The crystal structures of benzylammonium phenylacetate and its hydrate

The crystal packing of benzylammonium phenylacetate (1) and its hydrate (2) is governed by hydrogen bonds formed between the ammonium and acetate groups and the water molecule of crystallization (in 2 only). The benzyl moieties for hydrophobic layers with the aromatic rings adopting edge-to-face arrangements.


Chemical context
Many proteins can self-assemble into insoluble aggregates, socalled amyloids, with a high content of -strands. Amyloid fibrils are qualitatively similar for different proteins, with filaments of a few nanometers in diameter that can grow up to several micrometers in length (McManus et al., 2016). The amyloid state of proteins is linked to various human diseases, e.g. Alzheimer's disease (Eisenberg & Jucker, 2012). Besides proteins, oligopeptides (Ozbas et al., 2004) down to simple dipeptides (Reches & Gazit, 2003) and even the amino acid phenylalanine (Mossou et al., 2014;Do et al., 2015) can also self-assemble into stable nanofilaments in aqueous solution. Apart from the obvious link to amyloid diseases, such structures are also interesting for technical applications (Gazit, 2007;Manna et al., 2015). Hydrogen bonds between ammonium and carboxylate groups, as well as the presence of hydrophobic residues (e.g. aromatic residues) play an important role in the formation of self-assembled structures of (di)peptides or amino acids (Gö rbitz, 2010; Mossou et al., 2014;Reches & Gazit, 2003). Similarly, the packing motifs of ammonium carboxylate salts are governed by the formation of hydrogen-bonded networks between the ammonium and carboxylate groups, as well as the nature of the residues of the ammonium and carboxylate residues (Kinbara et al., 1996;Odendal et al., 2010). ISSN 2056-9890 Herein, we report the crystal structures of benzylammonium phenylacetate and its hydrate. Both show a similar crystal packing to the zwitterionic form of l-phenylalanine reported by Mossou et al. (2014). This resemblance raises the question of whether a system such as benzylammonium phenylacetate is also capable of forming nanofilaments.

Structural commentary
Benzylammonium phenylacetate (1) crystallizes in the monoclinic space group C2/c and its hydrate (2) in the monoclinic space group P2 1 /n. The asymmetric units of 1 and its hydrate 2 are shown in Fig. 1. In compound 1, the ammonium group of the benzylammonium is orientated almost perpendicular to the phenyl ring [90.2 (2) ], while the carboxylate group of the phenylacetate adopts a torsion angle of À70.2 (4) , while in the hydrate 2 the torsion angles between the phenyl rings and the functional groups are 72.4 (4) and 54.4 (4) for the phenylacetate and benzylammonium, respectively.

Crystal packing
The crystal packing of benzylammonium phenylacetate (1) consists of columns arranged around the twofold screw axis along b (Fig. 2). These columns are composed of hydrophilic channels, formed by the ammonium and carboxylate groups, surrounded by a shell made up by the phenyl moieties. The crystal packing of the hydrate (2) consists of hydrophilic and hydrophobic layers alternating along the c-axis direction, as shown in Fig. 3. The hydrophilic layer is composed of the water molecules, the ammonium and the carboxylate groups.

Intermolecular contacts and Hirshfeld analysis
We used CrystalExplorer17 to analyse the Hirshfeld surfaces of the molecules in the crystal structures of 1 and 2 and to quantify intermolecular contacts between them (Turner et al., 2017;McKinnon et al., 2007). Table 1  Crystal packing of 1 with views along the b axis (left) and along the c axis (right). Yellow dotted lines mark a column arranged around a twofold screw axis. Hydrophilic areas are highlighted in blue, hydrophobic areas in green.

Figure 3
Crystal packing of 2 with views along the a axis (left) and along the b axis (right). Hydrophilic areas are highlighted in blue, hydrophobic areas in green.
There are three main groups of (innerÁ Á Áouter) intermolecular contacts that can be found on the Hirshfeld surfaces, namely OÁ Á ÁH/HÁ Á ÁO, CÁ Á ÁH/HÁ Á ÁC and HÁ Á ÁH intermolecular contacts. Fig. 4 shows the fingerprint plots of the benzylammonium and phenylacetate molecules in 1 and 2, highlighting the OÁ Á ÁH/HÁ Á ÁO and CÁ Á ÁH/HÁ Á ÁC contacts. Mapping the Hirshfeld surfaces with different functions is a helpful tool for visualizing the nature of those intermolecular contacts. For example, the normalized contact distance d norm mapped on the Hirshfeld surface using a red-white-blue colour scheme indicates distances shorter, around or greater than the van der Waals separation distances, respectively. The normalized contact distance is defined by the following equation where d i and d e are the distances to the nearest atoms inside and outside the surface and r vdw is the van der Waals radius of the appropriate atom internal or external to the surface (McKinnon et al., 2007). Fig. 5 shows the benzylammonium and phenylacetate molecules in 1 with d norm mapped. A number of contacts with distances below the sum of the van der Waals radius can directly be identified by red spots. The most intense ones (A/A 0 , B/B 0 , C/C 0 in Fig. 5) can be attributed to N-HÁ Á ÁO hydrogen bonds between the benzylammonium and phenylacetate molecules. The remaining spots are due to non-classical C-HÁ Á ÁO hydrogen bonds among the phenylacetate molecules (D/D 0 , E/E 0 in Fig. 5) and an aliphatic C-HÁ Á Á interaction between benzylammonium and phenylacetate (F/F 0 in Fig. 5). Fig. 6 shows the normalized contact distance d norm mapped on the Hirshfeld surface of the molecules in 2, highlighting the N-HÁ Á ÁO (C/C 0 , D/D 0 and E/E 0 ) and O-HÁ Á ÁO (A/A 0 , B/B 0 ) hydrogen bonds as the primary intermolecular interactions, followed by the non-classical C-HÁ Á ÁO hydrogen bonds (F/F 0 and G/G 0 ). Two further close contacts of the type C-HÁ Á ÁC (H/H 0 and I/I 0 ) can be identified.

Figure 4
Comparison of the fingerprint plots of the benzylammonium and phenylacetate molecules in 1 and 2, highlighting OÁ Á ÁH/HÁ Á ÁO and CÁ Á ÁH/HÁ Á ÁC contacts. d i and d e are plotted in Å on the x-and y-axis, respectively. Fig. 4 shows the fingerprint plots of the benzylammonium and phenylacetate molecules in 1 and 2. OÁ Á ÁH/HÁ Á ÁO contacts can be attributed mainly to classical and non-classical, i.e. C-HÁ Á ÁO, hydrogen bonds. Naturally no OÁ Á ÁH contacts, but only HÁ Á ÁO contacts are found on the Hirshfeld surface of the benzylammonium molecules, resulting in a single spike (i.e. N-HÁ Á ÁO hydrogen bonds) highlighted in the fingerprint plots (a) and (e) in Fig. 4. The phenylacetate molecules can act as hydrogen-bond acceptors via their oxygen atoms (i.e. OÁ Á ÁH contacts), visible through the intense spike in the fingerprint plots (c) and (d) in Fig. 4. In addition, HÁ Á ÁO contacts are observed for the phenylacetate molecules in 1 and 2. Such contacts can come from non-classical C-HÁ Á ÁO hydrogen bonds, where the phenylacetate acts as a donor. However, a spike in the fingerprint plots indicating short hydrogen-oxygen distances is only observed for phenylacetate in compound 1 (Fig. 4c) and not in compound 2 (Fig. 4g), implying that C-HÁ Á ÁO hydrogen bonds may be more important in 1 than in the hydrate 2. CÁ Á ÁH/HÁ Á ÁC intermolecular contacts can arise from close ring contacts of the phenyl rings in the hydrophobic layers, but also from aliphatic C-HÁ Á Á interactions. An examination of the crystal packings in Figs. 2 and 3 reveals that the phenyl rings are not stacked in a planar, parallel fashion. This is consistent with the absence of CÁ Á ÁC intermolecular contacts, which would be expected in such a case (Turner et al., 2017). OÁ Á ÁH/HÁ Á ÁO and CÁ Á ÁH/ HÁ Á ÁC contacts will be discussed in more detail below.
3.2.1. OÁ Á ÁH/HÁ Á ÁO intermolecular contacts. As mentioned above, OÁ Á ÁH/HÁ Á ÁO contacts can be attributed mainly to classical and non-classical hydrogen bonds. In compound 1, intermolecular oxygen-hydrogen contacts amount to about 16 and 26% of the Hirshfeld surface area for the benzylammonium and phenylacetate molecules, respectively. In the hydrate 2, the values are about 13 and 27%, respectively. The hydrogen-bond parameters for 1 and 2 are summarized in Tables 2 and 3, respectively. In 1, the classical hydrogenbonding system involves the benzylammonium molecule as a donor and the phenylacetate molecule as an acceptor for N-HÁ Á ÁO hydrogen bonds. In 2, this system is extended by the presence of the water molecule of crystallization acting as a hydrogen-bond donor and acceptor at the same time. The hydrogen-bonding system in 1 can be described by chain patterns corresponding to a second level graph set  Table 3 Hydrogen-bond geometry (Å , ) for 2. (4) (4)  147 Symmetry codes: (i) x; y À 1; z; (ii) Àx þ 1; Ày þ 1; Àz þ 1; (iii) Àx; Ày þ 1; Àz þ 1; (iv) Àx; Ày; Àz þ 1.
Cg1 is the centroid of the C3-C8 ring. (2) (Bernstein et al., 1995). However, a more obvious feature is the ring structure denoted by a third level pattern R 3 4 ð10Þ (Fig. 7a). The R 3 4 ð10Þ ring pattern is a common feature of ammonium carboxylate salts and has been described earlier (Kinbara et al., 1996). Related to this particular ring pattern is an electrostatic ladder motif. Two benzylammonium-phenylacetate (cation-anion) pairs form a dimeric ring, which associates with further cation-anion pairs to form a ladder running along the twofold screw axis of the crystal (Fig. 7b). Such a motif is common in ammonium carboxylate salts (Odendal et al., 2010). Evidently, the presence of crystal water in 2 leads to a change in the hydrogen-bonding system compared to 1. Going from 1 to 2, water replaces one of the N-HÁ Á ÁO bonds between benzylammonium and phenylacetate. Consequently, the fused R 3 4 ð10Þ pattern in 1 is disrupted and two alternating R 2 4 ð8Þ patterns bridged by a carboxylate group are formed (Fig. 8a). Those rows are then connected among each other via the freed N-H donor group of the benzylammonium molecules and water molecules as acceptors to form a twodimensional hydrogen-bonding network network (Fig. 8b). Non-classical hydrogen bonds in 1 are formed exclusively between the phenylacetate molecules, forming fused R 2 2 ð8Þ and R 2 2 ð10Þ ring patterns alternating along the columns around the twofold screw axis along b. The hydrogen-bonding system is shown in Fig. 9a. In 2, the benzylammonium molecule acts as a donor for two discrete non-classical C-HÁ Á ÁO hydrogen bonds (Fig. 9b), one with the water molecule of crystallization as acceptor (C9-H9BÁ Á ÁO3) and a second one with an oxygen atom of the carboxylate group of phenylacetate (C15-H15Á Á ÁO2).
3.2.2. CÁ Á ÁH/HÁ Á ÁC intermolecular contacts. Carbonhydrogen intermolecular contacts contribute to around one quarter of the Hirshfeld surface areas of the benzylammonium and phenylacetate molecules in both 1 and 2. As explained above, those contacts are mainly due to close contacts between the phenyl rings in the hydrophobic layers of the crystal packing, but also to (aliphatic) C-HÁ Á Á interactions. An automated search using PLATON (Spek, 2009) revealed four short ring interactions and one aliphatic C-HÁ Á Á interaction in 1 (Fig. 10) and six short ring interactions and one aliphatic C-HÁ Á Á interaction in 2 (Fig. 11). The phenyl rings adopt 'Y'-and 'T'-shaped edge-to-face arrangements (Martinez & Iverson, 2012) with centroid-centroid distances of 5.019 (1)-5.738 (1) Å in 1 and 5.177 (2)-5.961 (2)   (a) Hydrogen-bonding patterns in 1. A section of the C 1 2 (4) chain pattern is highlighted in orange, and a section of one of the two possible C 2 2 (6) chain patterns is highlighted in red. The R 3 4 (10) ring pattern is highlighted in blue. Colour code for the hydrogen bonds: N1-H11Á Á ÁO1 green, N1-H12Á Á ÁO2 magenta, N1-H13Á Á ÁO2 blue. (b) Cation-anion ladder motif in 1 formed by the repetition of benzylammonium-phenylacetate pairs. Phenyl rings and CH 2 H atoms are omitted for clarity.    distances are in the same range as the centroid-centroid distance observed in crystalline benzene (Klebe & Diederich, 1993). Close HÁ Á ÁC contacts, i.e. smaller than the sum of the van der Waals radii (Bondi, 1964;Hu et al., 2014) of the two elements, are found as part of the aliphatic C-HÁ Á Á interactions. In 1, the aliphatic C-HÁ Á Á interaction is observed between benzylammonium (donor) and phenylacetate (acceptor), with the shortest distance being 2.762 Å between Short ring and aliphatic C-HÁ Á Á interactions in 1.
C9-H9BÁ Á ÁC4 (Fig. 10c). In 2, phenylacetate acts as a donor and benzlyammonium as an acceptor for the aliphatic C-HÁ Á Á interaction. The closest distance of 2.811 Å is found between C2-H2BÁ Á ÁC10 (Fig. 11d). Two more close contacts of the type (C-)HÁ Á ÁC can be identified in 2 via the d normmapped Hirshfeld surfaces (see H/H 0 and I/I 0 in Fig. 6). In the first case, the carbon hydrogen distance C5-H5Á Á ÁC1 (2.812 Å ) between two phenylacetate molecules is just below the sum of the van der Waals distances. In the second case, the carbon hydrogen distance C9-H9AÁ Á ÁC4 between benzylammonium and phenylacetate is 2.798 Å .

Synthesis and crystallization
Benzylamine (185701), phenylacetic acid (P16621) and methanol (32213) were obtained from Sigma-Aldrich. Benzylammonium phenylacetate (1) was obtained as follows. 40 mg of phenylacetic acid (0.29 mmol) were dissolved in 1 ml of methanol and 32 ml of benzylamine (0.29 mmol) were added under gentle stirring. The solvent was then evaporated slowly under ambient conditions to yield colourless crystals of compound 1.
Benzylammonium phenylacetate hydrate (2) was obtained by dissolving 40 mg of phenylacetic acid (0.29 mmol) in 200 ml of methanol and 32 ml of benzylamine (0.29 mmol) were added under gentle stirring. The solution was diluted with 1.8 ml of ultra-pure water and evaporated slowly at ambient conditions to yield colourless crystals of compound 2.

Benzylammonium phenylacetate (1)
Crystal data Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. Refinement. C-H: constr N-H: refall Reflections affected by the beamstop or those of higher order and significant higher Fo 2 than Fc 2 (caused by X-ray mirror) have been omitted in the refinement.

Hydrogen-bond geometry (Å, º)
Cg1 is the centroid of the C3-C8 ring. where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.30 e Å −3 Δρ min = −0.27 e Å −3 Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.