4-(2-Carboxy­ethyl)morpholin-4-ium chloride

The title compound, C₇H₁₄NO₃⁺·Cl⁻, is a hydro­chloric acid salt of 3-(morpholin-4-yl)propionic acid, which is an important inter­mediate for the synthesis of biologically active heterocyclic compounds. The morpholine ring adopts a chair conformation with the hydro­carbon chain and the H atom on the N atom in equatorial and axial orientations, respectively. The structure is stabilized by a combination of strong N—H...Cl and O—H...Cl and weak C—H...O hydrogen bonds.

Key indicators

• Single-crystal X-ray study
• T = 295 K
• Mean [sigma](C-C) = 0.004 Å
• R factor = 0.054
• wR factor = 0.133
• Data-to-parameter ratio = 19.5

checkCIF/PLATON results

No syntax errors found



Alert level C
PLAT026_ALERT_3_C Ratio Observed / Unique Reflections too Low ....         46 Perc.
PLAT242_ALERT_2_C Check Low       Ueq as Compared to Neighbors for         C9
PLAT480_ALERT_4_C Long H...A H-Bond Reported H6A    ..  O2      ..       2.65 Ang.
PLAT480_ALERT_4_C Long H...A H-Bond Reported H3B    ..  O1      ..       2.69 Ang.
PLAT480_ALERT_4_C Long H...A H-Bond Reported H7B    ..  O2      ..       2.69 Ang.
PLAT790_ALERT_4_C Centre of Gravity not Within Unit Cell: Resd.  #          2
              Cl

   0 ALERT level A = In general: serious problem
   0 ALERT level B = Potentially serious problem
   6 ALERT level C = Check and explain
   0 ALERT level G = General alerts; check

   0 ALERT type 1 CIF construction/syntax error, inconsistent or missing data
   1 ALERT type 2 Indicator that the structure model may be wrong or deficient
   1 ALERT type 3 Indicator that the structure quality may be low
   4 ALERT type 4 Improvement, methodology, query or suggestion
   0 ALERT type 5 Informative message, check

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S1. Comment

Morpholine derivatives are known to exhibit a wide spectrum of biological activities, including antifungal (Asselin & Humber, 1977), antidepressant (Kelley et al., 1996) or anorectic (Meyer & Weintraub, 1981) properties. Additionally, they are used as an intermediate for the synthesis of the antispasmodic drugs and other biologically active heterocycles (Boronnet et al., 1974). In view of the versatility of these compounds, the title compound was synthesized and we herein report its molecular and crystal structure.

In the crystal structure of the proton is transferred from the hydrochloride molecule to the morpholine N1 atom, as confirmed by location of the H atom in a difference Fourier map, leading to coexistence of the hydrogen-bonded 3-morpholin-4-yl-propionic cation and chloride anion. The morpholine ring adopts the usual chair conformation with the C7 atom at the equatorial and the H1N proton at the axial position. The hydrocarbon (CH₂)₂COOH chain exists in the extended trans conformation, which is reflected in the values of the N1—C7—C8—C9 and C7—C8—C9—O1 torsion angles of -168.0 (3) and 178.5 (3)°, respectively. The carboxyl group has the typical cis conformation with the O2—C9—O1—H1O torsion angle of 6.0 (4)°. The dihedral angle between the best plane of the hydrocarbon chain and C2/C3/C5/C6 ring atoms is 36.9 (4)°. The bond distances and angles are within the expected ranges observed for related compounds.

The strong N3—H3o···Cl hydrogen bonds (Table 1) are observed between ionic pairs. The Cl^- ion forms also H-bond with the carboxylic O1—H1O proton from the adjacent cation. As can be seen in Fig. 2, one-dimensional cationic chains, propagated along the [101] direction, can be distinguished in the structure. Within the chain the cations lacated around the (0, 1/2, 1/2) inversion centre are connected together through chelating C6—H6A···O2ⁱⁱ and C7—H7A···O2ⁱⁱ hydrogen bonds. The C3—H3A···O4ⁱⁱⁱ H-bonds links cations located around the next (1/2, 1, 1) center of symmetry. The cationic layers are associated into three-dimensional structure primarily by interactions involving the chloride anions.

Related literature

For general background, see: Asselin & Humber (1977); Kelley et al. (1996); Meyer & Weintraub (1981); Boronnet et al. (1974).

S2. Experimental

A mixture of 3-morpholin-4-yl-propionic acid hydrazide (0.01 mol) and 4,4'-methylene-bis(phenylisocyanate) (0.01 mol) was heated at the temperature 383–393 K for 20 h. The product, 4,4'-methylene-bis{[1-(3-morpholin-4-yl-propionic)-4-phenyl]semicarbazide} was washed with diethyl ether to remove the unreacted isocyanate, dried and crystallized from ethanol (yield 83%). The final product, 3-morpholin-4-yl-propionic acid hydrochloride, was prepared by refluxing semicarbazide with 2% NaOH (40 ml) for 15 h. After cooling, the solution was neutralized with dilute hydrochloric acid. The product was filtered and recrystallized from ethanol (m.p. 353–356 K, yield 89%). Anal. Calcd. for C₇H₁₄NO₃Cl: C, 42.96; H, 7.21; N, 7.15%; found: C, 42.91; H, 7.30; N, 7.18%. ¹H NMR (300 MHz, DMSO-d₆, p.p.m.): δ 2.87 (2H, t, CH₂); 2.98–3.06 (4H, m, 2CH₂); 3.27 (2H, t, CH₂); 3.77–3.87 (4H, m, 2CH₂); 11.98 (1H, s, OH).

S3. Refinement

H atoms bonded to O1 and N1 atoms were located in the difference Fourier map and refined. Other H atoms were positioned geometrically and allowed to ride on their parent atoms, with C—H bond distances of 0.97 Å. The displacement parameters of the H atoms were U_iso(H) = 1.2 U_eq(C).

Computing details

Data collection: CrysAlis CCD (Oxford Diffraction, 2005); cell refinement: CrysAlis RED (Oxford Diffraction, 2005); data reduction: CrysAlis RED (Oxford Diffraction, 2005); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: SHELXTL/PC (Sheldrick, 1990); software used to prepare material for publication: SHELXL97 (Sheldrick, 1997) and enCIFer (Allen et al., 2004).

Figures

	Fig. 1. The molecular structure showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 30% probability level. N—H···Cl hydrogen bond is shown as dashed line.
	Fig. 2. The molecular packing viewed down the a axis. Dashed lines indicate hydrogen bonds.

4-(2-Carboxyethyl)morpholin-4-ium chloride

Crystal data

C7H14NO3^+·Cl^−	F(000) = 416
Mr = 195.64	Dx = 1.332 Mg m^−3
Monoclinic, P21/n	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2yn	Cell parameters from 62 reflections
a = 6.024 (2) Å	θ = 5–12°
b = 11.593 (3) Å	µ = 0.36 mm^−1
c = 14.095 (6) Å	T = 295 K
β = 97.72 (3)°	Plate, colourless
V = 975.4 (6) Å^3	0.36 × 0.30 × 0.10 mm
Z = 4

Data collection

Oxford Diffraction Xcalibur diffractometer	Rint = 0.034
Radiation source: fine-focus sealed tube	θmax = 27.6°, θmin = 2.3°
Graphite monochromator	h = −7→7
ω/2θ scans	k = 0→15
2326 measured reflections	l = −18→0
2244 independent reflections	3 standard reflections every 100 reflections
1033 reflections with I > 2σ(I)	intensity decay: 0.03%

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.054	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.133	H atoms treated by a mixture of independent and constrained refinement
S = 0.97	w = 1/[σ^2(Fo^2) + (0.0671P)^2] where P = (Fo^2 + 2Fc^2)/3
2244 reflections	(Δ/σ)max < 0.001
115 parameters	Δρmax = 0.31 e Å^−3
0 restraints	Δρmin = −0.26 e Å^−3

Special details

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F² against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F², conventional R-factors R are based on F, with F set to zero for negative F². The threshold expression of F² > σ(F²) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F² are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

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

	x	y	z	Uiso*/Ueq
Cl	−0.11080 (14)	0.77228 (7)	0.73370 (6)	0.0430 (2)
O1	0.3892 (5)	0.7281 (2)	0.44710 (19)	0.0718 (8)
H1O	0.401 (7)	0.713 (4)	0.379 (3)	0.086*
O2	0.2681 (4)	0.5478 (2)	0.44468 (16)	0.0580 (7)
C9	0.3233 (5)	0.6344 (3)	0.4881 (2)	0.0415 (8)
C8	0.3297 (6)	0.6491 (3)	0.5935 (2)	0.0448 (8)
H8A	0.2363	0.7140	0.6061	0.054*
H8B	0.4819	0.6656	0.6221	0.054*
C7	0.2479 (6)	0.5419 (2)	0.6384 (2)	0.0406 (7)
H7A	0.1101	0.5161	0.6008	0.049*
H7B	0.3584	0.4812	0.6374	0.049*
N1	0.2066 (4)	0.5621 (2)	0.73937 (16)	0.0315 (5)
H1N	0.114 (5)	0.624 (3)	0.741 (2)	0.038*
C2	0.4146 (5)	0.5824 (3)	0.8066 (2)	0.0434 (8)
H2A	0.4905	0.6504	0.7869	0.052*
H2B	0.5145	0.5170	0.8052	0.052*
C3	0.3592 (6)	0.5992 (3)	0.9067 (2)	0.0511 (8)
H3A	0.4962	0.6115	0.9501	0.061*
H3B	0.2658	0.6671	0.9086	0.061*
O4	0.2450 (4)	0.5014 (2)	0.93676 (16)	0.0550 (7)
C5	0.0404 (6)	0.4839 (3)	0.8757 (2)	0.0459 (8)
H5A	−0.0541	0.5514	0.8779	0.055*
H5B	−0.0376	0.4184	0.8985	0.055*
C6	0.0796 (5)	0.4627 (2)	0.7742 (2)	0.0397 (7)
H6A	−0.0629	0.4539	0.7338	0.048*
H6B	0.1644	0.3920	0.7708	0.048*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Cl	0.0448 (4)	0.0416 (4)	0.0444 (4)	−0.0075 (4)	0.0131 (3)	0.0005 (4)
O1	0.124 (2)	0.0516 (13)	0.0467 (14)	−0.0211 (16)	0.0360 (16)	−0.0001 (13)
O2	0.0743 (18)	0.0602 (15)	0.0420 (13)	−0.0196 (13)	0.0168 (12)	−0.0035 (11)
C9	0.0377 (17)	0.0478 (18)	0.0415 (19)	−0.0011 (15)	0.0153 (15)	0.0029 (15)
C8	0.054 (2)	0.0422 (16)	0.0411 (19)	−0.0106 (16)	0.0171 (16)	−0.0017 (15)
C7	0.0509 (19)	0.0402 (16)	0.0341 (16)	−0.0062 (15)	0.0181 (15)	−0.0051 (13)
N1	0.0318 (14)	0.0330 (12)	0.0311 (13)	0.0003 (11)	0.0090 (11)	0.0004 (10)
C2	0.0343 (17)	0.0495 (18)	0.0464 (19)	−0.0020 (14)	0.0054 (14)	0.0033 (15)
C3	0.048 (2)	0.061 (2)	0.0410 (19)	−0.0043 (17)	−0.0039 (16)	0.0017 (17)
O4	0.0500 (14)	0.0733 (16)	0.0410 (14)	−0.0037 (13)	0.0037 (11)	0.0169 (11)
C5	0.0445 (19)	0.055 (2)	0.0409 (18)	−0.0036 (16)	0.0146 (16)	0.0072 (15)
C6	0.0399 (19)	0.0384 (16)	0.0430 (18)	−0.0038 (13)	0.0132 (15)	0.0038 (14)

Geometric parameters (Å, º)

O1—C9	1.316 (4)	C2—C3	1.505 (5)
O1—H1o	0.99 (4)	C2—H2A	0.9700
O2—C9	1.200 (4)	C2—H2B	0.9700
C9—C8	1.492 (4)	C3—O4	1.420 (4)
C8—C7	1.506 (4)	C3—H3A	0.9700
C8—H8A	0.9700	C3—H3B	0.9700
C8—H8B	0.9700	O4—C5	1.420 (4)
C7—N1	1.496 (4)	C5—C6	1.502 (4)
C7—H7A	0.9700	C5—H5A	0.9700
C7—H7B	0.9700	C5—H5B	0.9700
N1—C2	1.485 (4)	C6—H6A	0.9700
N1—C6	1.502 (3)	C6—H6B	0.9700
N1—H1N	0.91 (3)
C9—O1—H1o	111 (2)	C3—C2—H2A	109.6
O2—C9—O1	123.1 (3)	N1—C2—H2B	109.6
O2—C9—C8	124.9 (3)	C3—C2—H2B	109.6
O1—C9—C8	112.0 (3)	H2A—C2—H2B	108.1
C9—C8—C7	111.0 (3)	O4—C3—C2	110.7 (3)
C9—C8—H8A	109.4	O4—C3—H3A	109.5
C7—C8—H8A	109.4	C2—C3—H3A	109.5
C9—C8—H8B	109.4	O4—C3—H3B	109.5
C7—C8—H8B	109.4	C2—C3—H3B	109.5
H8A—C8—H8B	108.0	H3A—C3—H3B	108.1
N1—C7—C8	112.1 (2)	C3—O4—C5	110.4 (2)
N1—C7—H7A	109.2	O4—C5—C6	111.5 (3)
C8—C7—H7A	109.2	O4—C5—H5A	109.3
N1—C7—H7B	109.2	C6—C5—H5A	109.3
C8—C7—H7B	109.2	O4—C5—H5B	109.3
H7A—C7—H7B	107.9	C6—C5—H5B	109.3
C2—N1—C7	113.5 (2)	H5A—C5—H5B	108.0
C2—N1—C6	109.7 (2)	C5—C6—N1	109.7 (2)
C7—N1—C6	110.4 (2)	C5—C6—H6A	109.7
C2—N1—H1N	109.0 (19)	N1—C6—H6A	109.7
C7—N1—H1N	108.9 (18)	C5—C6—H6B	109.7
C6—N1—H1N	105.2 (19)	N1—C6—H6B	109.7
N1—C2—C3	110.1 (3)	H6A—C6—H6B	108.2
N1—C2—H2A	109.6
O2—C9—C8—C7	−2.4 (5)	N1—C2—C3—O4	58.5 (3)
O1—C9—C8—C7	178.5 (3)	C2—C3—O4—C5	−60.9 (3)
C9—C8—C7—N1	−168.0 (3)	C3—O4—C5—C6	60.8 (3)
C8—C7—N1—C2	−68.7 (3)	O4—C5—C6—N1	−57.3 (3)
C8—C7—N1—C6	167.7 (3)	C2—N1—C6—C5	54.0 (3)
C7—N1—C2—C3	−178.7 (3)	C7—N1—C6—C5	179.8 (3)
C6—N1—C2—C3	−54.8 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1N···Cl	0.91 (3)	2.18 (3)	3.092 (3)	176 (3)
O1—H1O···Cl^i	0.99 (4)	2.04 (4)	3.008 (3)	164 (4)
C6—H6A···O2^ii	0.97	2.65	3.491 (3)	145
C7—H7A···O2^ii	0.97	2.40	3.337 (3)	162
C3—H3A···O4^iii	0.97	2.45	3.241 (4)	138
C3—H3B···O1^iv	0.97	2.69	3.575 (3)	152
C7—H7B···O2^v	0.97	2.69	3.445 (3)	136

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