Crystal structure of serotonin

The crystal structure of the free base of the ubiquitous neurotransmitter serotonin is reported for the first time.

Abstract

The title compound, serotonin or 5-hy­droxy­tryptamine (5-HT) [systematic name: 3-(2-amino­eth­yl)-1H-indol-5-ol], C₁₀H₁₂N₂O, has one mol­ecule in the asymmetric unit. The conformation of the ethyl­amino side chain is gauche–gauche [C_a—C_a—C_m—C_m and C_a—C_m—C_m—N (a = aromatic, m = methyl­ene) torsion angles = −64.2 (3) and −61.9 (2)°, respectively]. In the crystal, the mol­ecules are linked into a three-dimensional network by N—H⋯O and O—H⋯N hydrogen bonds.

Chemical context

Serotonin, C₁₀H₁₂N₂O, systematic name 3-(2-amino­eth­yl)-1H-indol-5-ol, is the primary neurotransmitter in humans, regulating mood, anxiety and happiness (Young & Leyton, 2002 ▸). While it is best known for its role in the central nervous system, serotonin is found throughout the human body and impacts a wide array of bodily functions. Roughly ninety-five percent of the body’s serotonin is actually found in the gastrointestinal tract, where it regulates intestinal movement (Berger et al., 2009 ▸). Serotonin is produced in the human body through biosynthesis from the essential amino acid tryptophan (Fitzpatrick, 1999 ▸), and broken down by mono­amine oxidase to generate 5-hy­droxy­indole­acetic acid. As such, mono­amine oxidase inhibitors and other compounds that increase serotonin concentration have been used to treat depression (Suchting et al., 2021 ▸).

Serotonin is not unique to humans, but is found throughout life on Earth including all bilateral animals, where it also functions as a neurotransmitter (Bacqué-Cazenave et al., 2020 ▸). It is found in plants, notably in seeds, where serotonin stimulates the digestive tract of animals, leading to excretion of the seeds (Akula et al., 2011 ▸). Serotonin and related tryptamines are well known to be present in a number of fungi (Tyler, 1958 ▸; Sherwood et al., 2020 ▸). A variety of related tryptamines found in plants, fungi, and toads, which are active at serotonin receptors, have garnered significant attention as psychedelic drugs to treat mood disorders including anxiety, depression, and addiction (Carhart-Harris & Goodwin, 2017 ▸). Serotonin was discovered by Vittorio Erspaner in 1935, characterized as 5-hy­droxy­tryptamine (5-HT) in 1949 by Rapport, and synthesized by Upjohn pharmaceutical in 1951 (Whitaker-Azmitia, 1999 ▸). Despite the simplicity of its structure and universally recognized biological significance, the single-crystal structure of pure free base serotonin has never been reported. Herein, we report this structure to fill in the gap from the scientific record.

Structural commentary

Serotonin or 5-hy­droxy­tryptamine (5-HT) is an indolamine with a 5-hy­droxy substitution. In the solid state, serotonin crystallizes with one mol­ecule in the asymmetric unit (Fig. 1 ▸) in the chiral space group P2₁2₁2₁. The 5-hy­droxy­indole fused-ring unit is almost planar with the non-hydrogen atoms showing an r.m.s. deviation from planarity of 0.030 Å. The ethyl­amino arm is turned away from the indole ring, with a C7—C8—C9—C10 torsion angle of −64.2 (3)°. The ethyl­amino arm itself turns back toward the indole ring with a C8—C9—C10—N2 torsion angle of −61.9 (2)°.

Figure 1.

The mol­ecular structure of serotonin free base showing the atomic labeling. Displacement ellipsoids are drawn at the 50% probability level.

Supra­molecular features

In the crystal, the serotonin mol­ecules are linked by a series of hydrogen bonds that produce a three-dimensional network in the solid state. The hy­droxy groups form hydrogen bonds to the amine N atoms on an adjacent serotonin mol­ecules forming O1—H1⋯N2 hydrogen bonds. The indole N atoms form hydrogen bonds to the hy­droxy groups of adjacent serotonin mol­ecules through N1—H1A⋯O1 hydrogen bonds. Half of the amine H atoms link to the hy­droxy groups of nearby mol­ecules through N2—H2B⋯O1 hydrogen bonds. There are no observed π–π stacking inter­actions. Fig. 2 ▸ outlines the hydrogen bonds, which are detailed in Table 1 ▸. The crystal packing of serotonin is shown in Fig. 3 ▸.

Figure 2.

The different hydrogen-bonding inter­actions between the serotonin mol­ecules. Hydrogen atoms not involved in hydrogen bonding are omitted for clarity. Symmetry codes: (i)  − x, 1 − y,  + z (ii) 2 − x, −  + y,  − z (iii) 3/2 − x, −y, −  + z.

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O1—H1⋯N2i	0.88 (1)	1.77 (1)	2.636 (2)	170 (3)
N1—H1A⋯O1ii	0.88 (1)	2.10 (1)	2.967 (2)	169 (2)
N2—H2B⋯O1iii	0.91 (1)	2.19 (1)	3.092 (3)	168 (2)

Symmetry codes: (i) ; (ii) ; (iii) .

Figure 3.

The crystal packing of serotonin free base viewed along the a-axis. Hydrogen bonds are shown as dashed lines. Hydrogen atoms not involved in hydrogen bonds are omitted for clarity.

Database survey

The previous structural reports of serotonin are all complex mixtures containing serotonin in its C₁₀H₁₃N₂O⁺ cationic form. These include the creatine sulfate monohydrate (Karle et al., 1965 ▸: Cambridge Structural Database refcode HTRCRS), the hydrogen oxalate salt (Amit et al., 1978 ▸: SERHOX), the hydro­adipate salt (Rychkov et al., 2013 ▸: VIKWIX), the picrate monohydrate (Thewalt & Bugg, 1972 ▸: SERPIC) and two compounds where it is co-crystallized with 1,3,6,8-tetra­sulfonato­pyrene (Feng et al., 2017 ▸: RAWDIF, RAWDOL). The two most closely reported free-base structures to serotonin are the natural product bufotenine, 5-hy­droxy-N,N-di­methyl­tryptamine (Falkenberg, 1972 ▸: BUFTEN) and 5-meth­oxy­tryptamine (Quarles et al., 1974 ▸: MXTRYP). 5-Meth­oxy­tryptamine has also been reported as its picrate (Nagata et al., 1995 ▸: ZILMIQ) and chloride (Pham et al., 2021 ▸: CCDC 2106050) salts. The free base reported here shows the ethyl­amino arm turned away from the indole plane. The majority of the cationic tryptamine structures show ethyl­amino arms that are nearly in-plane with the indole ring. Only the picrate salt has a structure similar to that of the title compound, showing an ethyl­amino arm turned similarly away from the indole ring. The torsion angles associated with the ethyl­amino arms of the different structures are summarized in Table 2 ▸.

Table 2. Torsion angles of the ethyl­amino arms of different serotonin structures (our atom-numbering scheme).

	Space group	C7—C8—C9—C10	C8—C9—C10—N2	Reference
5-HT free base	P212121	−64.2 (3)	−61.9 (2)	This work
HTRCRS	C2/c	166.7	172.6	Karle et al. (1965 ▸)
SERHOX	P21/n	171.7	179.7	Amit et al. (1978 ▸)
SERPIC	P21/c	67.5	66.6	Thewalt & Bugg (1972 ▸)
VIKWIX	P	178.7	177.2	Rychkov et al. (2013 ▸)
RAWDIF	Pca21	177.8	177.6	Feng et al. (2017 ▸)
RAWDOL a	Cc	178.7	175.1	Feng et al. (2017 ▸)
RAWDOL b	Cc	102	43	Feng et al. (2017 ▸)

Notes: (a, b) RAWDOL contains two mol­ecules in the asymmetric unit. The b mol­ecule is probably disordered and the geometrical data are less certain.

Synthesis and crystallization

Single crystals suitable for X-ray diffraction studies were grown from the slow evaporation of a tetra­hydro­furan solution of a commercial sample of serotonin free base (Chem-Impex).

Refinement

Crystal data, data collection and structure refinement details are summarized in Table 3 ▸. Hydrogen atoms H1, H1A, H2A and H2B were found from a difference-Fourier map and were refined isotropically, using DFIX restraints with an N—H(indole) distance of 0.87 (1) Å, N—H(amine) distances of 0.90 (1) Å, and an O—H distance of 0.86 (1) Å. Isotropic displacement parameters were set to 1.2 U _eq of the parent nitro­gen atoms and 1.5 U _eq of the parent oxygen atom. All other hydrogen atoms were placed in calculated positions with C—H = 0.93 Å (sp ²) or 0.97 Å (sp ³). Isotropic displacement parameters were set to 1.2 U _eq of the parent carbon atoms. The absolute structure of the crystal chosen for data collection was indeterminate in the present refinement.

Table 3. Experimental details.

Crystal data
Chemical formula	C10H12N2O
M r	176.22
Crystal system, space group	Orthorhombic, P212121
Temperature (K)	297
a, b, c (Å)	8.2248 (6), 8.7542 (6), 13.0712 (10)
V (Å3)	941.15 (12)
Z	4
Radiation type	Mo Kα
μ (mm−1)	0.08
Crystal size (mm)	0.18 × 0.10 × 0.02
Data collection
Diffractometer	Bruker D8 Venture CMOS
Absorption correction	Multi-scan (SADABS; Bruker, 2018 ▸)
T min, T max	0.711, 0.745
No. of measured, independent and observed [I > 2σ(I)] reflections	25138, 1783, 1590
R int	0.052
(sin θ/λ)max (Å−1)	0.610
Refinement
R[F 2 > 2σ(F 2)], wR(F 2), S	0.030, 0.073, 1.05
No. of reflections	1783
No. of parameters	134
No. of restraints	4
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å−3)	0.13, −0.13
Absolute structure	Flack x determined using 609 quotients [(I +)-(I -)]/[(I +)+(I -)] (Parsons et al., 2013 ▸)
Absolute structure parameter	−1.2 (6)

Computer programs: APEX3 (Bruker, 2018 ▸), SAINT (Bruker, 2018 ▸), SHELXT2014 (Sheldrick, 2015a ▸), SHELXL2018 (Sheldrick, 2015b ▸), OLEX2 (Dolomanov et al., 2009 ▸), publCIF (Westrip, 2010 ▸).

Supplementary Material

CCDC reference: 2156646

Additional supporting information: crystallographic information; 3D view; checkCIF report

supplementary crystallographic information

Crystal data

C10H12N2O	Dx = 1.244 Mg m−3
Mr = 176.22	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, P212121	Cell parameters from 6263 reflections
a = 8.2248 (6) Å	θ = 3.1–25.4°
b = 8.7542 (6) Å	µ = 0.08 mm−1
c = 13.0712 (10) Å	T = 297 K
V = 941.15 (12) Å3	Block, colourless
Z = 4	0.18 × 0.10 × 0.02 mm
F(000) = 376

Data collection

Bruker D8 Venture CMOS diffractometer	1590 reflections with I > 2σ(I)
φ and ω scans	Rint = 0.052
Absorption correction: multi-scan (SADABS; Bruker, 2018)	θmax = 25.7°, θmin = 2.8°
Tmin = 0.711, Tmax = 0.745	h = −10→10
25138 measured reflections	k = −10→10
1783 independent reflections	l = −15→15

Refinement

Refinement on F2	Hydrogen site location: mixed
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F2 > 2σ(F2)] = 0.030	w = 1/[σ2(Fo2) + (0.0372P)2 + 0.1115P] where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.073	(Δ/σ)max < 0.001
S = 1.05	Δρmax = 0.13 e Å−3
1783 reflections	Δρmin = −0.13 e Å−3
134 parameters	Absolute structure: Flack x determined using 609 quotients [(I+)-(I-)]/[(I+)+(I-)] (Parsons et al., 2013)
4 restraints	Absolute structure parameter: −1.2 (6)

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
O1	0.91964 (18)	0.18734 (16)	0.08462 (10)	0.0398 (4)
H1	0.868 (3)	0.263 (2)	0.054 (2)	0.078 (9)*
N1	0.6390 (2)	0.0903 (2)	0.45983 (14)	0.0445 (5)
H1A	0.633 (3)	0.012 (2)	0.5016 (15)	0.051 (7)*
N2	0.7279 (2)	0.6020 (2)	0.47447 (15)	0.0458 (5)
H2A	0.725 (3)	0.5092 (18)	0.5030 (18)	0.050 (7)*
H2B	0.8312 (19)	0.638 (3)	0.465 (2)	0.072 (9)*
C1	0.5533 (3)	0.2238 (2)	0.47087 (16)	0.0433 (5)
H1B	0.487070	0.246998	0.526412	0.052*
C2	0.7237 (2)	0.0960 (2)	0.36910 (15)	0.0343 (4)
C3	0.8303 (2)	−0.0077 (2)	0.32446 (16)	0.0388 (5)
H3	0.856712	−0.098830	0.357097	0.047*
C4	0.8956 (2)	0.0283 (2)	0.23057 (16)	0.0375 (5)
H4	0.967797	−0.039127	0.199600	0.045*
C5	0.8552 (2)	0.1654 (2)	0.18068 (14)	0.0316 (4)
C6	0.7543 (2)	0.27075 (19)	0.22632 (14)	0.0304 (4)
H6	0.731045	0.362796	0.193965	0.036*
C7	0.6874 (2)	0.2373 (2)	0.32214 (14)	0.0300 (4)
C8	0.5785 (2)	0.3173 (2)	0.38953 (14)	0.0349 (4)
C9	0.5130 (2)	0.4756 (2)	0.37352 (17)	0.0391 (5)
H9A	0.434413	0.497950	0.426806	0.047*
H9B	0.456668	0.479381	0.308368	0.047*
C10	0.6446 (3)	0.5971 (2)	0.37477 (16)	0.0412 (5)
H10A	0.723268	0.575700	0.321372	0.049*
H10B	0.596386	0.696063	0.360712	0.049*

Atomic displacement parameters (Ų)

	U11	U22	U33	U12	U13	U23
O1	0.0473 (8)	0.0370 (8)	0.0351 (7)	0.0049 (7)	0.0058 (6)	−0.0021 (6)
N1	0.0536 (11)	0.0411 (10)	0.0390 (10)	0.0009 (9)	0.0040 (9)	0.0125 (8)
N2	0.0465 (11)	0.0406 (10)	0.0502 (12)	0.0012 (9)	−0.0064 (9)	−0.0055 (9)
C1	0.0441 (11)	0.0456 (13)	0.0402 (11)	0.0009 (10)	0.0064 (9)	0.0025 (9)
C2	0.0378 (10)	0.0309 (9)	0.0342 (10)	−0.0019 (8)	−0.0068 (9)	0.0044 (8)
C3	0.0434 (11)	0.0268 (9)	0.0461 (11)	0.0031 (8)	−0.0094 (10)	0.0058 (8)
C4	0.0366 (10)	0.0325 (10)	0.0435 (11)	0.0061 (8)	−0.0055 (9)	−0.0036 (9)
C5	0.0322 (9)	0.0299 (9)	0.0328 (9)	−0.0033 (7)	−0.0037 (8)	−0.0034 (8)
C6	0.0360 (9)	0.0230 (8)	0.0323 (9)	−0.0004 (8)	−0.0052 (8)	0.0010 (7)
C7	0.0304 (9)	0.0282 (9)	0.0315 (9)	−0.0012 (7)	−0.0060 (7)	0.0001 (7)
C8	0.0348 (9)	0.0347 (10)	0.0353 (10)	0.0004 (8)	−0.0024 (9)	−0.0004 (8)
C9	0.0377 (10)	0.0390 (11)	0.0406 (11)	0.0078 (9)	−0.0006 (9)	−0.0009 (9)
C10	0.0493 (12)	0.0340 (10)	0.0404 (11)	0.0045 (9)	−0.0001 (10)	−0.0030 (9)

Geometric parameters (Å, º)

O1—H1	0.878 (13)	C3—C4	1.376 (3)
O1—C5	1.376 (2)	C4—H4	0.9300
N1—H1A	0.879 (12)	C4—C5	1.406 (3)
N1—C1	1.373 (3)	C5—C6	1.376 (3)
N1—C2	1.376 (3)	C6—H6	0.9300
N2—H2A	0.894 (12)	C6—C7	1.399 (3)
N2—H2B	0.914 (13)	C7—C8	1.438 (3)
N2—C10	1.473 (3)	C8—C9	1.501 (3)
C1—H1B	0.9300	C9—H9A	0.9700
C1—C8	1.358 (3)	C9—H9B	0.9700
C2—C3	1.391 (3)	C9—C10	1.518 (3)
C2—C7	1.412 (3)	C10—H10A	0.9700
C3—H3	0.9300	C10—H10B	0.9700
C5—O1—H1	109.1 (19)	C5—C6—H6	120.5
C1—N1—H1A	124.8 (16)	C5—C6—C7	119.01 (16)
C1—N1—C2	108.64 (16)	C7—C6—H6	120.5
C2—N1—H1A	126.4 (16)	C2—C7—C8	107.00 (17)
H2A—N2—H2B	113 (2)	C6—C7—C2	119.27 (17)
C10—N2—H2A	109.3 (16)	C6—C7—C8	133.72 (17)
C10—N2—H2B	108.5 (18)	C1—C8—C7	106.30 (17)
N1—C1—H1B	124.7	C1—C8—C9	127.65 (19)
C8—C1—N1	110.65 (19)	C7—C8—C9	126.01 (17)
C8—C1—H1B	124.7	C8—C9—H9A	109.0
N1—C2—C3	131.04 (18)	C8—C9—H9B	109.0
N1—C2—C7	107.41 (16)	C8—C9—C10	112.92 (16)
C3—C2—C7	121.54 (18)	H9A—C9—H9B	107.8
C2—C3—H3	121.0	C10—C9—H9A	109.0
C4—C3—C2	118.04 (17)	C10—C9—H9B	109.0
C4—C3—H3	121.0	N2—C10—C9	111.17 (17)
C3—C4—H4	119.4	N2—C10—H10A	109.4
C3—C4—C5	121.14 (18)	N2—C10—H10B	109.4
C5—C4—H4	119.4	C9—C10—H10A	109.4
O1—C5—C4	116.80 (17)	C9—C10—H10B	109.4
C6—C5—O1	122.29 (17)	H10A—C10—H10B	108.0
C6—C5—C4	120.90 (17)
O1—C5—C6—C7	177.03 (16)	C3—C2—C7—C6	2.9 (3)
N1—C1—C8—C7	0.2 (2)	C3—C2—C7—C8	−178.28 (17)
N1—C1—C8—C9	−177.44 (19)	C3—C4—C5—O1	−176.50 (17)
N1—C2—C3—C4	178.8 (2)	C3—C4—C5—C6	2.8 (3)
N1—C2—C7—C6	−178.03 (16)	C4—C5—C6—C7	−2.3 (3)
N1—C2—C7—C8	0.8 (2)	C5—C6—C7—C2	−0.5 (2)
C1—N1—C2—C3	178.3 (2)	C5—C6—C7—C8	−178.96 (18)
C1—N1—C2—C7	−0.7 (2)	C6—C7—C8—C1	178.0 (2)
C1—C8—C9—C10	113.0 (2)	C6—C7—C8—C9	−4.4 (3)
C2—N1—C1—C8	0.3 (3)	C7—C2—C3—C4	−2.4 (3)
C2—C3—C4—C5	−0.5 (3)	C7—C8—C9—C10	−64.2 (3)
C2—C7—C8—C1	−0.6 (2)	C8—C9—C10—N2	−61.9 (2)
C2—C7—C8—C9	177.08 (18)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···N2i	0.88 (1)	1.77 (1)	2.636 (2)	170 (3)
N1—H1A···O1ii	0.88 (1)	2.10 (1)	2.967 (2)	169 (2)
N2—H2B···O1iii	0.91 (1)	2.19 (1)	3.092 (3)	168 (2)

Symmetry codes: (i) −x+3/2, −y+1, z−1/2; (ii) −x+3/2, −y, z+1/2; (iii) −x+2, y+1/2, −z+1/2.

Funding Statement

This work was funded by National Science Foundation, Directorate for Mathematical and Physical Sciences grant CHE-1429086.