Structure elucidation of 2-amino-5-phenyl-2-oxazolin-4-one (pemoline) and X-ray structure of its hydrolysis product 5-phenyl-oxazolidine-2,4-dione

Article abstract of DOI:10.1515/znb-2005-0806

In this study we compare spectroscopic properties of pemoline (2-amino-5-phenyl-2-oxazolin-4-one) and its acid hydrolysis product 5-phenyl-oxazolidine-2,4-dione. Crystallization of pemoline from aqueous acetic acid gave single crystals of compound 2, the structure of which was determined by X-ray studies. All four crystallographically independent molecules form dimers linked by N-H?O=C hydrogen bonds.

Full text of DOI:10.1515/znb-2005-0806

Structure Elucidation of 2-Amino-5-phenyl-2-oxazolin-4-one (Pemoline)
and X-Ray Structure of its Hydrolysis Product 5-Phenyl-oxazolidine-2,4-
dione
Piotr Kus´a, Peter G. Jonesb, and Rafał Celin´skic
a Department of Chemistry, Silesian University, 9 Szkolna Street, 40-006 Katowice, Poland
b Institut fu¨r Anorganische und Analytische Chemie, Technische Universita¨t Braunschweig,
Postfach 3329, 38023 Braunschweig, Germany
c Forensic Medical Department, Silesian Medical Academy, 18 Medykow Street, 40-752 Katowice,
Poland
Reprint requests to Dr. P. Kus´. E-mail: pkus@ich.us.edu.pl
Z. Naturforsch. 60b, 853 – 857 (2005); received April 15, 2005
In this study we compare spectroscopic properties of pemoline (2-amino-5-phenyl-2-oxazolin-
4-one) and its acid hydrolysis product 5-phenyl-oxazolidine-2,4-dione. Crystallization of pemoline
from aqueous acetic acid gave single crystals of compound 2, the structure of which was deter-
mined by X-ray studies. All four crystallographically independent molecules form dimers linked by
N-H···O=C hydrogen bonds.
Key words: Pemoline, 2-Amino-5-phenyl-2-oxazolin-4-one, 5-Phenyl-oxazolidine-2,4-dione,
Raman Spectra, X-Ray Structure
Pemoline (1; phenylisohydantoin, phenylpseudohy- pound 2 or its derivatives can be used as precursors in
dantoin, 2-amino-5-phenyl-2-oxazolin-4-one, 2-ami- the synthesis of substituted penicillins [10].
no-5-phenyl-1,3-oxazol-4(5H)-one) is known to be a
central nervous system stimulant; it has narcotic activ-
ity and also enhances effects exerted by other drugs
[1, 2]. It is poorly soluble in the majority of organic
solvents and in water, but is soluble in acetic and prop-
ionic acids.
Magnesium complexes of pemoline have more po-
tent biological activity than pemoline alone, and have
been reported to exhibit a protective effect against
lethal doses of ionizing radiation [3].
Pemoline has one asymmetric carbon atom at C-5
of the oxazoline ring and it thus occurs in two enan-
tiomeric forms; it has been a subject of chromato-
graphic studies [4]. Acid hydrolysis of pemoline leads
to substitution of the amino by a carbonyl group [5].
The ease with which this process occurs can result
in false interpretation of the chromatography results
(when the mobile phase contains an acid component),
or of UV analysis (spectra are recorded in acidic aque-
ous solutions [6]). The hydrolysis product, 5-phenyl-
oxazolidine-2,4-dione (2), can also be obtained by ox-
idative hydroxylation of substituted barbituric acid [7],
hydrolysis of pemoline N-acetyl derivative [8] or di-
For our studies pemoline was obtained from ethyl
mandelate and thiourea, as described in [5] and com-
pound 2 by subsequent acidic hydrolysis. The purity of
both compoundswas confirmed by analytical and spec-
troscopic methods. We attempted to solve the prob-
lem of possible pemoline isomers, as discussed in [12],
by establishing its crystal structure. Unfortunately, we
were not able to obtain single crystals of this com-
pound in any “neutral” (non-acidic) solvent. The acetic
acid/water mixture used as a solvent allowed us to ob-
tain (after one year) crystals of moderate quality, the
crystal structure of which (see below) showed, how-
ever, that the crystallized substance was not pemoline
but its hydrolysis product 2.
The published UV spectrum of 1, which could pro-
rect synthesis from ethyl mandelate and urea [9]. Com- vide fundamental data characterizing pemoline [6], is
c
0932–0776 / 05 / 0800–0853 $ 06.00 ꢀ 2005 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
Unauthenticated
Download Date | 11/18/19 6:27 AM

854
P. Kus´ et al. · 2-Amino-5-phenyl-2-oxazolin-4-one (Pemoline)
◦
˚
Table 1. Characteristic IR bands and Raman lines for pemo- Table 2. Selected bond lengths [A] and angles [ ] for com-
line 1 and compound 2.
Pemoline 1 [cm−1
pound 2.
O(1)-C(2)
O(1)-C(5)
O(2)-C(2)
C(2)-N(3)
N(3)-C(4)
O(4)-C(4)
C(4)-C(5)
C(5)-C(11)
O(1’)-C(2’)
O(1’)-C(5’)
O(2’)-C(2’)
C(2’)-N(3’)
N(3’)-C(4’)
O(4’)-C(4’)
C(4’)-C(5’)
C(5’)-C(11’)
1.352(4) O(1”)-C(5”)
1.449(4) O(2”)-C(2”)
1.194(4) C(2”)-N(3”)
1.377(5) N(3”)-C(4”)
1.368(5) O(4”)-C(4”)
1.209(5) C(4”)-C(5”)
1.524(6) C(5”)-C(11”)
1.507(5) O(1#)-C(2#)
1.341(4) O(1#)-C(5#)
1.459(4) O(2#)-C(2#)
1.196(4) C(2#)-N(3#)
1.383(5) N(3#)-C(4#)
1.364(5) O(4#)-C(4#)
1.214(5) C(4#)-C(5#)
1.507(5) C(5#)-C(11#)
1.510(5) O(1”)-C(2”)
1.452(4)
1.201(4)
1.370(5)
1.372(5)
1.193(4)
1.529(5)
1.494(5)
1.339(4)
1.457(4)
1.199(4)
1.372(5)
1.363(5)
1.214(4)
1.509(5)
1.505(5)
1.339(4)
]
Compound 2 [cm−1
]
IR
Raman
IR
Raman
3265
3167
3062
3036
3295
3067
3058
3008
2947
3061
3041
3065
2946
2944
2945
2933
1805
1824
1733
1719
1660
1721
1606
1590
1604
1588
1564
1498
1459
1450
1350
1530
1497
1455
1382
1329
1298
1282
C(2)-O(1)-C(5)
O(2)-C(2)-O(1)
O(2)-C(2)-N(3)
O(1)-C(2)-N(3)
C(4)-N(3)-C(2)
O(4)-C(4)-N(3)
O(4)-C(4)-C(5)
N(3)-C(4)-C(5)
O(1)-C(5)-C(11)
O(1)-C(5)-C(4)
C(11)-C(5)-C(4)
C(2’)-O(1’)-C(5’)
O(2’)-C(2’)-O(1’)
O(2’)-C(2’)-N(3’)
O(1’)-C(2’)-N(3’)
C(4’)-N(3’)-C(2’)
O(4’)-C(4’)-N(3’)
O(4’)-C(4’)-C(5’)
N(3’)-C(4’)-C(5’)
109.9(3) O(1’)-C(5’)-C(4’)
122.1(4) O(1’)-C(5’)-C(11’)
128.9(4) C(4’)-C(5’)-C(11’)
109.0(3) C(2”)-O(1”)-C(5”)
112.4(3) O(2”)-C(2”)-O(1”)
127.9(4) O(2”)-C(2”)-N(3”)
127.1(3) O(1”)-C(2”)-N(3”)
104.9(3) C(2”)-N(3”)-C(4”)
110.4(3) O(4”)-C(4”)-N(3”)
103.7(3) O(4”)-C(4”)-C(5”)
113.7(4) N(3”)-C(4”)-C(5”)
109.9(3) O(1”)-C(5”)-C(11”)
122.9(4) O(1”)-C(5”)-C(4”)
128.0(3) C(11”)-C(5”)-C(4”)
109.0(3) C(2#)-O(1#)-C(5#)
111.9(3) O(2#)-C(2#)-O(1#)
127.2(4) O(2#)-C(2#)-N(3#)
127.1(3) O(1#)-C(2#)-N(3#)
105.7(3) C(4#)-N(3#)-C(2#)
103.4(3)
109.9(3)
114.8(3)
109.9(3)
122.2(4)
128.2(4)
109.6(3)
112.3(3)
128.1(4)
127.4(3)
104.5(3)
110.5(3)
103.5(3)
113.1(3)
109.9(3)
123.0(3)
127.7(4)
109.3(3)
111.9(3)
1286
1277
1225
1136
1080
1038
1023
1200
1192
1180
1164
1206
1192
1154
1070
1048
1027
1017
965
1027
1004
976
1030
1003
972
932
934
930
887
852
930
857
867
763
867
768
767
753
739
727
730
699
656
626
539
482
683
659
628
538
474
693
638
699
640
620
O(4#)-C(4#)-N(3#) 127.5(4) O(4#)-C(4#)-C(5#)
N(3#)-C(4#)-C(5#)
O(1#)-C(5#)-C(4#)
126.9(3)
110.0(3)
116.3(4)
105.6(3) O(1#)-C(5#)-C(11#)
103.1(3) C(11#)-C(5#)-C(4#)
540
491
1588 cm−1 for 2 can be assigned to carbonyl (amido)
units of both molecules. Strong lines at 1027 cm−1
for 1 and 1030 cm−1 for 2 in the Raman spectra and
bands at 1023 cm−1 for 1 and 1017 cm−1 for 2 in the
IR spectra are associated with δCH vibrations of aro-
matic rings. In the Raman spectra the most characteris-
tic lines are those of νC=Csym of aromatic rings at 1004
and 1003 cm−1 for 1 and 2, respectively; they are ab-
sent in the IR spectra.
identical with that of compound 2. These spectra were
however recorded in acidic solutions; thus in both
cases they could pertain to the same substance, com-
pound 2. Unfortunately, precise determination of ε val-
ues for both compounds was not successful because of
insufficient solubility.
The IR spectra (Table 1) show two carbonyl bands
for both compounds at 1719 cm−1 and 1660 cm−1 for 1
and 1824 and 1733 cm−1 for 2. The vibration occur-
The ESI-MS spectrum of 1 reveals a pseudomolec-
ring at 1719 cm−1 for pemoline is of low intensity ular ion at m/z = 177[1 + H]+, but the most abun-
and can be assigned to the imino group. In the Raman dant ion is a dimer of the pseudomolecular ion at
spectra lines at 1721 and 1805 cm−1 for 1 and 2, re- m/z = 353[2 × 1 + H]+. The spectrum also features
spectively, represent the carbonyl group. Also, the vi- an ion at m/z = 106 [C6H5CHO]+ and a very small
brations at 1606 and 1590 cm−1 for 1 and 1604 and signal at m/z = 529[3 × 1 + H]+. Under the impact
Unauthenticated
Download Date | 11/18/19 6:27 AM

P. Kus´ et al. · 2-Amino-5-phenyl-2-oxazolin-4-one (Pemoline)
855
Fig. 1. The four independent molecules of
compound 2 in the crystal. Ellipsoids repre-
sent 50% probability levels. Dashed lines rep-
resent hydrogen bonds.
◦
˚
Table 3. Hydrogen bonds [A and ] for compound 2.
D-H. . . A
N(3)-H(3). . . O(2’)
N(3’)-H(3’). . . O(2)
N(3”)-H(3”). . . O(2”)#1 0.82(2) 2.21(3)
N(3#)-H(3#). . . O(2#)#2 0.83(2) 2.11(3)
N(3)-H(3). . . O(1#)#3
N(3’)-H(3’). . . O(1”)
d(D-H) d(H. . . A) d(D. . . A) ꢀ(DHA)
0.83(2) 2.15(3)
0.83(2) 2.11(3)
2.911(4) 153(4)
2.877(4) 155(4)
2.954(4) 150(4)
2.906(4) 162(4)
3.083(4) 125(4)
3.020(4) 120(4)
3.055(4) 133(4)
2.968(4) 116(4)
0.83(2) 2.53(4)
0.83(2) 2.52(4)
N(3”)-H(3”). . . O(1’)#4 0.82(2) 2.43(4)
N(3#)-H(3#). . . O(1)#2 0.83(2) 2.51(4)
C(5”)-H(5”). . . O(4)#3
C(5#)-H(5#). . . O(4’)#5
C(5)-H(5). . . O(4”)#2
C(5’)-H(5’). . . O(4#)#6
1.00
1.00
1.00
1.00
2.54
2.56
2.49
2.60
3.412(5)
3.490(5)
3.390(5)
3.517(5)
145.9
155.2
148.9
151.7
Symmetry transformations used to generate equivalent atoms:
#1
−x + 2,−y + 2,−z; #2 −x + 1,−y + 2,−z; #3 −x + 1,−y + 1,−z;
#4
x,y+1,z; #5 x−1,y,z; #6 x+1,y−1,z.
of increased ms/ms conditions, the ion at m/z = 353
becomes fragmented into an ion at m/z = 177 (pemo-
line). In the negative ion mode the mass spectrum of 1
is complicated and the intensities of the peaks are very
low. The ESI-MS spectrum of 2 can be recorded only
in the negative ion mode. Only one intense peak is ob-
served at m/z = 176[M-H]−. In the positive ion mode
the intensities of the peaks are very low.
The crystal structure of 2 is complex, with four in-
dependent molecules in the asymmetric unit (Fig. 1,
Table 2). Molecules 2, 3 and 4 are distinguished by
adding prime, double prime or hash symbols to the
atom names. Despite the moderate crystal quality, atom
types could be assigned unambiguously and hydrogen
Fig. 2. Packing diagram of compound 2 viewed perpendicu-
lar to the xy plane in the region z ≈ 0. Hydrogen bonds are in-
dicated by thick dashed lines. Hydrogen atoms not involved
in H bonding are omitted. Hydrogen-bonded pairs may be
located as follows: Top centre, molecules 1/2; top left, two
molecules 3; under these, two molecules 4.
Unauthenticated
Download Date | 11/18/19 6:27 AM

856
P. Kus´ et al. · 2-Amino-5-phenyl-2-oxazolin-4-one (Pemoline)
atoms were located in difference syntheses, thus con- and EI mass spectra (70 eV) were measured on a AMD 604
(AMD Intectra) spectrometer.
firming the formula 2. Bond lengths and angles may
be considered normal (e. g. C2-N3 1.370– 1.383(5)
and C4-N3 1.363– 1.372(5); cf. the standard value of
1.376 for O=C-NH-C=O systems [12]). The molecules
have a torsional degree of freedom about the C5-C11
bond, and the torsion angles are appreciably different;
2-Amino-5-phenyl-2-oxazolin-4-one (1)
The compound was synthesized from racemic ethyl man-
delate and thiourea as described in [5]. Yield: ∼ 40%. M. p.
◦
◦
254 – 256 C (lit. 257 C [8]). – UV (propionic acid – wa-
C12-C11-C5-O1 is 150.9, −94.6, 152.3 and −95.6 for ter): λmax = 251, 256, 262, 268 nm. – 1H NMR (CDCl3
dispersion): δ = 8.8 (bs, 2H), 7.33 – 7.50 (m, 5H), 5.80 (s,
1H). – 1H NMR (CDCl3 + DMSO-d6): δ = 8.64 (s, 1H),
8.36 (s, 1H), 7.20 – 7.9 (m, 5H), 5.53 (s, 1H). – HR MS:
176.05951 (calcd. for C9H8O2N2 176.05858). – MS (EI,
70 eV): m/z (%) = 176(100) [M+], 148(9), 147(8), 108(8),
107(82), 105(28), 90(44), 89(38), 79(27), 78(8), 77(35),
71(9), 70(22), 63(11), 51(19), 50(9), 42(20). – C9H8O2N2
(176): calcd. C 61.34, H 4.58, N 15.91; found C 60.91,
H 4.68, N 15.41.
the R enantiomers of the four molecules. The crystal
packing (Fig. 2) involves pairs of molecules, one R and
one S in each case, linked by N-H···O=C hydrogen
bonds (Table 3, first four entries; in each case O2 is
the acceptor). Molecules 1 and 2 form such a dimer,
whereas molecules 3 and 4 are paired as homo-dimers
across inversion centres. The second four entries in Ta-
ble 2 represent N-H···O1 contacts that might be re-
garded as weak components of three-centre H bond
systems (not shown in Fig. 2). The carbonyl oxygen
atoms O4 are not involved in classical H bonding but
accept weak H bonds from C5-H5 (last four entries in
Table 3; not shown in Fig. 2).
The X-ray structure of 3, the sulphur analogue of
pemoline (with sulphur in position 1 of the hetero-
cyclic ring) has been reported; there are two mod-
ifications, both crystallizing in space group P21/c
with two independent molecules. In one form, the
two independent molecules form a dimer via two
N-H···N hydrogen bonds [13, 14]; in the other [15],
these dimers display inversion symmetry. Both modi-
fications additionally form two N-H···O=C hydrogen
bonds.
5-Phenyl-oxazolidine-2,4-dione (2)
A slurry of 0.1 g of pemoline 1 in 10 ml of 10% aqueous
sulfuric acid was boiled for 0.5 h. During this time the solid
dissolved. The mixture was cooled and filtered. The white
powder was washed with water and dried in air to give 0.09 g
(90%) of product.
◦
M. p. 108 – 109 C (lit. 111 – 112 ◦C [5]). – UV (pro-
pionic acid / water): λmax = 250, 255, 262, 268 nm. –
1H NMR (DMSO-d6): δ = 12.15 (s, 1H), 7.3 – 7.6 (m, 5H),
6.04 (s, 1H). – HR MS: 177.04165 (calcd. for C9H8O3N
177.04259). – MS (EI, 70 eV): m/z (%) = 177(100) [M+],
107(20), 106(50), 105(65), 91(7), 90(90), 89(41), 78(11),
77(35), 63(11), 51(20), 50(10). – C9H8O3N (177): calcd.
C 61.01, H 3.98, N 7.90; found C 60.70, H 4.02, N 7.63.
The structure of 4, the diphenyl derivative of 1,3-
oxazolidine-2,4-dione, is similar. This compound does
not, however, contain an asymmetric carbon atom and
its crystal structure is less complex, with only one in-
dependent molecule; a hydrogen bond N-H···O=C is
observed [16].
X-ray structure determination of compound 2
¯
Crystal data: Triclinic, space group P1, a = 9.666(2), b =
˚
9.985(2), c = ◦16.899(4) A, α = 97.785(5), β = 106.043(3),
3
−3
,
˚
γ = 90.185(5) , U = 1551.6 A , Z = 8, Dx = 1.517 Mg m
F(000) = 736, µ = 0.12 mm−1, T = −140 ◦C. Data collec-
tion: A crystal ca. 0.3 × 0.1 × 0.07 mm was used to record
12980 intensities (Mo-Kα radiation, 2θmax = 52.6◦) on a
Bruker SMART 1000 CCD diffractometer. Structure refine-
ment: The structure was refined anisotropically against F2
(program SHELXL-97, G. M. Sheldrick, Univ. of Go¨ttingen)
to wR2 = 0.177, R1 = 0.087 for 482 parameters and all 6233
Experimental Section
The proton NMR spectra were recorded with a Bruker
spectrometer (500 MHz), chemical shifts are in ppm
(CDCl3/TMS). Electronic spectra were recorded on a
Genesys 6 (ThermoSpectronic) spectrophotometer in propi-
onic acid-water (1:1, v/v) solutions. IR spectra were recorded
with the Nicolet FT-IR Magna 560 spectrometer in KBr
pellets. The Raman spectra were measured using the Ra-
man accessory with the Nicolet FT-IR Magna 560 spec-
independent reflections; max. ∆ρ = 0.32 eA−3, S = 1.11.
˚
Hydrogen atoms of NH groups were refined freely with dis-
tance restraints, other H atoms were included using a riding
model.
Complete crystallographic data (excluding structure fac-
trometer (Nd:WVO4 laser worked in the near infrared range tors) have been deposited at the Cambridge Crystallographic
(9600 cm−1)). ESI mass spectra were recorded on a LCQ Data Centre under the number CCDC-268342. Copies can
DUO FINNINGAN THERMOQUEST instrument. HRMS be obtained free of charge from CCDC, 12 Union Road,
Unauthenticated
Download Date | 11/18/19 6:27 AM

P. Kus´ et al. · 2-Amino-5-phenyl-2-oxazolin-4-one (Pemoline)
857
Cambridge CB2 1EZ, U.K. (Fax: Int.+1223-336-033; e-mail:
deposit@ccdc.cam.ac.uk).
[9] F. E. King, J. W. Clark-Lewis, J. Chem. Soc. 3077
(1951)
[10] J. C. Sheenan, G. D. Laubach, J. Am. Chem. Soc. 73,
4752 (1951).
[11] C. S. Howell, N. Q. Quinones, R. A. Hardy (Jr.), J. Org.
Chem. 27, 1686 (1962).
[1] J. Kulikowska, R. Celin´ski, A. Soja, H. Sybirska, Prob-
lems of Forensic Sciences, Institute of Forensic Re-
search, Cracow, Poland, Vol. XLIX, p. 99 (2002).
[2] M. Kała, P. Adamowicz, Problems of Forensic Sci-
ences, Institute of Forensic Research, Cracow, Poland,
Vol. LIII, p. 38 (2003).
[12] F. H. Allen, O. Kennard, D. G. Watson, L. Brammer,
A. G. Orpen, R. Taylor, J. Chem. Soc., Perkin Trans. 2,
S1 (1987).
[3] H. Levan, D. L. Hebron, J. Pharm. Sci. 57, 1033 (1968).
[4] C. Zhu, X. Lin, Y. Wei, J. Pharm. Biomed. Anal. 30,
293 (2002).
[13] L. A. Plastas, J. M. Stewart, Chem. Commun. 811
(1969).
[5] C. S. Howell, N. Q. Quinones, R. A. Hardy (Jr.), J. Org.
Chem. 27, 1679 (1962).
[14] J.-P. Mornon, B. Raveau, Acta Crystallogr. B27, 95
(1971).
[15] J.-P. Mornon, R. Bally, Acta Crystallogr. B28, 2074
(1972).
[6] Clerk’s Analysis of Drugs and Poisons, A. C. Moffat,
M. D. Osselton, B. Widdop (eds.), Third Edition. Vol.
2, p. 1400, Pharmaceutical Press, London 2004.
[7] W. Stadlbauer, T. Kappe, Monatsh. Chem. 116, 1005
(1985).
[16] P. W. Codding, Acta. Crystallogr. C40, 2071 (1984).
[8] S. M. Ramsh, N. G. Zheltonog, L. P. Shamina, Y. G. Ba-
sowa, A. I. Ginak, Khim. Geterotsikl. Soedin. 19, 601
(1983).
Unauthenticated
Download Date | 11/18/19 6:27 AM