The title compound, bis­(4-hy­droxy- N -isopropyl- N -methyl­tryptammonium) (4-HO-MiPT) fumarate (systematic name: bis­{[2-(4-hy­droxy-1 H -indol-3-yl)eth­yl](meth­yl)propan-2-yl­aza­nium} but-2-enedioate), 2C 14 H 21 N 2 O + ·C 4 H 2 O 4 2− , has a singly protonated tryptammonium cation and one half of a fumarate dianion in the asymmetric unit. The tryptammonium and fumarate ions are held together in one-dimensional chains by N—H⋯O and O—H⋯O hydrogen bonds. These chains are a combination of R 4 2 (20) rings, and C 2 2 (15) and C 4 4 (30) parallel chains along (110). They are further consolidated by N—H⋯π inter­actions. There are two two-component types of disorder impacting the tryptammonium fragment with a 0.753 (7):0.247 (7) occupancy ratio and one of the fumarate oxygen atoms with a 0.73 (8):0.27 (8) ratio.

1. Chemical context A wide variety of naturally occurring organisms, including over 200 species of `magic' mushrooms, contain psychoactive tryptamine compounds (Stamets, 1996 ). Of these compounds, psilocybin has received the most scientific and commercial attention because of recent studies demonstrating its potential for treating mood disorders including addiction, anxiety, depression and PTSD (Johnson & Griffiths, 2017 ; Carhart-Harris & Goodwin, 2017 ). Although psilocybin is currently classified as a schedule I drug, the US Food and Drug Administration recently designated treatment using psilocybin a `breakthrough therapy'. This status has allowed psilocybin to be administered in clinical trials to treat major depressive disorder and treatment-resistant depression (Feltman, 2019 ). Recent reports also suggest that psychedelic microdosing can improve memory, attention and sociability (Cameron, et al. 2020 ). Psilocybin is one of at least ten psychoactive tryptamines present in `magic' mushrooms, with natural psilocybin analogs being identified as recently as 2019 (Lenz et al., 2017 ; Blei et al., 2020 ). Variations in the three-dimensional structure of these natural analogs (as well as synthetic analogs) correlate with differences in their cellular and clinical pharmacology through their structure–activity relationship (SAR) (Nichols, 2018). Understanding the SAR for psilocybin analogs requires the attainment of accurate information about each compound's 3D structure, best provided through single crystal X-ray diffraction. Last year, we reported the structure of 4-acet­oxy-N,N-di­methyl ­tryptamine (4-AcO-DMT) fumarate, which is a syn­thetic analogue of psilocybin. The compound crystallized as a one-to-one tryptammonium/hydro­fumarate salt (Chadeayne et al., 2019c ). We later synthesized bis­(4-acet­oxy-N,N-di­methyl­tryprammonium)­fumarate by treating 4-AcO-DMT fumarate with one half equivalent of lead(II) acetate, precipitating half of the fumarate dianions as lead(II) fumarate (Chadeayne, Golen & Manke, 2019a ). 4-Hy­droxy-N-methyl-N-iso­propyl­tryptamine (4-HO-MiPT), aka `miprocin', is a psilocybin analogue. Its synthesis was first reported in 1981 by Repke and co-workers (Repke et al., 1981 ); its psychedelic effects were later described in collaboration with Alexander Shulgin (Repke et al., 1985 ). Miprocin is reported to produce an experience that is both relaxing, stoning and mildly sedating with a marked physical stimulation that distinguishes it from related substances such as psilocybin mushrooms. In a report last year, we presented the first structure of 4-HO-MiPT (Chadeayne, Pham et al., 2019a ), which crystallizes as the hydro­fumarate monohydrate. Herein we report the reaction of this salt with lead(II) acetate to generate the 4-hy­droxy-N-isopropyl-N-methyl­tryptam­in­ium/fumarate compound in a 2:1 ratio. The solid state structure of the new salt is presented here.

2. Structural commentary The asymmetric unit of bis­(4-hy­droxy-N-isopropyl-N-methyl­trypt­ammo­nium) fumarate contains one tryptammonium cation and one half of a fumarate dianion (Fig. 1 ). The cation possesses a near planar indole, with mean deviation from planarity of 0.014 Å. The methyl­amino group is turned away from this plane, with a C1—C8—C9—C10 torsion angle of −74.2 (2)°. The N-isopropyl-N-methyl­trypt­ammo­nium group is disordered over two orientations in a 0.753 (7):0.247 (7) ratio, with the two moieties related to each other by a pseudo-mirror operation. In solution, the two conformations are most likely inter­converting into each other by rapid de- and reprotonation. One oxygen atom of the half fumarate anion is also disordered over two positions in a 0.73 (8):0.27 (8) ratio. Half of the fumarate dianion is present in the asymmetric unit, with the other half generated by inversion; it is slightly distorted from planarity with r.m.s. deviations of 0.020 and 0.070 Å for the two components. The carboxyl­ate unit is fairly delocalized, with C—O distances ranging from 1.251 (10) to 1.284 (2) Å.

Figure 1

The mol­ecular structure of bis­(4-hy­droxy- N -isopropyl- N -methyl­tryptammonium)­fumarate, showing the atom labeling. Displacement ellipsoids are drawn at the 50% probability level. Hydrogen bonds are shown as dashed lines. Symmetry code: (i) 1 − x , 1 − y , 1 − z .

3. Supra­molecular features There are N2—H2⋯O2 and N2A—H2A⋯O2 hydrogen bonds between the two configurations of the ammonium cations and one fumarate oxygen. These two different N—H⋯O hydrogen bonds, resulting from the disorder, are also likely to be what produces the fumarate disorder. There is an O1—H1⋯O2 hydrogen bond between the phenol hy­droxy group and one fumarate oxygen atom. Two tryptammonium cations and two fumarate anions are joined together through the N—H⋯O and O—H⋯O hydrogen bonds (Fig. 2 ), forming rings with graph-set notation R 4 2(20) (Etter et al., 1990 ). The rings are joined together by two parallel chains along (110). These chains have graph-set notation C 2 2(15) and C 4 4(30). The chains and rings are shown in Fig. 3 . The ions are further linked through N—H⋯π inter­actions between the indole N–H and the aromatic ring of the indole of another tryptammonium ion (Fig. 2 ). The hydrogen bonds in the system are outlined in Table 1 . The packing of the compound is shown in Fig. 4 . Table 1

Hydrogen-bond geometry (Å, °) Cg2 is the centroid of the C1–C6 ring. D —H⋯ A D —H H⋯ A D ⋯ A D —H⋯ A O1—H1⋯O2 0.89 (1) 1.75 (1) 2.618 (2) 165 (2) N2—H2⋯O2 i 0.88 (1) 1.85 (1) 2.730 (5) 175 (3) N2 A —H2 A ⋯O2 i 0.87 (1) 1.89 (4) 2.727 (12) 160 (11) N1—H1 A ⋯ Cg 2 ii 0.87 (1) 2.78 (2) 3.552 (3) 148 (2) ; (ii) .

Symmetry codes: (i); (ii)

Figure 2

π inter­action shown. Displacement ellipsoids are drawn at the 50% probability level. Hydrogen atoms not involved in hydrogen bonds are omitted for clarity. Symmetry codes: (i) − x , − y , 1 − z , (ii) − x , − + y , − z . The hydrogen bonding of the tryptammonium cation in the structure of the title compound (Table 1 ), with hydrogen bonds shown as dashed lines. There is also an N—H⋯inter­action shown. Displacement ellipsoids are drawn at the 50% probability level. Hydrogen atoms not involved in hydrogen bonds are omitted for clarity. Symmetry codes: (i), 1 −, (ii), −

Figure 3

The hydrogen-bonding network along (110), which consists of R 4 2 (20) rings that are joined together by two parallel C 2 2 (15) and C 4 4 (30) chains. The three components described in graph-set notation and the combined chain are shown. Displacement ellipsoids are drawn at the 50% probability level. Hydrogen atoms not involved in hydrogen bonding are omitted for clarity. Hydrogen bonds are shown as dashed lines.

Figure 4

a axis. The N—H⋯O and O—H⋯O hydrogen bonds (Table 1 The crystal packing of the title compound, viewed along theaxis. The N—H⋯O and O—H⋯O hydrogen bonds (Table 1 ) are shown as dashed lines. Hydrogen atoms not involved in hydrogen bonding are omitted for clarity.

4. Database survey The structure of a number of neutral tryptamines have been reported, including psilocin (Petcher & Weber, 1974 ), psilocybin (Weber & Petcher, 1974 ), bufotenine (Falkenberg, 1972b ), DMT (Falkenberg, 1972a ) and MPT (Chadeayne, Golen & Manke, 2019b ). A series of one-to-one tryptammonium hydro­fumarate salts have been structurally characterized, including psilacetin (Chadeayne et al., 2019c ), miprocin and MiPT (Chadeayne, Pham et al., 2019a ). As discussed above, the two-to-one tryptammonium/fumarate salt of 4-AcO-DMT was previously prepared and its structure reported (Chadeayne, Golen & Manke, 2019a ). The only other reported two-to-one tryptammonium fumarate salt was that of 4-HO-DPT, or procin (Chadeayne, Pham et al., 2019b ). The metrical parameters of the tryptammonium cations of 4-HO-MiPT are comparable to those observed for the other reported tryptamine structures.

5. Synthesis and crystallization 61.2 mg of 4-HO-MiPT fumarate were dissolved in 10 mL of deionized water. 29.3 mg of lead(II) acetate was dissolved in 2 mL of deionized water and then added to the tryptamine solution. After sonication, a white precipitate formed. The powder was removed via vacuum filtration. The solvent was removed from the resulting solution in vacuo to yield a sticky powder. The powder was recrystallized from methanol to yield single crystals suitable for X-ray diffraction.

6. Refinement Crystal data, data collection and structure refinement details are summarized in Table 2 . Hydrogen atoms H1, H1A, H2 and H2A were found from a difference- Fourier map and were refined isotropically, using DFIX restraints with N—H distances of 0.87 (1) Å and an O—H distance of 0.88 (1) Å. Isotropic displacement parameters were set to 1.2U eq of the parent indolic nitro­gen atom and 1.5U eq of the parent oxygen atom and the parent ammonium nitro­gen atoms. All other hydrogen atoms were placed in calculated positions with appropriate carbon–hydrogen bond lengths: (sp2) 0.95 Å, (CH 3 ) 0.98 Å, (CH 2 ) 0.99 Å and (CH) 1.00 Å. Isotropic displacement parameters were set to 1.2U eq (C) for sp2, CH and CH 2 parent carbon atoms and 1.5U eq (C-meth­yl). Atoms N2 and C11–C14 were modeled as being disordered over two sets of sites [0.753 (7):0.247 (7)] and refined with SADI (0.03) restraints on C—C(meth­yl) and N—C(meth­yl) bonds to maintain consistent bond lengths in the disorder. Oxygen atom O3 was also modeled as disordered over two sites [0.73 (8):0.27 (8)]. Table 2

Experimental details Crystal data Chemical formula C 14 H 21 N 2 O + ·C 2 HO 2 − M r 290.35 Crystal system, space group Monoclinic, C 2/ c Temperature (K) 200 a , b , c (Å) 19.770 (13), 9.477 (6), 17.620 (12) β (°) 105.78 (2) V (Å 3 ) 3177 (4) Z 8 Radiation type Mo K α μ (mm −1 ) 0.08 Crystal size (mm) 0.25 × 0.2 × 0.1 Data collection Diffractometer Bruker D8 Venture CMOS Absorption correction SADABS ; Bruker, 2018 Multi-scan (; Bruker, 2018 T min , T max 0.692, 0.745 No. of measured, independent and observed [ I > 2 σ ( I )] reflections 39417, 2890, 2007 R int 0.086 (sin θ / λ ) max (Å −1 ) 0.606 Refinement R [ F 2 > 2 σ ( F 2 )], wR ( F 2 ), S 0.047, 0.105, 1.06 No. of reflections 2890 No. of parameters 265 No. of restraints 11 H-atom treatment H atoms treated by a mixture of independent and constrained refinement Δ ρ max , Δ ρ min (e Å −3 ) 0.15, −0.13 APEX3 and SAINT (Bruker, 2018 SHELXT2014 (Sheldrick, 2015 a ), SHELXL2018 (Sheldrick, 2015 b ), OLEX2 (Dolomanov et al. , 2009 publCIF (Westrip, 2010

Computer programs:and(Bruker, 2018 ),(Sheldrick, 2015 ),(Sheldrick, 2015 ),(Dolomanov, 2009 ), and(Westrip, 2010 ).