Crystal structure of glycidamide: the mutagenic and genotoxic metabolite of acryl­amide

Hemgesberg, M.N.; Bonck, T.; Merz, K.-H.; Sun, Y.; Schrenk, D.

doi:10.1107/S2056989016010859

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Volume 72| Part 8| August 2016| Pages 1179-1182

https://doi.org/10.1107/S2056989016010859

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Crystal structure of glycidamide: the mutagenic and genotoxic metabolite of acrylamide

Melanie N. Hemgesberg,^a Thorsten Bonck,^b Karl-Heinz Merz,^a Yu Sun ^c and Dieter Schrenk ^a ^*

^aFood Chemistry and Toxicology, University of Kaiserslautern, 67663 Kaiserslautern, Germany, ^bTheoretical Chemistry, University of Kaiserslautern, 67663 Kaiserslautern, Germany, and ^cInorganic Chemistry, University of Kaiserslautern, 67663 Kaiserslautern, Germany
^*Correspondence e-mail: schrenk@rhrk.uni-kl.de

Edited by H. Stoeckli-Evans, University of Neuchâtel, Switzerland (Received 24 June 2016; accepted 5 July 2016; online 22 July 2016)

The title compound, glycidamide (systematic name: oxirane-2-carboxamide), C₃H₅NO₂, is the mutagenic and genotoxic metabolite of acrylamide, a food contaminant and industrial chemical that has been classified as being probably carcinogenic to humans. Synthesized via the reaction of acrylonitrile and hydrogen peroxide, it crystallizes with both enantiomers occurring as two crystallographically independent molecules (A and B) in the asymmetric unit. They have similar conformations with an r.m.s. deviation of 0.0809 Å for molecule B inverted on molecule A. In the crystal, molecules are linked by N—H⋯O hydrogen bonds, which lead to the formation of β-sheet structures enclosing R₂²(8) and R₄²(8) loops. The β-sheets are linked by weaker C—H⋯O hydrogen bonds, forming a supramolecular three-dimensional structure.

Keywords: crystal structure; glycidamide; acrylamide; mutagenic; genotoxic metabolite; hydrogen bonding; β-sheet.

CCDC reference: 1490160

1. Chemical context

The formation of glycidamide (GA) is considered to cause the carcinogenicity of acrylamide (AA; Udovenko & Kolzunova, 2008 ), which is a widely used chemical in industry (EPA, 1994 ). Typical applications include the production of copolymers, flocculation agents and carrier material for gel electrophoresis. Moreover, it is formed if certain foods are heated to temperatures above 393 K at low moisture. AA was found at the highest levels in solid coffee substitutes, fried potato products and gingerbread, thus contributing to human exposure (EFSA, 2015 ). AA forms predominantly from asparagine in the presence of reducing sugars during the Maillard reaction via a Strecker-type degradation (Mottram et al., 2002 ; Stadler et al., 2002 ; Tareke et al., 2002 ; Yaylayan et al., 2003 ). Besides being a food contaminant, AA is also a component of tobacco smoke (Papoušek et al., 2014 ). It has also been classified as `probably carcinogenic to humans (Group 2A)' by the International Agency for Research on Cancer (IARC, 1994 ). It has not been found to be mutagenic or genotoxic without metabolic activation to GA at biologically relevant concentrations (Watzek et al., 2012 ).

GA is a genotoxic and mutagenic compound formed in vivo metabolically from AA, mainly in the liver by cytochrome P450 2E1 (Baum et al., 2005 ). As a reactive epoxide, GA is able to react with nucleophilic centers of proteins and DNA, thus forming DNA adducts and hemoglobin conjugates (Ghanayem et al., 2005 ). As a consequence, mutations may occur, which represent stages of chemical mutagenesis and carcinogenesis (Gamboa da Costa et al., 2003 ). We synthesized GA via the reaction of acrylonitrile and hydrogen peroxide.

2. Structural commentary

Owing to its size, GA shows few structural features. Both enantiomers occur as two crystallographically independent molecules (A and B) in the asymmetric unit (Fig. 1). They have similar conformations with an r.m.s. deviation of 0.0809 Å for molecule B inverted on molecule A. The amide group is inclined to the epoxide plane by 77.9 (2)° in molecule A (N1/C1/O1 vs O2/C2/C3), and by 72.6 (2)° in molecule B (N11/C11/O11 vs O12/C12/C13).

Figure 1
The molecular structure of the two independent molecules (A and B) of the title compound, glycidamide (GA), with atom labelling. Displacement ellipsoids are drawn at the 50% probability level.

Of interest are the C—C as well as the C—O bond lengths in the epoxide fragment (Table 1). The values of bond lengths in the epoxide fragments of both enantiomers are compared to the mean values and their standard deviation of a selection of 149 similarly substituted compounds featuring an epoxide fragment (Table 1), which were reported to the Cambridge Structural Database (CSD, Version 5.37, Update 2 Feb 2016; Groom et al., 2016 ). While the epoxide C—O bonds in GA match the mean values quite well, the C—C bond is more at the upper end for bond lengths. Nevertheless, the C—C bond length is still in the range of one standard deviation to the mean value of the database entries. Omitting oxirane itself, GA is the smallest example of an epoxide crystal structure reported in the CSD. Summing up, the epoxide fragment in GA seems to be representative for this class of epoxides.

Table 1
Experimental bond lengths (Å) compared to a database survey of 149 compounds featuring epoxide fragments

	Bond	Molecule A	Bond	Molecule B	Database survey
C—C	C2—C3	1.463 (2)	C12—C13	1.458 (2)	1.442±0.028
CH₂—O	C3—O2	1.436 (2)	C13—O12	1.433 (2)	1.431±0.026
XCH—O	C2—O2	1.429 (2)	C12—O12	1.424 (2)	1.432±0.026

3. Supramolecular features

In the crystal, there are as expected, hydrogen bonds dominating the solid-state structure. The protons of the amino moiety undergo strong N—H⋯O hydrogen bonding to the carbonyl groups of adjacent GA molecules (Table 2, Fig. 2). This results in the formation of a β-sheet structure, which is parallel to the crystallographic b axis and encloses R₂²(8) and R₄²(8) loops. The β-sheets are also oriented parallel to each other (Fig. 3). They are further interlinked by additional but weaker C—H⋯O hydrogen bonds (Table 2), between the protons ot the –CH₂– units with the carbonyl group and the epoxy function from the neighbouring β-sheets, which leads to the formation of a supramolecular three-dimensional structure (Fig. 4).

Table 2
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1B⋯O2	0.86 (2)	2.45 (2)	2.7770 (17)	103 (1)
N11—H11B⋯O12	0.87 (2)	2.39 (2)	2.7408 (17)	105 (1)
N1—H1A⋯O11ⁱ	0.86 (2)	2.12 (2)	2.9651 (16)	167 (2)
N1—H1B⋯O1ⁱⁱ	0.86 (2)	2.12 (2)	2.8482 (14)	142 (2)
N11—H11A⋯O1ⁱⁱⁱ	0.87 (2)	2.08 (2)	2.9447 (16)	173 (2)
N11—H11B⋯O11ⁱⁱ	0.87 (2)	2.11 (2)	2.8495 (14)	144 (2)
C3—H3A⋯O11ⁱⁱ	0.99	2.59	3.5839 (19)	179
C3—H3B⋯O2^iv	0.99	2.59	3.4470 (18)	144
C13—H13A⋯O12^v	0.99	2.44	3.3991 (19)	163
Symmetry codes: (i) $[x, -y+{\script{1\over 2}}, z-{\script{1\over 2}}]$ ; (ii) x, y+1, z; (iii) $[x, -y+{\script{1\over 2}}, z+{\script{1\over 2}}]$ ; (iv) $[-x+1, y-{\script{1\over 2}}, -z+{\script{3\over 2}}]$ ; (v) $[-x, y-{\script{1\over 2}}, -z+{\script{1\over 2}}]$ .

Figure 2
A partial view of the crystal packing of the title compound, showing the β-sheet arrangement, formed through strong N—H⋯O hydrogen bonds (dashed lines; see Table 2

for details), propagating along the b-axis direction.

Figure 3
A view along the b axis of the crystal packing of the title compound, showing the β-sheet arrangement formed through strong N—H⋯O hydrogen bonds (dashed lines; see Table 2

for details). The C-bound H atoms have been omitted for clarity (A molecules = black; B molecules = red).

Figure 4
A view along the b axis of the crystal packing of the title compound. The N—H⋯O and C—H⋯O hydrogen bonds are shown as dashed lines (see Table 2

for details). H atoms not involved in these interactions have been omitted for clarity (A molecules = black; B molecules = red).

4. Database survey

As noted in Section 2, a search of the Cambridge Structural Database (Groom et al., 2016) revealed the presence of 149 similarly substituted compounds featuring an epoxide fragment. However, up to now there has been no report of the structure of the title compound (GA).

5. Synthesis and crystallization

The synthesis of the title compound (GA) was performed according to a published method with modifications (Payne & Williams, 1961 ). The conventional literature procedure by controlled pH and temperature resulted in an unfavorable decomposition of hydrogen peroxide. GA was synthesized by dropwise addition of 1 M NaOH (60 ml) to acrylonitrile (80.1 g, 1.22 mol) in water (500 ml) and 30% H₂O₂ (102 ml, 1 mol). The pH was kept at 7.3–7.5 and the temperature was maintained at 308–310 K. After the reaction was completed (about 12 h), the mixture was treated with 5% palladium on charcoal, stored overnight in a refrigerator and then filtered. The solvent was evaporated and the crude product (yield: 55 g; 63%) was recrystallized from dry acetone at low temperature. Colourless crystals formed after 3–5 days at 243 K. GA is very hygroscopic, so purification of the raw product was carried out in an inert atmosphere. The compound was stored in dry argon at 243 K. Identity and purity were checked by NMR spectroscopic methods and elemental analysis. ¹H-NMR (600.13 MHz, 295.15 K, p.p.m., D₂O): δ 3,49 (dd, ²J_HH = 4.08 Hz, ³J_HH = 2.58 Hz,1H); 3,02 (t, 5.16 Hz, 1H); 2,87 (dd, ²J_HH = 5.52 Hz, ³J_HH = 2.58 Hz, 1H). ¹³C-{¹H}-NMR (100.66 MHz, 294.05 K, p.p.m., DMSO-d₆): δ 170.1 (C1), 48.5 (C2), 45.6 (C3). Elemental analysis for C₃H₅NO₂. Required: C 41.36%; H 5.79%; N 16.09%; found: C 41.41%; H 5.47%; N 16.27%.

6. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 3. The H atoms bound to the nitrogen atoms, N1 and N11, were located in a difference Fourier map, and refined with a distance restraint: N—H = 0.86 (2) Å with U_iso(H) = 1.2U_eq(N). The C-bound H were placed in calculated positions and refined using a riding model: C—H = 0.99–1.00 Å with U_iso(H) = 1.2U_eq(C).

Table 3
Experimental details

Crystal data
Chemical formula	C₃H₅NO₂
M_r	87.08
Crystal system, space group	Monoclinic, P2₁/c
Temperature (K)	150
a, b, c (Å)	15.5186 (7), 5.1007 (2), 10.9250 (5)
β (°)	107.651 (5)
V (Å³)	824.06 (7)
Z	8
Radiation type	Cu Kα
μ (mm⁻¹)	1.02
Crystal size (mm)	0.22 × 0.16 × 0.16

Data collection
Diffractometer	Rigaku Xcalibur (Sapphire3, Gemini ultra)
Absorption correction	Multi-scan (CrysAlis PRO; Rigaku Oxford Diffraction, 2015 $[Rigaku Oxford Diffraction (2015). CrysAlis PRO. Rigaku Corporation, Tokyo, Japan.]$ )
T_min, T_max	0.837, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections	4485, 1310, 1207
R_int	0.022
(sin θ/λ)_max (Å⁻¹)	0.577

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.035, 0.093, 1.10
No. of reflections	1310
No. of parameters	121
No. of restraints	4
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρ_max, Δρ_min (e Å⁻³)	0.34, −0.17
Computer programs: CrysAlis PRO (Rigaku Oxford Diffraction, 2015 $[Rigaku Oxford Diffraction (2015). CrysAlis PRO. Rigaku Corporation, Tokyo, Japan.]$ ), SIR2014 (Burla et al., 2015 ), SHELXL2014 (Sheldrick, 2015 ), Mercury (Macrae et al., 2008 ) and PLATON (Spek, 2009 ).

Supporting information

CCDC reference: 1490160

Crystal structure: contains datablocks I, Global. DOI: https://doi.org/10.1107/S2056989016010859/su5309sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989016010859/su5309Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989016010859/su5309Isup3.cml

checkCIF report

Computing details top

Data collection: CrysAlis PRO (Rigaku Oxford Diffraction, 2015); cell refinement: CrysAlis PRO (Rigaku Oxford Diffraction, 2015); data reduction: CrysAlis PRO (Rigaku Oxford Diffraction, 2015); program(s) used to solve structure: SIR2014 (Burla et al., 2015); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015); molecular graphics: Mercury (Macrae et al., 2008) and PLATON (Spek, 2009); software used to prepare material for publication: SHELXL2014 (Sheldrick, 2015) and PLATON (Spek, 2009).

Oxirane-2-carboxamide top

Crystal data top

C₃H₅NO₂	F(000) = 368
M_r = 87.08	D_x = 1.404 Mg m⁻³
Monoclinic, P2₁/c	Cu Kα radiation, λ = 1.54184 Å
a = 15.5186 (7) Å	Cell parameters from 2255 reflections
b = 5.1007 (2) Å	θ = 6.0–62.6°
c = 10.9250 (5) Å	µ = 1.02 mm⁻¹
β = 107.651 (5)°	T = 150 K
V = 824.06 (7) Å³	Transparent prism, colorless
Z = 8	0.22 × 0.16 × 0.16 mm

Data collection top

Rigaku Xcalibur (Sapphire3, Gemini ultra) diffractometer	1310 independent reflections
Radiation source: fine-focus sealed X-ray tube	1207 reflections with I > 2σ(I)
Detector resolution: 16.1399 pixels mm^-1	R_int = 0.022
ω scans	θ_max = 62.8°, θ_min = 6.0°
Absorption correction: multi-scan (CrysAlis PRO; Rigaku Oxford Diffraction, 2015)	h = −17→14
T_min = 0.837, T_max = 1.000	k = −5→5
4485 measured reflections	l = −8→12

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.035	Hydrogen site location: difference Fourier map
wR(F²) = 0.093	H atoms treated by a mixture of independent and constrained refinement
S = 1.10	w = 1/[σ²(F_o²) + (0.0458P)² + 0.238P] where P = (F_o² + 2F_c²)/3
1310 reflections	(Δ/σ)_max < 0.001
121 parameters	Δρ_max = 0.34 e Å⁻³
4 restraints	Δρ_min = −0.17 e Å⁻³

Special details top

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 (Å²) top

	x	y	z	U_iso*/U_eq
C1	0.34078 (9)	0.3918 (3)	0.43936 (13)	0.0242 (3)
C2	0.41336 (9)	0.3997 (3)	0.56563 (14)	0.0292 (4)
H2	0.4507	0.2371	0.5900	0.035*
C3	0.40088 (10)	0.5531 (3)	0.67215 (13)	0.0342 (4)
H3A	0.3427	0.6464	0.6580	0.041*
H3B	0.4285	0.4861	0.7604	0.041*
N1	0.31052 (9)	0.6180 (2)	0.38512 (12)	0.0303 (3)
H1A	0.2683 (11)	0.620 (4)	0.3127 (15)	0.036*
H1B	0.3322 (11)	0.766 (3)	0.4175 (16)	0.036*
O1	0.31121 (7)	0.17614 (19)	0.39333 (9)	0.0300 (3)
O2	0.46035 (7)	0.6420 (2)	0.60247 (10)	0.0361 (3)
C11	0.16824 (9)	0.1061 (3)	0.56672 (13)	0.0262 (3)
C12	0.11401 (10)	0.1195 (3)	0.42784 (14)	0.0320 (4)
H12	0.1266	−0.0195	0.3709	0.038*
C13	0.02176 (11)	0.2199 (3)	0.39198 (15)	0.0392 (4)
H13A	−0.0228	0.1437	0.3153	0.047*
H13B	−0.0030	0.2724	0.4618	0.047*
N11	0.18834 (8)	0.3303 (2)	0.62832 (12)	0.0294 (3)
H11A	0.2208 (11)	0.332 (4)	0.7085 (14)	0.035*
H11B	0.1752 (11)	0.480 (3)	0.5899 (16)	0.035*
O11	0.18951 (7)	−0.11167 (18)	0.61662 (9)	0.0323 (3)
O12	0.09383 (8)	0.3738 (2)	0.37277 (11)	0.0441 (3)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C1	0.0286 (7)	0.0184 (8)	0.0250 (7)	−0.0003 (5)	0.0071 (5)	−0.0010 (5)
C2	0.0280 (7)	0.0245 (8)	0.0313 (7)	−0.0010 (6)	0.0032 (6)	−0.0015 (6)
C3	0.0337 (7)	0.0403 (9)	0.0263 (7)	−0.0070 (7)	0.0060 (6)	−0.0045 (6)
N1	0.0408 (7)	0.0163 (7)	0.0266 (6)	−0.0025 (5)	−0.0004 (5)	−0.0008 (5)
O1	0.0388 (6)	0.0157 (5)	0.0298 (5)	−0.0012 (4)	0.0017 (4)	−0.0015 (4)
O2	0.0330 (6)	0.0383 (6)	0.0358 (6)	−0.0118 (4)	0.0084 (4)	−0.0103 (5)
C11	0.0281 (7)	0.0191 (8)	0.0286 (7)	−0.0011 (5)	0.0044 (6)	0.0009 (5)
C12	0.0384 (8)	0.0253 (8)	0.0279 (7)	−0.0024 (6)	0.0035 (6)	−0.0002 (5)
C13	0.0364 (8)	0.0361 (9)	0.0363 (8)	−0.0010 (7)	−0.0022 (6)	0.0007 (7)
N11	0.0377 (7)	0.0162 (6)	0.0265 (6)	−0.0004 (5)	−0.0022 (5)	0.0021 (5)
O11	0.0411 (6)	0.0171 (6)	0.0317 (5)	0.0005 (4)	0.0008 (4)	0.0006 (4)
O12	0.0484 (7)	0.0370 (7)	0.0364 (6)	−0.0047 (5)	−0.0027 (5)	0.0135 (5)

Geometric parameters (Å, º) top

C1—O1	1.2383 (17)	C11—O11	1.2373 (17)
C1—N1	1.3169 (18)	C11—N11	1.3154 (19)
C1—C2	1.494 (2)	C11—C12	1.497 (2)
C2—O2	1.4294 (17)	C12—O12	1.4242 (19)
C2—C3	1.463 (2)	C12—C13	1.458 (2)
C2—H2	1.0000	C12—H12	1.0000
C3—O2	1.4362 (19)	C13—O12	1.433 (2)
C3—H3A	0.9900	C13—H13A	0.9900
C3—H3B	0.9900	C13—H13B	0.9900
N1—H1A	0.860 (15)	N11—H11A	0.868 (15)
N1—H1B	0.856 (15)	N11—H11B	0.864 (15)

O1—C1—N1	123.91 (12)	O11—C11—N11	124.39 (12)
O1—C1—C2	118.80 (12)	O11—C11—C12	118.71 (12)
N1—C1—C2	117.26 (12)	N11—C11—C12	116.89 (12)
O2—C2—C3	59.53 (9)	O12—C12—C13	59.62 (10)
O2—C2—C1	117.44 (12)	O12—C12—C11	116.98 (12)
C3—C2—C1	120.29 (12)	C13—C12—C11	119.53 (14)
O2—C2—H2	115.9	O12—C12—H12	116.2
C3—C2—H2	115.9	C13—C12—H12	116.2
C1—C2—H2	115.9	C11—C12—H12	116.2
O2—C3—C2	59.07 (9)	O12—C13—C12	59.02 (10)
O2—C3—H3A	117.9	O12—C13—H13A	117.9
C2—C3—H3A	117.9	C12—C13—H13A	117.9
O2—C3—H3B	117.9	O12—C13—H13B	117.9
C2—C3—H3B	117.9	C12—C13—H13B	117.9
H3A—C3—H3B	115.0	H13A—C13—H13B	115.0
C1—N1—H1A	119.5 (12)	C11—N11—H11A	119.9 (12)
C1—N1—H1B	122.9 (12)	C11—N11—H11B	122.2 (12)
H1A—N1—H1B	117.6 (17)	H11A—N11—H11B	117.5 (17)
C2—O2—C3	61.40 (10)	C12—O12—C13	61.35 (10)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1B···O2	0.86 (2)	2.45 (2)	2.7770 (17)	103 (1)
N11—H11B···O12	0.87 (2)	2.39 (2)	2.7408 (17)	105 (1)
N1—H1A···O11ⁱ	0.86 (2)	2.12 (2)	2.9651 (16)	167 (2)
N1—H1B···O1ⁱⁱ	0.86 (2)	2.12 (2)	2.8482 (14)	142 (2)
N11—H11A···O1ⁱⁱⁱ	0.87 (2)	2.08 (2)	2.9447 (16)	173 (2)
N11—H11B···O11ⁱⁱ	0.87 (2)	2.11 (2)	2.8495 (14)	144 (2)
C3—H3A···O11ⁱⁱ	0.99	2.59	3.5839 (19)	179
C3—H3B···O2^iv	0.99	2.59	3.4470 (18)	144
C13—H13A···O12^v	0.99	2.44	3.3991 (19)	163

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

Experimental bond lengths (Å) compared to a database survey of 149 compounds featuring epoxide fragments top

	Bond	Molecule A	Bond	Molecule B	Database survey
C—C	C2—C3	1.463 (2)	C12—C13	1.458 (2)	1.442±0.028
CH₂-O	C3—O2	1.436 (2)	C13—O12	1.433 (2)	1.431±0.026
XCH—O	C2—O2	1.429 (2)	C12—O12	1.424 (2)	1.432±0.026

Acknowledgements

We thank the Fonds der Chemischen Industrie for financial support of this work.

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