Crystal structure of 2-methyl-1,2,3,4-tetrahydroisoquinoline trihydrate

The crystal structure of the title heterocyclic amine was determined in the presence of water. The compound co-crystallizes with three water molecules in the asymmetric unit, which leads to the formation of hydrogen bonding in the crystal.


Chemical context
Tetrahydroisoquinolines are heterocyclic secondary amines that can be found in animal and human brains (Rommelspacher & Susilo, 1985). Many compounds of this class and their derivatives are bioactive and show promising pharmacological potential, for example as neuroprotectants or antitumor antibiotics (Scott & Williams, 2002;Antkiewicz-Michaluk et al., 2014). Studies show that some of these endogenous compounds function as Parkinsonism-inducing agents, while others can prevent Parkinsonism and are therefore promising candidates for treatment of Parkinson's disease (Kotake et al., 1995;Lorenc-Koci et al., 1999McNaught et al., 1998;Storch et al., 2002). Their structures are therefore analysed to gain a better understanding of their function and possible chemical and pharmaceutical properties. In this case, we report the crystal structure of 2-methyl-1,2,3,4,-tetrahydroisoquinoline, which co-crystallizes with water.

Structural commentary
The heterocyclic amine, itself an oil at room temperature, crystallizes in the presence of water at 243 K, and crystals are stable up to ca 273 K when they melt. The asymmetric unit of the molecular structure, in space group P2 1 /c, is illustrated in Fig. 1. In addition to the heterocyclic amine, the asymmetric unit contains three water molecules, which make up 27 mass % of the crystal. For poorly crystallizing organic compounds containing hydrogen-bond acceptors with weak polar interactions (such as the title compound), crystallization in the presence of water and therefore the formation of hydrate compounds seems to be an alternative strategy for crystal formation and/or purification. This holds true especially when the formation of ions, e.g. hydrochlorides, is not desired to ISSN 2056-9890 avoid structural changes caused by derivatization of the compounds.
The amine exhibits typical bond lengths and angles in the expected ranges (Allen et al., 1987). The compound contains two different ring systems. The aromatic ring (C4/C5/C7-C10) is planar as expected, while the non-aromatic ring (N1/C2-C6) has a half-boat conformation and can be described with the Cremer-Pople parameters with a total puckering amplitude of Q T = 0.5067 (11) Å , an azimuthal angle () of 133.22 (12) and a zenithal angle (È) of 208.82 (18) . The structure is comparable with those of other tetrahydroisochinoline derivatives such as 2-(2-chloroacetyl)-6,7-dimethoxy-1,2,3,4tetrahydroisoquinoline  or 5-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-phenyl-1,2,5-oxadiazole N-oxide , that also show a half-boat conformation of the non-planar ring. The nitrogen atom displays a tetrahedral environment, which indicates an sp 3 hybridization, as is to be expected for a tertiary amine. This is similar to the tetrahydroisoquinoline published by Xu et al., but in comparison the mentioned structure from Ling et al. shows a trigonal planar sp 2 -hybridized nitrogen atom. Some selected bond lengths and angles are listed in Table 1.

Supramolecular features
As a result of the high amount of crystal water, an extensive supramolecular hydrogen-bonding network is formed. Geometrical details of the hydrogen bonding are listed in Table 2.
The crystal water forms a matrix in the bc plane, to which the amines are bound with the help of another set of hydrogen bonds. A section of the supramolecular hydrogen bonding and crystal packing along the b-axis direction is shown in Fig. 2. In this view the water forms a channel along the c axis, and the bridging of the organic molecules by the nitrogen atoms is clearly visible. The organic molecules are stacked in parallel along the b axis with a distance of 5.9209 (6) Å . The isoquinolines on the other side of the infinite water channel are invertedly aligned along the c axis. This also results in the  Symmetry codes: (i) Àx þ 1; y þ 1 2 ; Àz þ 3 2 ; (ii) Àx þ 1; Ày þ 2; Àz þ 2; (iii) Àx þ 1; Ày þ 1; Àz þ 2.

Figure 2
View along the b axis through the crystal packing shows the hydrogenbonding network, the parallel stacked organic molecules and reveals the alternating hydrophobic and hydrophilic packing phases.

Figure 1
Asymmetric unit and molecular structure in the crystal of the title compound with the unit-cell boundaries and atom labelling. Displacement ellipsoids are drawn at the 50% probability level. formation of alternating hydrophilic and hydrophobic phases of the hydrogen-bonded water framework and organic phases of the heterocyclic amines along the a axis.
An alternative view of the crystal packing along the c axis shows that the heterocyclic amines are alternately connected to the hydrogen-bonding system along the axis, which leads in the formation of syndiotactic polymer chains in this dimension (see Fig. 3).
An analysis of the hydrogen-bonding network formed by the water molecules is illustrated in Fig. 4. Here the view along the a axis shows the formed water plane along the b and c axes with different ring systems (only counting the oxygen atoms) and the graph-set motifs of the hydrogen-bonding network. The infinite hydrogen-bonded network is formed along the c axis by chains of connected five-membered [R 5 5 (10)] rings (connected via hydrogen bond b) followed by chains of alternating four-and six-membered [R 4 4 (8)] and [R 4 6 (12)] rings (connected via hydrogen bond c) that are orientated along the b axis.
For the third oxygen atom (O3), the ideal tetrahedral environment (Bernal & Fowler, 1933) is achieved by formation of a weak hydrogen bond to the H6A hydrogen atom of the alpha carbon atom (C6), which is indicated by the short C6Á Á ÁO3 distance [3.4531 (3) Å ]. This can be highlighted by an Hirshfeld surface analysis, shown in Fig. 5. The short distance alone is not a clear evidence for a weak hydrogen bond, however the linear angle C6-H6AÁ Á ÁO3 of 168.8 (2) (without cone-correction; Kroon & Kanters, 1974) strongly supports this assumption. For an overview of the definition and characteristics of weak hydrogen bonding, see, for example: Desiraju & Steiner (1999).

Database survey
A survey of the Cambridge Crystallographic Database (CSD, Version 5.40, September 2019; Groom et al., 2016) shows about 1000 results for structures where the investigated amine is a substructure of a more complex structure. The beforementioned compounds C 13 H 16 ClNO 3  and C 20 H 21 N 3 O 4   View along the a axis through the crystal packing shows the hydrogenbonding network. For a better view, only one amine molecule is shown, to highlight the supramolecular water network in the bc plane. The various hydrogen bonds are labelled as examples for a four-, five-and sexmembered ring (red b-f), as well as an amine hydrogen bond (green a).

Figure 3
View along the c axis through the crystal packing showing the other side of the hydrogen-bonding network and the different arrangement of the organic molecules.
and C 22 H 23 NO 6 (Roques et al., 1978). Another example for a reported crystal structure is C 24 H 25 NO 3 Á2CH 3 OH, which is used as a PET radiotracer and has been tested in clinical evaluation for early diagnosis of Alzheimer's disease (Altomare et al., 2014). All derivates found during the survey have in common that they have more complex structures and are often O-functionalized compared to the title compound. Some small reported analogues of this compound are metallated derivatives with lithium and potassium, which were published in a study about stabilization of different amine anions by our group (Unkelbach et al., 2012).

Synthesis and crystallization
1,2,3,4-Tetrahydroisoquinoline (10 mL, 79.66 mmol) was dissolved in 30 mL of formic acid (99%). After adding formaldehyde (30 mL, 37% in water) the solution was stirred under reflux for 6 h and stirred at room temperature for an additional 12 h. Subsequently KOH was added to adjust to pH 13. In the next step, the two-phase system was extracted with diethyl ether (3 x 50 mL). The combined organic phases were dried with MgSO 4 . After removing the solvent the raw product was distilled (333 K, 0.25 mbar) and the pure amine could be obtained as a colourless oil (94% yield). The title compound crystallizes in the presence of water, by adding some drops of water to a solution of the amine in Et 2 O, mixing the two phases and then separating again to obtain a moist organic phase. Storage of the organic phase at 243 K results in crystallization of the title compound in colourless needles, which are stable up to 273 K before they start melting. The crystals were therefore selected for measurement with help of a X-Temp 2 low-temperature stage (Heine & Stalke, 1992;Stalke, 1998).
Because of the low stability of the crystals of the trihydrate, no further analysis of the trihydrate was carried out, except for NMR spectroscopy of the crystals, which reveals a broadened water signal in the 1 H NMR spectrum, which overlaps with other signals in d-acetonitrile.

2-Methyl-1,2,3,4-tetrahydroisoquinoline trihydrate
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.