5-Amino­levulinic acid hydro­chloride

The crystal structure of 5-amino­levulinic acid hydro­chloride (systematic name: 4-carb­oxy-2-oxobutan-1-aminium chloride), C₅H₁₀NO₃⁺·Cl⁻, has been solved and refined using synchrotron X-ray powder diffraction data, and optimized using density functional theory (DFT) techniques. The structure is compared to a recent single-crystal determination [Wang et al. (2025). Z. Kristallogr. New Cryst. Struct. 240, 413–414]. 5-Amino­levulinic acid hydro­chloride crystallizes in the space group Pbca (No. 61), with a = 8.20862 (9), b = 11.22253 (10), c = 16.8595 (2) Å, V = 1553.12 (4) ų, and Z = 8 at 298 K. The crystal structure consists of layers parallel to the ab plane. The center of the layers contains hydro­philic NH₃, Cl, and CO₂H groups, and the outer surface of the layers is composed of hydro­phobic CH₂ groups. Hydrogen bonds are prominent in the crystal structure. The ammonium group acts as a donor to three chloride anions, and one hydrogen bond is bifurcated to the carbonyl group. Each Cl⁻ anion is an acceptor in three N—H⋯Cl hydrogen bonds, plus one from the carb­oxy­lic acid group. These hydrogen bonds connect the cations and anions into the layers parallel to the ab plane. The powder pattern has been submitted to the Inter­national Centre for Diffraction Data (ICDD) for inclusion in the Powder Diffraction File (PDF)

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Chemical scheme

Structure description

5-Amino­levulinic acid hydro­chloride is a porphyrin precursor and a photosensitizing agent. It finds application in the treatment of skin problems, including actinic keratosis and early-stage carcinomas. The systematic name (CAS Registry Number 5451-09-2) is 4-carb­oxy-2-oxobutan-1-aminium chloride. X-ray powder diffraction data for 5-amino­levulinic acid hydro­chloride has been reported in Chinese Patent CN113149854A (Gu et al., 2021). The single-crystal structure of 5-amino­levulinic acid hydro­chloride has been determined very recently [Wang et al., 2025; Cambridge Structural Database (CSD; Groom et al., 2016) refcode MUPYOP]. This work is part of a project (Kaduk et al., 2014) to determine commercial pharmaceutical crystal structures and add high-quality powder diffraction data to the Powder Diffraction File (Kabekkodu et al., 2024).

The r.m.s. Cartesian displacement of the single-crystal (Wang et al., 2025) and Rietveld-refined structures is 0.159 Å. The r.m.s. agreement of the Rietveld-refined and VASP-optimized structures is 0.172 Å. The agreement of the single-crystal, Rietveld, and VASP structures is very good. The agreements are all well within the normal range for correct structures (van de Streek & Neumann, 2014). The isotropic displacement coefficients from the Rietveld refinement correlate very well to the isotropic equivalents calculated form the anisotropic displacement coefficients from the single-crystal refinement, providing another measure of the accuracy of the powder structure. The standard uncertainties on the fractional coordinates from the Rietveld refinement average about 3.5 times larger than those from the single-crystal structure. The powder structure is accurate, but less precise, than the single-crystal structure. The asymmetric unit with the atom numbering is presented in Fig. 1.

Figure 1 The asymmetric unit of 5-amino­levulinic acid hydro­chloride, with the atom numbering. The atoms are represented by 50% probability spheroids/ellipsoids. Image generated using Mercury (Macrae et al., 2020).

All of the bond distances, bond angles, and torsion angles fall within the normal ranges indicated by a Mercury Mogul Geometry check (Macrae et al., 2020). Quantum chemical geometry optimization of the isolated cation (DFT/B3LYP/6-31G*/water) using Spartan '24 (Wavefunction, 2023) indicated that it is 3.1 kcal mol⁻¹ higher in energy than the local minimum, which has a similar conformation (r.m.s. displacement = 0.087 Å). The global minimum-energy conformation has the same energy, but a slightly different conformation (r.m.s. difference = 0.917 Å), mainly at the periphery of the cation. The cation is apparently flexible, and inter­molecular inter­actions determine the solid-state conformation.

The crystal structure (Fig. 2) consists of layers parallel to the ab plane. The center of layers contains hydro­philic NH₃, Cl, and CO₂H groups, and the outer surface of the layers is composed of hydro­phobic CH₂ groups.

Figure 2 The crystal structure of 5-amino­levulinic acid hydro­chloride, viewed down the a axis. Image generated using DIAMOND (Putz & Brandenburg, 2025).

Analysis of the contributions to the total crystal energy of the structure using the Forcite module of Materials Studio (Dassault Systèmes, 2024) suggests that the intra­molecular deformation energy is dominated by angle distortion terms, while van der Waals attractions (which in this force field-based analysis include hydrogen bonds) dominate the inter­molecular energy.

Hydrogen bonds are prominent in the crystal structure. The ammonium group acts as a donor to three chloride anions, and one hydrogen bond is bifurcated to the O2 carbonyl group. Each chloride anion is an acceptor in three N—H⋯Cl hydrogen bonds, plus one from the carb­oxy­lic acid group. These hydrogen bonds connect the cations and anions into layers parallel to the ab plane. The energies of the N—H⋯O hydrogen bonds were calculated using the correlation of Wheatley & Kaduk (2019), and the energy of the O—H⋯Cl hydrogen bond was calculated using the correlation of Kaduk (2002). Three C—H⋯O/Cl hydrogen bonds also contribute to the lattice energy.

The Bravais–Friedel–Donnay–Harker (Bravais, 1866; Friedel, 1907; Donnay & Harker, 1937) morphology suggests that we might expect isotropic morphology for 5-amino­levulinic acid hydro­chloride. A second-order spherical har­monic model was included in the refinement. The texture index was 1.010 (0), indicating that preferred orientation was not significant in this rotated capillary specimen.

Synthesis and crystallization

5-Amino­levulinic acid hydro­chloride was a white powder purchased from TargetMol (Batch No. 146376), and was used as-received.

Refinement

The powder sample was analyzed at 298 K at the Wiggler Low Energy Beamline (Leontowich et al., 2021) of the Brockhouse X-ray Diffraction and Scattering Sector of the Canadian Light Source using a wavelength of 0.819325 (2) Å (15.1 keV). The pattern was indexed using JADE Pro (MDI, 2025) and the crystal structure was solved independently using direct methods, as implemented in EXPO2014 (Altomare et al., 2013). The original structure solution yielded the carb­oxy­lic acid group rotated ∼180° from the single-crystal structure. The single-crystal structure was 26.7 kcal/mol/cell lower in energy, and that conformation was adopted for the refinement.

Rietveld refinement (Fig. 3) was carried out using GSAS-II (Toby & Von Dreele, 2013). All non-H bond distances and angles were restrained according to a Mercury/Mogul Geometry Check (Sykes et al., 2011; Bruno et al., 2004). H atoms were included in calculated positions and recalculated during the refinement using the Mercury (Macrae et al., 2020) `Auto Edit' feature and the `Adjust Hydrogen' feature of Materials Studio (Dassault Systèmes, 2024). The Cl atom was refined anisotropically. the U_iso values of the C, N, and O atoms were refined individually, while the U_iso values for the H atoms were fixed at 1.2 times the U_iso of the C, N, and O atoms to which they are attached. The final refinement yielded R_wp = 0.10874. The largest features in the normalized error plot are in the positions of many of the strong low-angle peaks, and may indicate that the specimen changed during the measurement. The largest peak (0.55 Å from Cl1) and hole (1.86 Å from Cl1) in the difference Fourier map were 0.87 (18) and −0.81 (18) e Å⁻³, respectively.

Figure 3 The Rietveld plot for 5-amino­levulinic acid hydro­chloride. The blue crosses represent the observed data points and the green line is the calculated pattern. The cyan curve is the normalized error plot and the red line is the background curve. The blue tick marks indicate the peak positions. The vertical scale has been multiplied by a factor of ×10 for 2θ > 30.0°.

The crystal structure of 5-amino­levulinic acid hydro­chloride was optimized (fixed unit cell) with density functional theory (DFT) techniques using VASP (Version 6.0; Kresse & Furthmüller, 1996) through the MedeA graphical inter­face (Materials Design, 2024). Single-point density functional theory calculations (fixed experimental cell) and population analysis were carried out using CRYSTAL23 (Erba et al., 2023) using H, C, N, and O basis sets defined by Gatti et al. (1994) and the Cl basis set of Peintinger et al. (2013).

Experimental details are given in Table 1.

Table 1
Experimental details

Crystal data
Chemical formula	C5H10NO3^+·Cl^−
Mr	167.59
Crystal system, space group	Orthorhombic, Pbca
Temperature (K)	298
a, b, c (Å)	8.20862 (9), 11.22253 (10), 16.8595 (2)
V (Å^3)	1553.12 (4)
Z	8
Radiation type	Synchrotron, λ = 0.81933 Å
μ (mm^−1)	0.29
Specimen shape, size (mm)	Cylinder, 0.45 × 0.15
Data collection
Diffractometer	Wiggler Low Energy Beamline, Brockhouse X-ray Diffraction and Scattering Sector, Canadian Light Source
Specimen mounting	Kapton capillary
Data collection mode	Transmission
Scan method	Step
2θ values (°)	2θmin = −9.008 2θmax = 75.047 2θstep = 0.003
Refinement
R factors and goodness of fit	Rp = 0.071, Rwp = 0.109, Rexp = 0.002, R(F^2) = 0.09084, χ^2 = 2566.942
No. of parameters	64
No. of restraints	34
(Δ/σ)max	7.079
Computer programs: GSAS-II (Toby & Von Dreele, 2013).

Structural data

Computing details

4-Carboxy-2-oxobutan-1-aminium chloride

Crystal data

C5H10NO3^+·Cl^−	Z = 8
Mr = 167.59	Dx = 1.434 Mg m^−3
Orthorhombic, Pbca	Synchrotron radiation, λ = 0.81933 Å
a = 8.20862 (9) Å	µ = 0.29 mm^−1
b = 11.22253 (10) Å	T = 298 K
c = 16.8595 (2) Å	cylinder, 0.45 × 0.15 mm
V = 1553.12 (4) Å^3

Data collection

Wiggler Low Energy Beamline, Brockhouse X-ray Diffraction and Scattering Sector, Canadian Light Source diffractometer	Scan method: step
Specimen mounting: Kapton capillary	2θmin = −9.008°, 2θmax = 75.047°, 2θstep = 0.003°
Data collection mode: transmission

Refinement

Least-squares matrix: full	64 parameters
Rp = 0.071	34 restraints
Rwp = 0.109	0 constraints
Rexp = 0.002	Weighting scheme based on measured s.u.'s
R(F^2) = 0.09084	(Δ/σ)max = 7.079
33623 data points	Background function: Background function: "chebyschev-1" function with 3 terms: 7.73(3)e3, -1.90(5)e3, -8(3), Background peak parameters: pos, int, sig, gam: 9.68(4), 9.22(18)e6, 1.98(5)e5, 0.100,
Profile function: Finger-Cox-Jephcoat function parameters U, V, W, X, Y, SH/L: peak variance(Gauss) = Utan(Th)^2+Vtan(Th)+W: peak HW(Lorentz) = X/cos(Th)+Ytan(Th); SH/L = S/L+H/L U, V, W in (centideg)^2, X & Y in centideg 6.157, -1.198, 1.258, 0.000, 0.667, 0.002,	Preferred orientation correction: Simple spherical harmonic correction Order = 2 Coefficients: 0:0:C(2,0) = -0.185(6); 0:0:C(2,2) = -0.092(8)

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

	x	y	z	Uiso*/Ueq
Cl1	−0.08722 (19)	−0.38073 (14)	0.41224 (10)	0.0481
O2	0.0446 (6)	0.1463 (3)	0.4452 (3)	0.0436 (19)*
O3	0.1421 (6)	−0.1790 (3)	0.3666 (3)	0.072 (2)*
O4	−0.0889 (6)	−0.0777 (4)	0.3361 (2)	0.061 (2)*
N5	−0.1619 (6)	0.3359 (4)	0.4450 (3)	0.045 (2)*
C6	−0.0760 (7)	0.3045 (5)	0.3692 (4)	0.036 (3)*
C7	0.0829 (8)	0.1383 (5)	0.3041 (4)	0.028 (2)*
C8	0.0181 (8)	0.1909 (6)	0.3815 (5)	0.029 (2)*
C9	0.1717 (9)	0.0206 (6)	0.3188 (4)	0.037 (3)*
C10	0.0637 (10)	−0.0816 (7)	0.3375 (4)	0.057 (3)*
H11	−0.16952	0.29163	0.31995	0.0432*
H12	0.01136	0.37928	0.35232	0.0432*
H13	−0.07194	0.37918	0.48770	0.0535*
H14	−0.21369	0.25158	0.47304	0.0535*
H15	0.17071	0.20435	0.27562	0.0332*
H16	−0.02297	0.12117	0.26185	0.0332*
H17	0.26049	0.03343	0.37008	0.0438*
H18	0.24389	−0.00500	0.26360	0.0438*
H19	−0.26527	0.40077	0.43180	0.0535*
H20	0.07050	−0.24190	0.38070	0.0865*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Cl1	0.0527 (18)	0.0384 (15)	0.053 (2)	0.006 (3)	−0.026 (3)	−0.018 (3)

Geometric parameters (Å, º)

O2—C8	1.205 (8)	C8—C7	1.528 (8)
O3—C10	1.360 (7)	C9—C7	1.529 (7)
O3—H20	0.949 (4)	C9—C10	1.483 (8)
O4—C10	1.254 (8)	C9—H17	1.140 (6)
N5—C6	1.502 (8)	C9—H18	1.141 (7)
N5—H13	1.139 (5)	C10—O3	1.360 (7)
N5—H14	1.140 (5)	C10—O4	1.254 (8)
N5—H19	1.140 (5)	C10—C9	1.483 (8)
C6—N5	1.502 (8)	H11—C6	1.140 (6)
C6—C8	1.505 (6)	H12—C6	1.140 (6)
C6—H11	1.140 (6)	H13—N5	1.139 (5)
C6—H12	1.140 (6)	H14—N5	1.140 (5)
C7—C8	1.528 (8)	H15—C7	1.140 (6)
C7—C9	1.529 (7)	H16—C7	1.140 (6)
C7—H15	1.140 (6)	H17—C9	1.140 (6)
C7—H16	1.140 (6)	H18—C9	1.141 (7)
C8—O2	1.205 (8)	H19—N5	1.140 (5)
C8—C6	1.505 (6)	H20—O3	0.957 (4)
C10—O3—H20	113.3 (5)	C8—C7—H16	109.5 (6)
C6—N5—H13	109.5 (5)	C9—C7—H16	108.6 (5)
C6—N5—H14	109.4 (4)	H15—C7—H16	109.2 (5)
H13—N5—H14	109.5 (5)	O2—C8—C6	124.5 (8)
C6—N5—H19	109.4 (5)	O2—C8—C7	122.6 (7)
H13—N5—H19	109.5 (4)	C6—C8—C7	112.9 (7)
H14—N5—H19	109.5 (4)	C7—C9—C10	114.7 (6)
N5—C6—C8	108.8 (6)	C7—C9—H17	108.6 (5)
N5—C6—H11	109.5 (5)	C10—C9—H17	108.7 (6)
C8—C6—H11	109.8 (5)	C7—C9—H18	109.4 (6)
N5—C6—H12	109.5 (6)	C10—C9—H18	106.8 (5)
C8—C6—H12	109.6 (5)	H17—C9—H18	108.6 (6)
H11—C6—H12	109.6 (6)	O3—C10—O4	120.5 (8)
C8—C7—C9	111.1 (6)	O3—C10—C9	114.5 (7)
C8—C7—H15	109.1 (5)	O4—C10—C9	124.5 (7)
C9—C7—H15	109.2 (6)