2EtGlyCl and N-(n-propyl)glycinium in H2(n-PrGly)Cl) and one chloride anion while in an asymmetic unit of H2(i-PrGly)Cl, there are two N-(i-propyl)glycinium cations and two chloride anions. (Figure 2). In all chloride salts, cations and anions are connected through N1–H⋯Cl1(Cl11/Cl21) and O2–H⋯Cl1(Cl11/Cl21) hydrogen bonds (Table S1). N-alkylglycinium cations are hydrogen bond donors, with one hydrogen atom of the carboxylic group and two hydrogen atoms of the protonated amine group, while chloride anions are hydrogen bond acceptors. In all chloride salts, two N-alkylglycinium cations and two chloride anions are connected into centrosymmetric dimers by hydrogen bonds graph set R24(14), and dimers are additionally connected into endless chains (Figure 3 and Figure S2).

3.2.2. Crystal Structures of the N-Alkylglycinium Nitrates and Zwitterionic N-(n-Propyl)glycine Hydrate

H2EtGlyNO3 crystallizes in noncentrosymmetric orthorhombic space group Pmn21 while the other two nitrate salts, H2(i-PrGly)NO3 and H2(n-PrGly)NO3, crystallize in centrosymmetric monoclinic (P21/c) and triclinic space groups (P 1 ¯ ), respectively. H(n-PrGly)·1/3H2O crystallizes in the noncentrosymmetric orthorhombic space group Pca21 (Table 2). The asymmetric units of H2EtGlyNO3 and H2(i-PrGly)NO3 consist of one N-alkylglycinium cation (N-ethylglycinium in H2EtGlyNO3 and N-isopropylglycinium in H2(i-PrGly)NO3) and one nitrate anion, while in the asymmetic unit of H2(n-PrGly)NO3, there are two N-(n-propyl)glycinium cations and two nitrate anions. The asymmetric unit of compound H(n-PrGly)·1/3H2O consists of three zwiterrionic N-(n-propyl)glycine and one water molecule of crystallization (Figure 4).
In H2EtGlyNO3, H2(i-PrGly)NO3, H2(n-PrGly)NO3, N-alkylglycinium cations act as hydrogen bond donors, with one hydrogen atom of the carboxylic group and two hydrogen atoms of the protonated amine group, while nitrate anions are hydrogen bond acceptors (Table 3, Figure 5). In H2EtGlyNO3 and H2(n-PrGly)NO3, all three hydrogen bond donors in cations (both hydrogen atoms of amine group and hydrogen atom from carboxylic group) act as bifurcated donors for three nitrate anions (six oxygen acceptor atoms). In H2(i-PrGly)NO3, a hydrogen atom from the carboxylic group and one hydrogen atom of the amine group act as bifurcated donors for two nitrate oxygen atoms while the second hydrogen atom of the protonated amine group forms one N–H⋯O hydrogen bond with nitrate anion.
H2EtGlyNO3, H2(i-PrGly)NO3, and H2(n-PrGly)NO3 form 2D networks through hydrogen bonds, but of a different topology due to the different size and shape of the alkyl chain (Figure 6). Between the layers are hydrophobic chains of the N-alkylglycinium cations.
In H(n-PrGly)·1/3H2O, zwitterionic H(n-PrGly) molecules and water molecules of crystallization are connected into the 3D hydrogen bond networks (Table S1, Figure 7).

3.2.3. Hirshfeld Surface Analysis of N-Alkylated Glycine Derivatives

Hirshfeld surface analysis was performed to further investigate intermolecular interactions. The dnorm values were mapped onto a Hirshfeld surface of N-alkylglycinium cations or zwitterions. Two-dimensional fingerprint plots derivered from Hirshfeld surfaces for N-alkylglycinium cations in H2EtGlyCl, H2(n-PrGly)Cl and H2(i-PrGly)Cl are given in Figure 8 and for H2EtGlyNO3, H2(i-PrGly)NO3 and H2(n-PrGly)NO3 in Figure 9. Two-dimensional fingerprint plots derivered from Hirshfeld surfaces for H(n-PrGly)·1/3H2O are given in Figure 10. Fractions of interatomic contacts are given in Table S2 and Figures S3–S9.
Compounds can be distinguished by different interatomic contacts considering anions. Chloride salts have significantly more H⋯H and O⋯C contacts than nitrate salts. In chloride salts, H⋯H contacts are in the range of 46.8–52.4% of the Hirshfeld surface, while in nitrate salts, they are in the range of 27.9–36.1%. O⋯C contacts in chloride salts are in the range of 2.9–3.7% and in nitrate salts, they are in range of 0.4–2.0%. The reason for these differences is the shorter distance between cations in chloride salts, due to the smaller size of the anion. In nitrate salts, the most abundant contacts are H⋯O in the range of 55.5–64.4%, which is larger than the sum of H⋯O and H⋯Cl contacts in chloride salts (42.6–46.2%).
Zwitterionic H(n-PrGly)·1/3H2O has three symmetrically independent N-(n-propyl)glycine molecules and they have similar contacts and are different than either chloride or nitrate salts. Since the compound contains crystallization water molecules, the most abundant contacts are H⋯H in the range of 54.8–57.4%. The fraction of H⋯O contacts is between nitrate and chloride salts and comprises 40.5–41.5% of the Hirshfeld surface.
Crystals 13 01438 g010
Figure 10. Two-dimensional fingerprint plots derivered from Hirshfeld surfaces for H(n-PrGly)·1/3H2O.
Figure 10. Two-dimensional fingerprint plots derivered from Hirshfeld surfaces for H(n-PrGly)·1/3H2O.
Crystals 13 01438 g010

3.2.4. Infrared Spectroscopy

Infrared spectra of all chloride and nitrate salts of N-alkylglicine are characterized by the broad region with multiple bands in the range of 2350–3400 cm−1, corresponding to the streching of the O–H, N–H and C–H groups. The stretching of the C=O and NH2 groups in all compounds are at similar wave numbers in the ranges of 1747–1755 cm−1 and 1608–1612 cm−1, respectively (Figures S10–S15).

3.2.5. Thermal Analysis

The main difference in the thermal properties of the N-alkylglycinium chloride and nitrate salts is in the enthalpy of decomposition (Figure S16). All chloride salts decompose in endothermic, while nitrate salts decompose in exothermic, thermal events. Melting points and decomposition temperatures are comparable (Table 4, Figure S17). It is interesting to note that, in nitrate salts, the melting point of the H2EtGlyNO3 is higher than H2(n-PrGly)NO3 by approximately 30 °C. Chloride salts have higher melting points than nitrate salts, but the decomposition of chloride salts starts immediately after melting. H2EtGlyCl has the lowest melting point at 164.7 °C.

4. Conclusions

Seven N-alkylated glycine derivatives (alkyl = ethyl (Et), i-propyl (i-Pr) or n-propyl (n-Pr)) were obtained. Six of them are crystalized as chloride (H2EtGlyCl, H2(i-PrGly)Cl and H2(n-PrGly)Cl) or nitrate salts (H2EtGlyNO3, H2(i-PrGly)NO3, H2(n-PrGly)NO3) and one as a hydrate of a zwitterionic compound H(n-PrGly)·1/3H2O. Chloride salts have similar packing of N-alkylglycinium cations and chloride anions by hydrogen bonds into infinite chains of centrosymmetric dimers.
Nitrate salts form 2D hydrogen bond networks, but each compound has a different topology due to the different sizes and shapes of the alkyl chains. In H(n-PrGly)·1/3H2Ob, molecules form complex 3D framework through hydrogen bonds.
Chloride and nitrate salts can be distinguished by different interatomic contacts due to the different crystal packing of organic cations and the different shape, size and composition of anion. Chloride salts have more H⋯H and O⋯C contacts in comparison with nitrate salts, while nitrate salts have more O⋯H, H⋯C and N⋯H contacts.
The melting points of nitrate salts are lower than chloride salts. Chloride salts decompose immediately after melting, but at a higher temperature than nitrate salts.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cryst13101438/s1, the CIF data for H2EtGlyCl, H2(i-PrGly)Cl, H2(n-PrGly)Cl, H2EtGlyNO3, H2(i-PrGly)NO3, H2(n-PrGly)NO3 and H(n-PrGly)·1/3H2O, Figure S1: Microscopic images of the crystals of the N-alkylglycinium salts and the zwitterionic H(n-PrGly)∙1/3H2O; Figure S2: Hydrogen bonds forming endless chains in H2(i-PrGly)Cl and H2(n-PrGly)Cl. Hydrogen bonds are shown as dotted blue lines; Figure S3: Fraction of O⋯O contacts in symmetrically independent N-alkylglycinium cations and zwitterions; Figure S4: Fraction of O⋯N contacts in symmetrically independent N-alkylglycinium cations and zwitterions; Figure S5: Fraction of O⋯H contacts in symmetrically independent N-alkylglycinium cations and zwitterions; Figure S6: Fraction of O⋯C contacts in symmetrically independent N-alkylglycinium cations and zwitterions; Figure S7: Fraction of N⋯H contacts in symmetrically independent N-alkylglycinium cations and zwitterions; Figure S8: Fraction of H⋯H contacts in symmetrically independent N-alkylglycinium cations and zwitterions; Figure S9: Fraction of H⋯C contacts in symmetrically independent N-alkylglycinium cations and zwitterions; Figure S10: Infrared spectra of the H2EtGlyCl; Figure S11: Infrared spectra of the H2(i-PrGly)Cl; Figure S12: Infrared spectra of the H2(n-PrGly)Cl; Figure S13: Infrared spectra of the H2EtGlyNO3; Figure S14: Infrared spectra of the H2(i-PrGly)NO3; Figure S15: Infrared spectra of the H2(n-PrGly)NO3; Figure S16: DSC curves of the N-alkylglycinium salts; Figure S17: Thermogravimetric of the N-alkylglycinium salts; Table S1: Geometry of hydrogen bonds (Å, °) for compounds H2EtGlyCl, H2(i-PrGly)Cl, H2(n-PrGly)Cl, H2EtGlyNO3, H2(i-PrGly)NO3, H2(n-PrGly)NO3 and H(n-PrGly)·1/3H2O; Table S2: Fractions of atomic contacts on a Hirshfeld surface of symetrically independent N-alkylglycine cations or zwitterions. CCDC 2285208–2285214 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/ (accessed on 4 September 2023) (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; Fax: +44 1223 336033; E-mail: [email protected]).

Author Contributions

Conceptualization, D.V. and B.P.; methodology, D.V. and B.P.; validation, D.V. and B.P.; formal analysis, D.V., M.J., N.S. and B.P.; investigation, D.V., M.J., N.S. and B.P.; resources, D.V., N.S. and B.P.; data curation, D.V., M.J., N.S. and B.P.; writing—original draft preparation, D.V., M.J., N.S. and B.P.; visualization, D.V. and B.P.; supervision, D.V. and B.P.; project administration, D.V. and B.P.; funding acquisition, D.V. and B.P. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by project CIuK and co-financed by the Croatian Government and the European Union through the European Regional Development Fund—Competitiveness and Cohesion Operational Programme (Grant KK.01.1.1.02.0016) and by the Croatian Academy of Sciences and Arts (grant Solvatomorphism in copper complexes with derivatives of amino acids and heterocyclic bases).

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

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Crystals 13 01438 sch001
Scheme 1. Solution based synthesis of N-alkylglycinium chlorides (H2EtGlyCl, H2(i-PrGly)Cl and H2(n-PrGly)Cl).
Scheme 1. Solution based synthesis of N-alkylglycinium chlorides (H2EtGlyCl, H2(i-PrGly)Cl and H2(n-PrGly)Cl).
Crystals 13 01438 sch001
Crystals 13 01438 sch002
Scheme 2. Solution-based synthesis of N-alkylglycinium nitrates (H2EtGlyNO3, H2(i-PrGly)NO3, H2(n-PrGly)NO3) and H(n-PrGly)·1/3H2O.
Scheme 2. Solution-based synthesis of N-alkylglycinium nitrates (H2EtGlyNO3, H2(i-PrGly)NO3, H2(n-PrGly)NO3) and H(n-PrGly)·1/3H2O.
Crystals 13 01438 sch002
Crystals 13 01438 g001
Figure 1. Superposition of the cationic chains in H2EtGlyCl (dark red), H2EtGlyNO3 (orange), H2(n-PrGly)Cl (dark blue), H2(n-PrGly)NO3 (blue and light blue), H2(i-PrGly)Cl (dark and light green), H2(i-PrGly)NO3 (brown) and zwiterionic molecules in H(n-PrGly)·1/3H2O (purple, light purple and pink).
Figure 1. Superposition of the cationic chains in H2EtGlyCl (dark red), H2EtGlyNO3 (orange), H2(n-PrGly)Cl (dark blue), H2(n-PrGly)NO3 (blue and light blue), H2(i-PrGly)Cl (dark and light green), H2(i-PrGly)NO3 (brown) and zwiterionic molecules in H(n-PrGly)·1/3H2O (purple, light purple and pink).
Crystals 13 01438 g001
Crystals 13 01438 g002
Figure 2. ORTEP drawings of asymmetric units of H2EtGlyCl, H2(i-PrGly)Cl and H2(n-PrGly)Cl with atom labeling schemes.
Figure 2. ORTEP drawings of asymmetric units of H2EtGlyCl, H2(i-PrGly)Cl and H2(n-PrGly)Cl with atom labeling schemes.
Crystals 13 01438 g002
Crystals 13 01438 g003
Figure 3. Structural motifs of hydrogen bond of H2EtGlyCl in different orientations (upper pictures). Simplified hydrogen bond motifs where N-ethylgylcinium cations are represented with blue and chloride anions with green spheres (bottom pictures). Each sphere is positioned in the center of gravity of the corresponding ion.
Figure 3. Structural motifs of hydrogen bond of H2EtGlyCl in different orientations (upper pictures). Simplified hydrogen bond motifs where N-ethylgylcinium cations are represented with blue and chloride anions with green spheres (bottom pictures). Each sphere is positioned in the center of gravity of the corresponding ion.
Crystals 13 01438 g003
Crystals 13 01438 g004
Figure 4. ORTEP drawings of asymmetric units of H2EtGlyNO3, H2(i-PrGly)NO3, H2(n-PrGly)NO3 and H(n-PrGly)·1/3H2O.
Figure 4. ORTEP drawings of asymmetric units of H2EtGlyNO3, H2(i-PrGly)NO3, H2(n-PrGly)NO3 and H(n-PrGly)·1/3H2O.
Crystals 13 01438 g004
Crystals 13 01438 g005
Figure 5. Hydrogen bonds between N-alkylglycinium cations and nitrate anions in H2EtGlyNO3, H2(i-PrGly)NO3 and H2(n-PrGly)NO3. Hydrogen bonds are shown as dotted blue lines.
Figure 5. Hydrogen bonds between N-alkylglycinium cations and nitrate anions in H2EtGlyNO3, H2(i-PrGly)NO3 and H2(n-PrGly)NO3. Hydrogen bonds are shown as dotted blue lines.
Crystals 13 01438 g005
Crystals 13 01438 g006
Figure 6. Hydrogen bond 2D layers in (a) H2EtGlyNO3, (b) H2(i-PrGly)NO3, (c) H2(n-PrGly)NO3 (left pictures). Simplified hydrogen bond motifs in (a) H2EtGlyNO3, (b) H2(i-PrGly)NO3, (c) H2(n-PrGly)NO3 where N-alkylglycinium cations are represented with blue and nitrate ions as orange spheres (right pictures). Each sphere is positioned in the center of gravity of the corresponding ion.
Figure 6. Hydrogen bond 2D layers in (a) H2EtGlyNO3, (b) H2(i-PrGly)NO3, (c) H2(n-PrGly)NO3 (left pictures). Simplified hydrogen bond motifs in (a) H2EtGlyNO3, (b) H2(i-PrGly)NO3, (c) H2(n-PrGly)NO3 where N-alkylglycinium cations are represented with blue and nitrate ions as orange spheres (right pictures). Each sphere is positioned in the center of gravity of the corresponding ion.
Crystals 13 01438 g006
Crystals 13 01438 g007
Figure 7. Three-dimensional hydrogen bond frameworks in H(n-PrGly)·1/3H2O (left). Simplified hydrogen bond motifs where zwitterions are represented with blue and water molecules as red spheres (right). Each sphere is positioned in the center of gravity of the corresponding molecule.
Figure 7. Three-dimensional hydrogen bond frameworks in H(n-PrGly)·1/3H2O (left). Simplified hydrogen bond motifs where zwitterions are represented with blue and water molecules as red spheres (right). Each sphere is positioned in the center of gravity of the corresponding molecule.
Crystals 13 01438 g007
Crystals 13 01438 g008
Figure 8. Two-dimensional fingerprint plots derivered from Hirshfeld surfaces for H2EtGlyCl and two symmetrcally independent cations of H2(i-PrGly)Cl and H2(n-PrGly)Cl.
Figure 8. Two-dimensional fingerprint plots derivered from Hirshfeld surfaces for H2EtGlyCl and two symmetrcally independent cations of H2(i-PrGly)Cl and H2(n-PrGly)Cl.
Crystals 13 01438 g008
Crystals 13 01438 g009
Figure 9. Two-dimensional fingerprint plots derivered from Hirshfeld surfaces for H2EtGlyNO3, H2(i-PrGly)NO3 and two symmetrically independent cations of H2(n-PrGly)NO3.
Figure 9. Two-dimensional fingerprint plots derivered from Hirshfeld surfaces for H2EtGlyNO3, H2(i-PrGly)NO3 and two symmetrically independent cations of H2(n-PrGly)NO3.
Crystals 13 01438 g009
Table 1. Crystallographic data for H2EtGlyCl, H2(i-PrGly)Cl and H2(n-PrGly)Cl.
Table 1. Crystallographic data for H2EtGlyCl, H2(i-PrGly)Cl and H2(n-PrGly)Cl.
H2EtGlyClH2(i-PrGly)ClH2(n-PrGly)Cl
FormulaC4H10NO2ClC5H12NO2ClC5H12NO2Cl
Formula weight139.58153.61153.61
Crystal size/mm30.11 × 0.19 × 0.550.10 × 0.18 × 0.320.03 × 0.03 × 0.28
Crystal systemorthorhombicmonoclinicorthorhombic
Space groupPnmaP21/nPnma
a/Å9.6643(6)11.42754(16)27.2385(7)
b/Å5.4868(3)5.76655(8)5.6178(1)
c/Å13.0554(7)24.2416(3)5.4562(1)
α/°909090
β/°9090.2574(12)90
γ/°909090
V/Å3692.28(7)1597.44(4)834.91(3)
Z484
Dcalc/g cm−31.3391.2771.222
μ/mm−10.4713.7453.583
F(000)296656328
θ range/°4.5–27.03.6–77.53.2–79.2
T/K150298293
RadiationMoKα CuKα CuKα
Range of h, k, l−12–7, −7–6, −16–10−14–14, −7–7, −29–30−30–34, −7–7, −6–5
Reflections collected2742211844782
Independent reflections8283396979
Observed reflections [I ≥ 2σ(I)] (I ≥ 2σ)7323189925
Rint0.0200.0470.026
R 1, wR 2 [I ≥ 2σ(I)]0.0271, 0.07380.0465, 0.12880.0359, 0.1043
Goodness-of-fit, S 31.051.051.09
No. of parameters7016374
Δρmin, Δρmax (e Å−3)−0.34, 0.19−0.46, 0.69−0.22, 0.19
CCDC no.228520822852092285213
1 R = ∑||Fo| − |Fc||/∑|Fo|; 2 wR = [∑(Fo2 − Fc2)2/∑w(Fo2)2]1/2; 3 S = ∑[w(Fo2 − Fc2)2/(Nobs − Nparam)]1/2.
Table 2. Crystallographic data for H2EtGlyNO3, H2(i-PrGly)NO3, H2(n-PrGly)NO3 and H(n-PrGly)·1/3H2O.
Table 2. Crystallographic data for H2EtGlyNO3, H2(i-PrGly)NO3, H2(n-PrGly)NO3 and H(n-PrGly)·1/3H2O.
H2EtGlyNO3H2(i-PrGly)NO3H2(n-PrGly)NO3H(n-PrGly)·1/3H2O
FormulaC4H10N2O5C5H12N2O5C5H12N2O5C15H35N3O7
Formula weight166.14180.17180.17369.46
Crystal size/mm30.29 × 0.49 × 0.490.01 × 0.01 × 0.070.21 × 0.24 × 0.270.07 × 0.17 × 0.38
Crystal systemorthorhombicmonoclinictriclinicorthorhombic
Space groupPmn21P21/cP 1 ¯ Pca21
a/Å6.5719(1)5.6471(3)5.4914(1)16.2893(4)
b/Å5.0807(1)11.1482(8)11.6101(2)14.0655(3)
c/Å11.5516(2)13.5734(8)14.1453(4)8.8411(2)
α/°909093.467(2)90
β/°9097.364(5)91.114(2)90
γ/°909093.998(1)90
V/Å3385.706(12)847.47(9)897.75(3)2025.65(8)
Z2444
Dcalc/g cm−31.4311.4121.3331.212
μ/mm−11.1571.0971.0350.095
F(000)176384384808
θ range/°6.8–62.55.2–76.43.8–79.84.3–27.0
T/K298170298295
RadiationCuKα CuKα CuKα MoKα
Range of h, k, l−6–8, −6–6, −14–14−7–6, −13–14,
−16–16		−4–6, −14–14,
−17–17		−20–20, −17–17, −11–11
Reflections
collected		314946271096232737
Independent
reflections		883160037304413
Observed reflections [I ≥ 2σ(I)] (I ≥ 2σ)882122334403687
Rint0.0270.0440.0120.043
R 1, wR 2 [I ≥ 2σ(I)]0.0446, 0.10880.0469, 0.13820.0757, 0.21920.0403, 0.0914
Goodness-of-fit, S 31.181.111.201.02
No. of parameters76157217258
Δρmin, Δρmax (e Å−3)−0.33, 0.29−0.37, 0.29−0.37, 0.68−0.13, 0.14
CCDC no.2285211228521022852142285212
1 R = ∑||Fo| − |Fc||/∑|Fo|; 2 wR = [∑(Fo2 − Fc2)2/∑w(Fo2)2]1/2; 3 S = ∑[w(Fo2 − Fc2)2/(Nobs − Nparam)]1/2.
Table 3. Selected torsion angles in N-alkylglycinium cations in H2EtGlyCl, H2(i-PrGly)Cl, H2(n-PrGly)Cl, H2EtGlyNO3, H2(i-PrGly)NO3, H2(n-PrGly)NO3 and H(n-PrGly)·1/3H2O.
Table 3. Selected torsion angles in N-alkylglycinium cations in H2EtGlyCl, H2(i-PrGly)Cl, H2(n-PrGly)Cl, H2EtGlyNO3, H2(i-PrGly)NO3, H2(n-PrGly)NO3 and H(n-PrGly)·1/3H2O.
Compound∠(C1–C2–N1–C3)/°∠(C2–N1–C3–C4(or C5)/°
H2EtGlyCl180180
H2(i-PrGly)Cl 1170.62(15)
−171.05(15)		55.8(2) (or 178.25(16))
−55.7(2) (or −178.93(19))
H2(n-PrGly)Cl180180
H2EtGlyNO3180.00(1)−180.00(1)
H2(i-PrGly)NO3−164.28(17)179.51(18) (or −57.2(2))
H2(n-PrGly)NO3 1174.2(2)
176.4(2)		179.6(3)
178.5(2)
H(n-PrGly)·1/3H2O 2−67.0(3)
−71.5(3)
179.7(2)		−174.7(2)
−176.7(2)
178.7(2)
1 two N-alkylglycinium cations in H2(i-PrGly)Cl and H2(n-PrGly)NO3; 2 three N-(n-propyl)glycine zwitterionic molecules in H(n-PrGly)·1/3H2O.
Table 4. Melting and decomposition temperatures of N-alkylglycine chloride and nitrate salts.
Table 4. Melting and decomposition temperatures of N-alkylglycine chloride and nitrate salts.
CompoundMelting Point/°CStart of Decomposition/°C
H2EtGlyCl164.7175
H2(i-PrGly)Cl183.1190
H2(n-PrGly)Cl171.0180
H2EtGlyNO3143.5165
H2(i-PrGly)NO3112.5170
H2(n-PrGly)NO3111.6165
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MDPI and ACS Style

Vušak, D.; Jurković, M.; Smrečki, N.; Prugovečki, B. Syntheses and Solid-State Characterizations of N-Alkylated Glycine Derivatives. Crystals 2023, 13, 1438. https://doi.org/10.3390/cryst13101438

AMA Style

Vušak D, Jurković M, Smrečki N, Prugovečki B. Syntheses and Solid-State Characterizations of N-Alkylated Glycine Derivatives. Crystals. 2023; 13(10):1438. https://doi.org/10.3390/cryst13101438

Chicago/Turabian Style

Vušak, Darko, Mia Jurković, Neven Smrečki, and Biserka Prugovečki. 2023. "Syntheses and Solid-State Characterizations of N-Alkylated Glycine Derivatives" Crystals 13, no. 10: 1438. https://doi.org/10.3390/cryst13101438

APA Style

Vušak, D., Jurković, M., Smrečki, N., & Prugovečki, B. (2023). Syntheses and Solid-State Characterizations of N-Alkylated Glycine Derivatives. Crystals, 13(10), 1438. https://doi.org/10.3390/cryst13101438

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