Synthesis and properties of acetamidinium salts

Background Acetamidines are starting materials for synthesizing many chemical substances, such as imidazoles, pyrimidines and triazines, which are further used for biochemically active compounds as well as energetic materials. The aim of this study was to synthesise and characterise a range of acetamidinium salts in order to overcome the inconvenience connected with acetamidinium chloride, which is the only commercially available acetamidinium salt. Results Acetamidinium salts were synthesised and characterised by elemental analysis, mass spectrometry, NMR and - in the case of energetic salts - DTA. The structures of previously unknown acetamidinium salts were established by X-ray diffraction analysis. Hygroscopicities in 90% humidity of eight acetamidinium salts were evaluated. Conclusions The different values of hygroscopicity are corroborated by the structures determined by X-ray analysis. The acetamidinium salts with 2D layered structures (acetamidinium nitrate, formate, oxalate and dinitromethanide) show a lack of hygroscopicity, and the compounds with 3D type of structure (acetamidinium chloride, acetate, sulphate and perchlorate) and possessing rather large cavities are quite hygroscopic.


Background
Acetamidines are starting materials in the synthesis of many chemical substances, such as imidazoles, pyrimidines and triazines which are further used for biochemically active compounds [1][2][3][4][5]. In the field of energetic materials, acetamidine is a starting material for the synthesis of 2-methoxy-2-methylimidazolidine-4,5-dione [6] and 2-methylpyrimidine-4,6-diol [7][8][9]. Both are further transformed to 2,2-dinitroethene-1,1-diamine (FOX-7, DADNE), which is an energetic material with low sensitivity to external stimuli [6,10]. The free base acetamidine is hygroscopic. It decomposes into ammonia and acetonitrile at higher temperatures [11], and produces acetamidinium carbonate during one day at room temperature when stored in contact with air [12]. Therefore, it is unsuitable as a starting material for synthesis and the use of an acetamidinium salt is necessary.
The most commonly used and commercially available salt of acetamidine is acetamidinium chloride (1). It is prepared by the Pinner method from acetonitrile and alcohol in the presence of hydrogen chloride, followed by addition of ammonia to the intermediate iminoether [13]. Reaction of acetonitrile with cobalt or nickel nitrates and oximes gives acetamidinium nitrate (2) [14,15]. An easily accessible acetamidine salt is acetamidinium acetate (3), prepared by the reaction of triethyl orthoacetate, ammonia and ammonium acetate [16]. The method is convenient, both for laboratory and industrial use or the acetate may be further transformed into other salts, e.g. formate (4) [17] sulphate (5) [18] or dinitromethanide (6) [19]. Many synthetic routes for acetamidines have been reviewed [20,21].
The main disadvantage of acetaminium chloride is its relatively high hygroscopicity. The release of the free base in methanol by the use of sodium methoxide will produce sodium chloride, which is partly soluble in this solvent (~1 g/100 ml) [22]. The presence of any chloride sourse is unfavourable in certain syntheses, e.g. nitrations, and its complete removal is tedious [6].
Here we describe the synthesis, X-ray structure, hygroscopicity and thermal stability of some of the acetamidine salts listed in Figure 1.

Synthesis
The procedure for the preparation of acetamidinium sulphate (5) via an ion exchange reaction from acetamidinium chloride (1) was earlier described by us [22]. This procedure was now used for the synthesis of the nitrate (2) and the oxalate (7). Thus, it may be considered as a universal method for the preparation of acetamidine salts starting from 1 ( Figure 2).
The method used in the preparation of (5) [18], starting from acetamidine acetate and based on the reaction of the latter with an acid stronger than acetic acid, was now successfully used in the preparation of acetamidinium perchlorate (8) from 3 and perchloric acid. Acetamidinium perchlorate (8)was also prepared from 5 by an ion exchange reaction with barium perchlorate in water ( Figure 3).
The method starting with acetamidinium acetate (3) based on the reaction with a stronger acid than the one we used (acetic acid) for acetamidinium sulphate (5) [18] was now successfully used for preparation of acetamidinium perchlorate (8). This salt was also prepared from 5 by an ion exchange reaction with barium perchlorate in water ( Figure 3). Acetamidinium formate (4) was prepared from trimethyl orthoacetate and ammonium formate. A similar method has been published earlier by Taylor for preparation of 3 [16].

Hygroscopicities
Hygroscopicities of acetamidinium salts, determined at 90% humidity and 30°C [23] and the comparison of these results with ammonium acetate (10), guanidinium nitrate (11) and guanidinium chloride (12) are represented as the weight increase compared with the weight of the original sample, expressed in %. The results are given in Figure 4 and values for certain days are presented in Table 1. In the case of compounds with known structure determined by X-ray diffraction techniques, information about the spatial structure is also included. The influence of the structure on hygroscopicity is discussed later.  The nitrate (2), formate (4), dinitromethanide (6) and oxalate (7) salts are almost anhygroscopic. The chloride (1), acetate (3), sulphate (5) and hydrogensulphate (9) compounds are hygroscopic. The hygroscopicity of acetamidinium chloride (1) is almost the same as for guanidinium chloride (12), and acetamidinium acetate (3) is very similar to ammonium acetate (10).

X-ray crystallography
The acetamidinium cation is frequently used as a counterion for a wide variety of anions like simple halogenides, carboxylates, complex metal anions and others. The parent acetamidine reveals large cavities and an extensive system of hydrogen bonding within the structure. The distances between the pivot carbon atom and the amino and imido nitrogen atoms are rather distinct (1.344 Å for C-NH 2 and 1.298 Å for C = NH group) [24].
The perchlorate and oxalate structures are rather unique in the set of acetamidinium structures determined, the distances between the pivot carbon atom and the NH 2 moiety are rather different -1.323(3) Å for the C-NH 2 group bonded by H-bonds only to one oxygen atom of the perchlorate ion, and 1.297(4) Å for the C-NH 2 group bonded by two H-bonds to the perchlorate ion. In the oxalate structure, the differences between these groups are even greater 1.339(5) Å and 1.280(5) Å, which disagree with a delocalisation concept and the data found in the literature (1.302-1.312 Å). In   (1)(2)(3)(4)(5)(6)(7)(8) and comparison with ammonium acetate (9), guanidinium nitrate (11) and guanidinium perchlorate (12). these groups, the H-bonds to the oxalate moiety are equidistant.
The molecular structure of the oxalate is made up of two mutually similar acetamidinium units and one oxalate ion. All these ions in both compounds are interconnected by extensive hydrogen bonding systems. In the oxalate (7), eight-and fourteen-membered rings are formed ( Figure  7). The twenty two-membered rings are the main element of the perchlorate (8) structure (Figure 8).
From a study of the above mentioned data and motifs, in combination with the data in Table 1 on the hygroscopicities of the compounds, it is clear that the compounds with layered 2D (counterions linked by H-bridges) structures (2, 4, 6, 7, and 11: for 7, see Figure 9) are not hygroscopic. On the other hand, the compounds that display 3D structures (1, 3, 5, and 8: for 8, see Figure 10) have rather high hygroscopicities. This is probably caused by an easier incorporation of water molecules into the larger cavities in the compounds with 3D structure, compared to the intercalation into the compounds with 2D structures.

NMR spectroscopy
NMR data for acetamidinium salts 2, 4, 7 and 8 are summarised in Table 2. A closer inspection of the proton NMR spectra measured in D 2 O revealed that there is an equilibrium between deuterated and non-deuterated molecules (strongly decreased intensity of the signals of the acidic protons). The equilibrium is shifted almost entirely to the side of the deuterated sample (approximately 98%). There is a contradiction between these observations and those published by Kopylovich [14], where no deuteration was described and two signals per 2H were observed.
On the other hand, the position of the equillibrium is reversed in DMSO-d6 where approximately 90% of the non-deuterated form can be found for all the samples measured.
In all cases (excluding 4 in DMSO-d6), two separated broadened signals belonging to the 2 × NH a H b arrangement were observed, probably due to the delocalisation  of the positive charge throughout the amidinium group. The only exception is acetamidinium formate 4 in DMSO-d6 where one broad signal comprising all four NH protons was detected. This is in accordance with the observation published by Krechl [17] and similar to the results obtained by Tominey [27] for acetamidinium tetrazolate complexes. This may be caused by different interactions between the formate anion and amidinium group in defferent solvents. The interactions inside some acetamidinium complexes were studied by Tominey and Krechl by means of NMR, X-ray analysis and quantum chemical treatment [17,27].

Differential thermal analysis
Acetamidinium nitrate (2), acetamidinium dinitromethanide (6) and acetamidinium perchlorate (8) are energetic materials. Their potential use is in pyrotechnic applications where they may replace guanidinium salts (nitrate or perchlorate). The difference is the higher carbon content of acetamidinium salts compared to the analogous guanidinium ones (replacement of the amino group in guanidines by a methylgroup). Nevertheless, acetamidinium salts still have a relatively high nitrogen content. Compounds 6 and 8 have acceptable decomposition temperatures measured by differential thermal analysis (DTA). Both the nitrate 2 and the perchlorate 8 decompose on melting. Thus, the decomposition temperatures of 2 and 8 are considered as being 183°C and 248°C, respectively ( Figure 11). The maxima of decompositions for 2 and 8 are 255°C and 390°C, respectively. For comparison, guanidinium nitrate starts to decompose at 270°C and guanidinium perchlorate at 350°C, using the same thermal stability device.

Conclusions
Acetamidinium salts were synthesised and characterised by elemental analysis, electrospray mass spectrometry, NMR and, in the case of energetic salts, by DTA. The structures of previously unknown acetamidines have been proved by X-ray diffraction analysis. Hygroscopicities in 90% humidity of eight acetamidinium salts have been evaluated. The different values of hygroscopicity are corroborated by the structures determined by X-ray analysis: acetamidinium salts with 2D layered structures are not hygroscopic while acetamidinium salts with 3D layered structures are quite hygroscopic.

Experimental Caution
Acetamidines 2, 6, and 8 are explosives, sensitive to mechanical stimuli and heat, and should be handled with care. NMR spectra were measured using a Bruker AVANCE III spectrometer operating at 400.13 MHz ( 1 H) and 100.61 MHz ( 13 C). The proton spectra in deuterium oxide were calibrated on the HDO signal of the solvent (δ = 4.80) whereas the spectra in DMSO-d6 were standardised on the residual signal of the solvent (δ = 2.50). Carbon spectra in D 2 O were standardised on internal neat methanol (δ = 49.50, value taken from [30] and the spectra in DMSO-d6 were calibrated on the middle of the solvent multiplet (δ = 39.61). The carbon spectra were measured with broadband proton decoupling.
The electrospray (ESI) mass spectra were measured on a Quattro Premiere XE tandem quadrupole mass spectrometer (Waters) equipped with a T-wave™ collision cell in both positive (ESI+) and negative (ESI-) ion mode. Typical ion source conditions were as follows. ESI+: capillary voltage 3.7 kV, cone voltage: 30 V, source temperature: 100°C, desolvation temperature: 200°C, desolvation gas: N 2 (100 l hr -1 ); ESI-: capillary voltage 2.5 kV, cone voltage: 30 V, source temperature: 100°C, desolvation temperature: 200°C, desolvation gas: N 2 (200 l hr -1 ). Approximately 10 -4 mol l -1 solutions of acetamidine salts in water were directly infused into the electrospray ion source using the built-in syringe pump at a flow rate of 5 μl min -1 . Generally, in the ESI+ mass spectra, the protonated acetamidine (denoted as AH + ) was observed together with the less abundant ions of the general formula M n AH + , where M is a molecule of the salt consisting of acetamidine A (CH 3 C(NH)NH 2 ) and acid X (for example HNO 3 ). Similarly in the ESI-mass spectra, the deprotonated acids (X-H)and cluster ions M n (X-H)were observed.
The thermal analysis was studied using differential thermal analyzer DTA 550Ex (OZM Research). The 50 mg samples were tested in open glass microtest tubes (in contact with air) and the heating rate was 5°C min -1 . The melting points were measured on a Kofler bench and are uncorrected. Acetamidinium nitrate (2) Sodium (3.36 g, 146.2 mmol) was gradually dissolved in ethanol (95 mL) and acetamidinium chloride (14.00 g, 148.1 mmol) in ethanol (90 mL) was slowly added. The mixture was stirred for one hour at room temperature and the precipitated sodium chloride was filtered off. To the filtrate, 65% nitric acid (14.4 g, 148.1 mmol) was then added to the solution of acetamidine in ethanol. The product immediately precipitated. It was filtered, washed with cold ethanol and dried to yield 14.01 g (79.1%). M.p. 186-188°C. 1     The crystals suitable for X-ray crystallography analysis were prepared by crystallisation from water using solvent evaporation at 5°C. Acetamidinium perchlorate (8) (A) Perchloric acid (70%, 0.42 mL, 10 mmol) was slowly added to a solution of acetamidinium acetate (1.18 g, 10 mmol) in 10 mL ethanol. The reaction mixture was allowed to stand to let the solvent evaporated slowly. The product crystallized in the form of colourless crystals. Yield 1.41 g (89%), m.p. 268-269°C. The crystals obtained were suitable for X-ray crystallography analysis. 1   (B) Acetamidinium sulphate (1.07 g, 5 mmol) was dissolved in 5 mL water. This solution was added to a solution of barium perchlorate (1.68 g, 5 mmol) in water (5 mL). The white precipitate of barium sulphate that immediately formed was filtered off. Acetamidine perchlorate was finally isolated from the aqueous Figure 11 DTA thermograms of acetamidinium nitrate (2), acetamidinium dinitromethanide (6) and acetamidinium perchlorate (8 [18], dinitromethanide (6) [19], hydrogensulphate (9) [22] Crystallography of 7 and 8 The X-ray data for colourless crystals of 7 and 8 were obtained at 150 K using an Oxford Cryostream low-temperature device on a Nonius Kappa CCD diffractometer with MoK α radiation (λ = 0.71073 Å), a graphite monochromator, and using the and χ scan mode. Data reductions were performed with DENZO-SMN [32]. The absorption was corrected by integration methods [33]. Structures were solved by direct methods (Sir92) [34] and refined by full matrix least-square based on F 2 (SHELXL97) [35]. Hydrogen atoms were mostly localised on a Fourier difference map; however, to ensure uniform treatment of crystals, all hydrogens were recalculated into idealized positions (riding model) and assigned temperature factors H iso (H) = 1.2 U eq (pivot atom) or 1.5U eq for the methyl moiety with C-H = 0.96, and 0.97 Å for methyl, methylene and methine hydrogen atoms, respectively. Crystallography data for 7 and 8 are given in Table 3.
Crystallography data for structural analysis have been deposited with the Cambridge Crystallographic Data Centre, CCDC no. 834605 and 834606 for 8 and 7, respectively. Copies of this information may be obtained free of charge from The Director, CCDC, 12 Union Road, Cambridge CB2 1EY, UK (fax: +44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk or www: http://www. ccdc.cam.ac.uk).

Sample preparation and hygroscopicity evaluation [23]
Samples weighed to within 0.1 mg were placed in bottles with cap style stopper: The weights of the samples were 5-6 g, with the exception of acetamidinium dinitromethanide and acetamidinium perchlorate where the weight was around 1.5 g, and dried over phosphorous pentoxide for two days. Then the samples were quickly removed to a desiccator containing 18.6% sulphuric acid (relative humidity of 90% is thus obtained). The samples were kept at 30°C. With 24-72 hours interval, the samples were weighed (during weighing the cap was in place).