13C CP MAS NMR, FTIR, X-ray diffraction and PM3 studies of some N-(ω-carboxyalkyl)morpholine hydrohalides

Article abstract of DOI:10.1016/S0022-2860(00)00754-7

N-(ω-carboxyalkyl)morpholine hydrochlorides, OC₄H₈N(CH₂)_nCOOH·HCI, n = 1-5, were obtained and analyzed by ¹³C cross polarization (CP) magic angle spinning (MAS) NMR, FTIR and PM3 calculations. The structure of N-(3-carboxy-propyl)morpholine hydrochloride (n = 3) has been solved by X-ray diffraction method at 100 K and refined to the R = 0.031. The crystals are monoclinic, space group P2₁/c, a = 14.307(3), b = 9.879(2), c = 7.166(1) A?, β = 93.20(3)°, V = 1011.3(3) A?³, Z = 4. In this compound the nitrogen atom is protonated and two molecules form a centrosymmetric dimer, connected by two N⁺-H···Cl^- (3.095(1) A?) and two O-H···Cl^- (3.003(1) A?) hydrogen bonds. ¹³C CP MAS NMR spectra, contrary to the solution, showed non-equivalence of the ring carbon atoms. The PM3 calculations predict a molecular dimer without proton transfer for an HCl complex, while for an HBr complex an ion pairs with proton transfer, and reproduces correctly the conformation of both dimers but overestimates H-bond distances. Shielding constants calculated from the PM3 geometry of ion pairs gave a linear correlation with the ¹³C chemical shifts in solids.

Full text of DOI:10.1016/S0022-2860(00)00754-7

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Journal of Molecular Structure 560 (2001) 261±273
www.elsevier.nl/locate/molstruc
13C CP MAS NMR, FTIR, X-ray diffraction and PM3 studies of
some N-(v-carboxyalkyl)morpholine hydrohalides
a,
a
b
a
*
Z. Dega-Szafran , I. GaÎszczyk , D. Maciejewska , M. Szafran ,
E. Tykarskaa, I. Wawerb
aFaculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60-780 Poznan, Poland
bFaculty of Pharmacy, Medical University of Warsaw, 02-097 Warsaw, Poland
Received 10 May 2000; revised 2 August 2000; accepted 29 September 2000
Abstract
N-(v-carboxyalkyl)morpholine hydrochlorides, OC4H8N(CH2)nCOOH´HCl, n ˆ 1±5; were obtained and analyzed by 13C
cross polarization (CP) magic angle spinning (MAS) NMR, FTIR and PM3 calculations. The structure of N-(3-carboxy-
propyl)morpholine hydrochloride ꢀn ˆ 3† has been solved by X-ray diffraction method at 100 K and re®ned to the R ˆ
ꢀ
0:031: The crystals are monoclinic, space group P21/c, a ˆ 14:307ꢀ3†; b ˆ 9:879ꢀ2†; c ˆ 7:166ꢀ1† A; b ˆ 93:20ꢀ3†8; V ˆ
ꢀ 3
1011:3ꢀ3† A ; Z ˆ 4: In this compound the nitrogen atom is protonated and two molecules form a centrosymmetric dimer,
2
connected by two N1±H´´´Cl2 (3.095(1) A) and two O±H´´´Cl (3.003(1) A) hydrogen bonds. 13C CP MAS NMR spectra,
contrary to the solution, showed non-equivalence of the ring carbon atoms. The PM3 calculations predict a molecular dimer
without proton transfer for an HCl complex, while for an HBr complex an ion pairs with proton transfer, and reproduces
correctly the conformation of both dimers but overestimates H-bond distances. Shielding constants calculated from the PM3
geometry of ion pairs gave a linear correlation with the 13C chemical shifts in solids. q 2001 Elsevier Science B.V. All rights
reserved.
Ê
Ê
Keywords: N-(v-carboxyalkyl)morpholine hydrohalides; 13C CP MAS NMR; X-ray diffraction; PM3 calculations; Hydrogen bond
1. Introduction
important interactions is hydrogen bonding which
only takes place between an electron lone pair and a
proton that faces directly at the lone pair. Another
signi®cant interaction is electron transfer in charge
transfer (CT) complexes. According to the Mulliken
overlap and orientational principles [2,3] the mutual
orientation of donor and acceptor molecules should
provide the most effective overlap of the orbitals
involved in the CT interaction. In other words, both
H-bonding and CT interaction are directional and
saturable, which limits a species from strong inter-
actions with multiple surrounding species. In
contrast, the charge interaction between ions is neither
directional nor saturable. The ions in salts and
In the case of charged molecules there can be
essential differences between their geometries in
gas-phase and in crystals. The principles of crystal
packing, as given by Brock and Dunitz [1] are: (1)
maximize density and minimize free volume; (2)
satisfy H-bond donors, acceptors, and any other
speci®c types of intermolecular interaction; and (3)
minimize electrostatic energy. One of the most
* Corresponding author. Tel.: 148-61-8291216; fax: 148-61-
865-8008.
E-mail address: degasz@amu.edu.pl (Z. Dega-Szafran).
0022-2860/01/$ - see front matter q 2001 Elsevier Science B.V. All rights reserved.
PII: S0022-2860(00)00754-7

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Z. Dega-Szafran et al. / Journal of Molecular Structure 560 (2001) 261±273
Scheme 1.
hydrogen-bonded ion pairs are involved in multiple
charge (Coulombic) interactions and are therefore
highly stabilized [4].
structures of dimers of N-(v-carboxyalkyl)morpho-
line hydrohalides, OC4H8N(CH2)nCOOH´HX, n ˆ
1±5; X ˆ Cl, Br, to get more information on the
formation two hydrogen bonds by Cl2 and Br2 ions.
The zwitterionic molecules (e.g. betaines) are
oriented according to the electrostatic (Coulombic)
interactions [5,6]. In the gas-phase only intramol-
ecular forces operate, while in crystals both intra-
and intermolecular interactions take place, and the
latter are responsible for the structural differences
between these two phases. N-Alkyl-aminoacids and
particularly their hydrohalides [7±9] are good exam-
ples illustrating conformation differences between
the gas-phase and crystals. In crystals the molecules
are planar, maximally extended and are held together
by a network of two intermolecular hydrogen
bonds of the types N1±H´´´X2 and O±H´´´X2. In
the gas-phase these molecules are folded and form
a cyclic ring via two hydrogen bonds N´H´X and
O´H´X.
2. Experimental
2.1. Synthesis
Ethyl v-bromoalkanocarboxylate (0.1 M) was
slowly added to morpholine (0.2 M) in diethyl ether
solution on cooling and the mixture was stirred up to
solidi®cation (Scheme 1). The morpholine hydrobro-
mide was ®ltered off as precipitate. The residue, ethyl
v-(N-morpholine)alkanocarboxylate, was heated on a
water bath with 15% HCl for 6 h. After evaporation of
the acid and water under reduced pressure, the N-(v-
carboxyalkyl)morpholine hydrochloride was recrys-
tallized from acetonitrile:methanol (1:1) solution.
The melting points and results of the elemental
analyses are given in Table 1.
Previously we reported results of X-ray and PM3
studies of N-(4-carboxybutyl)piperidine hydrobromide
[9]. In this paper we extend our investigation over the
Table 1
The melting points, yields, elemental analysis and nCyO bands of the OC4H8N1H(CH2)nCOOH´Cl2
n
m.p. (8C)
Yield (%)
Observed (%)
C
Required (%)
C
nCyO (cm21
)
H
N
H
N
1
2
3
4
5
160±161a
205±207b
183±184
156±157
179±182
97
83
78
96
81
39.66
42.75
45.62
48.27
50.33
6.68
7.31
7.67
8.09
8.57
7.71
7.11
6.59
6.44
6.09
39.68
42.97
45.83
48.32
50.52
6.66
7.21
7.69
8.11
8.48
7.71
7.16
6.68
6.26
5.89
1737
1729
1727
1725
1722
a
Hygroscopic.
b
m.p. 206±2078C from Ref. [10].

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263
Table 2
Crystal data and structure re®nement for N-(3-carboxypropyl)mor-
113v instrument, which was evacuated to avoid
water and CO2 absorptions. Each spectrum consists
of 250 scans taken at 308C.
pholine hydrochloride
Empirical formula
C8H16ClNO3
209.67
Molecular weight
2.4. NMR spectra
Crystal system, space group
Unit cell dimensions
monoclinic, P21/c
The 1H and 13C chemical shifts were measured on a
Varian Gemini 300VT spectrometer at 300.07 and
75.46 MHz, respectively, in D2O with respect to
internal dioxane and were recalculated relative to
TMS by adding 3.5 and 67.40 ppm, respectively.
The spectra were run at 294 K. The concentration of
Ê
14.307(3) A
Ê
9.879(2) A
Ê
7.166(1) A
a
b
c
b
Volume
93.20(3)8
1011.3(3) A
Ê 3
Z
4
1.377 Mg/m3
0.355 mm21
448
1
the sample was 0.5 mol/dm3. The 2D H±13C corre-
Calculated density
Absorption coef®cient
F(000)
lation spectra were obtained with standard Varian
software.
Crystal size
Temperature
0.35 £ 0.30 £ 0.25 mm
Cross polarization (CP) magic angle spinning
(MAS) solid state 13C NMR spectra were recorded
on a Bruker MSL-300 instrument at 75.5 MHz.
Powder samples were spun at 8.1±10.0 kHz in
4 mm ZrO2 rotor, a contact time of 5 ms, a repetition
time of 6 s and a spectral width of 20 kHz were used
for accumulation of 800±1200 scans. Chemical shifts
were calibrated indirectly through the glycine CO
signal recorded at 176.0 ppm relative to TMS. Spectra
were performed at 297 K. Measurements of very
hygroscopic N-(carboxymethyl)morpholine hydro-
chloride was unsuccessful.
100(2) K
Ê
0.71073 A
Wavelength
u range for data collection
Index range for data collection
1.43±28.068
0 # h # 18; 0 # k # 13;
29 # l # 9
Re¯ections collected/unique
Completeness to 2u ˆ 28:06
Re®nement method
2758/2458 [R(int) ˆ 0.0128]
94.6%
Full matrix least squares on F2
2458/0/182
Data/restraints/parameters
Goodness-of-®t on F2
1.074
Final R indices ‰I . 2sꢀI†Š
R indices (all data)
R1 ˆ 0:0305; wR2 ˆ 0:0809
R1 ˆ 0:0340; wR2 ˆ 0:0834
Ê 23
Largest diff. Peak and hole
0.352 and 20.420 e A
2.2. Crystallography
2.5. Calculations
Single crystals of N-(3-carboxypropyl)morpholine
hydrochloride were grown from 1:1 acetonitrile
methanol solution. Table 2 summarizes the crystal
data and experimental details concerning X-ray data
collection and structure re®nement. Intensity data
were collected on a KM-4 diffractometer in cryogenic
conditions (100 K). Two standard re¯ections recorded
every 100 re¯ections showed any signi®cant
variations (1.35%). The structure was solved by
shelxs-86 and re®ned by shelxl-97 [11,12]. All
non-hydrogen atoms were re®ned with anisotropic
displacement parameters. The hydrogen atoms were
located on a difference Fourier map and re®ned with
isotropic displacement parameter.
The molecular geometries and energies of the
compounds tested were calculated using the PM3
semiempirical method [13] as implemented in the
ampac 6.0 program package [14]. For the calculation
of NMR shielding constants the ab initio GIAO-CPHF
approach, implemented in gaussian 98, Rev. A. 7
package, was used [15].
3. Results and discussion
3.1. X-ray diffraction study
The atomic numbering scheme and the confor-
mation of N-(3-carboxypropyl)morpholine hydro-
chloride as observed in the crystal are shown in
Fig. 1. The ®nal atomic coordinates, thermal para-
meters and anisotropic displacement parameters are
listed in Tables 3 and 4, respectively. Bond lengths
2.3. FTIR spectra
The FTIR spectra were measured in Nujol and
Fluorolube at 4 cm21 resolution using Bruker IFS

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264
Z. Dega-Szafran et al. / Journal of Molecular Structure 560 (2001) 261±273
Fig. 1. The atom numbering of H-bonded dimers related by the symmetry center of N-(3-carboxypropyl)morpholine hydrochloride in P21/c; the
thermal ellipsoids were drawn at 50% probability level; (symmetry codes: (i) x,y,z; and (ii) 2x 1 2; 2y; 2z 1 1†:
Table 3
Atomic coordinates ( £ 104) and equivalent isotropic displacement
and angles are collected in Table 5. The proton is
transferred from the hydrochloride molecule to the
amino acid component leading to coexistence of the
chloride and morpholinium ions. The ions form
centrosymmetric H-bonded dimers. The Cl2 ion is
3
Ê 2
parameters (A £ 10 ) for non-hydrogen atoms for N-(3-carboxy-
propyl)morpholine hydrochloride. U(eq) is de®ned as one third of
the trace of the orthogonalized Uij tensor
engaged in two H-bonds, one with the N1±H group
of the morpholinium system and the second with the
OH group of the carboxyl moiety. Geometry of these
hydrogen bonds is presented in Table 6. In addition,
the Cl2 ion interacts with three other cations forming
®ve C±H´´´Cl2 hydrogen bonds (contacts), four of
which involve the slightly acidic N1CH2 protons,
x
y
z
U(eq)
Cl
N(1)
7036(1)
7152(1)
2435(1)
2354(1)
2942(1)
2132(1)
1252(1)
6781(1)
2483(1)
1677(2)
2324(2)
1795(1)
2672(2)
2052(2)
1792(2)
2686(2)
1975(2)
2805(2)
2122(1)
3970(1)
3690(2)
2090(2)
370(2)
14(1)
13(1)
15(1)
18(1)
19(1)
18(1)
17(1)
14(1)
16(1)
16(1)
15(1)
20(1)
22(1)
C(2)
6248(1)
C(3)
5431(1)
O(4)
C(5)
5499(1)
6324(1)
1819(1)
C(6)
7198(1)
1125(1)
C(7)
7963(1)
21132(1)
2709(1)
21667(1)
21363(1)
2228(1)
22048(1)
2432(14)
21841(15)
2913(15)
2492(14)
2216(17)
1739(15)
2757(16)
1215(17)
1494(16)
22044(16)
21007(15)
197(17)
C(8)
C(9)
8904(1)
9646(1)
Table 4
3
Ê 2
Anisotropic displacement parameters (A £ 10 ) for N-(3-carboxy-
C(10)
O(1)
O(2)
10 610(1)
10 959(1)
11 028(1)
7158(11)
6216(10)
6275(10)
4866(10)
5404(11)
6288(10)
6347(10)
7227(11)
7752(11)
7838(10)
7937(9)
propyl)morpholine hydrochloride. The anisotropic displacement
¼
factor exponent takes the form: 22p2‰h2a*2U11 1
1
2hka*b*U12Š
H(1N)
H(21)
H(22)
H(31)
H(32)
H(51)
H(52)
H(61)
H(62)
H(71)
H(72)
H(81)
H(82)
H(91)
H(92)
H(1)
U11
U22
U33
U23
U13
1(1)
U12
0(1)
1750(2)
3680(2)
4040(2)
2320(2)
740(2)
Cl
14(1)
12(1)
13(1)
14(1)
17(1)
19(1)
17(1)
13(1)
13(1)
15(1)
14(1)
17(1)
18(1)
16(1)
14(1)
16(1)
22(1)
20(1)
16(1)
13(1)
15(1)
16(1)
15(1)
15(1)
19(1)
24(1)
12(1)
12(1)
1(1)
1(1)
N(1)
C(2)
C(3)
O(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
O(1)
O(2)
2(1)
0(1)
0(1)
22(1)
1(1)
16(1) 21(1)
18(1)
21(1)
0(1)
1(1)
2(1)
22(1)
0(1)
2(1)
4(1)
2720(2)
2100(2)
480(2)
19(1) 21(1)
20(1) 2(1)
2(1)
21(1)
1(1)
15(1) 22(1)
17(1) 23(1)
18(1) 22(1)
16(1) 21(1)
2(1)
9053(11)
8878(11)
9496(11)
9656(10)
11 536(15)
2310(2)
3990(2)
2300(2)
620(2)
1(1)
1(1)
2764(16)
22585(17)
21576(16)
2180(2)
2(1)
4(1)
1(1)
2(1)
25(1)
24(1)
6(1)
8(1)
23(1)
0(1)
23(1)
2(1)
2560(3)