Synthesis of New Complexons: N-Hydroxy-a, a`

Synthesis of New Complexons: N-Hydroxy-a, a`

Synthesis of New Complexons: N-Hydroxy-a,a'-iminodipropionic- and
N-Hydroxyiminodiacetic Acid
E. Kocha, H. K neifelb, and E. Bayera *
a Institut für Organische Chemie der Universität Tübingen,
A u f der M orgenstelle 18, D -7400 Tübingen
b Institut für Biotechnologie der Kernforschungsanlage Jülich. D -5170 Jülich
Z. Naturforsch.
41b, 359—362 (1986); received N ovem ber 12, 1985
C om plexons, Synthesis, N-Hydroxyim inodicarboxylic Acids
R eaction conditions for the synthesis of N -hydroxy-a,a'-im inodipropionic acid, the ligand o f
naturally occurring amavadin, and N-hydroxyiminodiacetic acid, the first m ember o f this class of
com plexon s, have been investigated.
Am avadin (1), the complex of V O 2* with two m ole­
cules o f N -hydroxy-a,a'-im inodipropionic acid (2a) is
the only natural vanadium containing compound, the
structure o f which has been determined [1, 2].
H3C
o
Y
0'
H3 C ^ > N |'
HO
h 3c
COOH
R^COOH
T
0 0 i n ^ oh
\ II..- \ ^ c h 3
COOH
R -C H -C O O H
R -C H -C 0 0 H
I
I
N -0 H
R '-C H - C00H
NH20H ♦ 2 R -C H X C00H
H -N -O H
R'^COO®
"0
2a
2b
R = R' = CH3
R =R'= H
1
N-hydroxyiminodicarboxylic acids (2) are closely
related to com plexons such as ethylenediaminetetraacetic acid (E D T A ) or iminodiacetic acid (ID E). A f­
ter our success in synthesizing optically active N-hydroxy-a,a'-L,L-im inodipropionic acid to confirm the
structure of amavadin (1) [3], we began systematic
investigations on the synthesis of this uncommon
class of com plexons. Synthesis of compounds 2 by
Felcman et al. [11], based on our first reports [1, 2],
did not yield pure products. Especially in the case of
com pound 2a the authors were unable to obtain the
m etal-free form.
For the synthesis of compounds 2, two pathways
seem ed possible:
a) oxidation of the corresponding imino compounds
3 and
b) the alkylation of hydroxylamine by a-halocarboxylic acids (see eq. ( 1)).
* Reprint request to Prof. Dr. E. Bayer.
Verlag der Zeitschrift für Naturforschung, D-7400 Tübingen
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First attempts to obtain 2 by oxidation of 3 with
common oxidants such as hydrogen peroxide/sodium
tungstate or sodium persulfate/silver nitrate were un­
successful. Reaction of hydroxylamine with D ,L -achloropropionic acid gave only m odest yields [4],
Conditions for the reaction of hydroxylamine with
D,L-a-brom opropionic- and brom oacetic acid were
m odified systematically. The formation of com ­
pounds 2 was checked by high pressure liquid
chromatography. Under the conditions used for the
synthesis of compound 2a in our preliminary report
[3] (80 °C, sodium bicarbonate as base) the product
decom posed rapidly and the resulting yield was only
m odest. Maximum yield was obtained at pH 7 and
m oderate temperature. Under these conditions,
com pound 2b could be obtained for the first time.
Separation from the reaction mixture was achieved
as described earlier [3] by precipitation of the zinc
com plex. The white precipitate was dissolved in di­
luted hydrochloric acid, adsorbed on a strongly
acidic cation exchange resin and the product eluted
with sodium hydroxide. In this way the free N-hydroxyimino acids 2a and 2b could be readily pre­
pared in 10 g amounts. The structure of these com ­
pounds was confirmed by field desorption mass spec­
troscopy, nuclear magnetic resonance and elem en­
tary analysis.
In the case of com pound 2a, two identical asym­
metric carbon atoms are present. H ence an enan-
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360
E. Koch et al. • Synthesis o f N ew C om plexons
3
Fig. 1. Separation o f L.L-( l) .D .D -( 2 ) and m eso-N hvdroxy-a,a'-im inodipropionic acid dim ethylester (3). D e ­
activated [7] glass capillary colum n 20 m x 0.25 mm coated
with Chirasil-Val. Carrier gas H 2; tem perature 95 °C.
tiomeric pair and an optically inactive m eso-form are
possible. Separation could be achieved by gas
chromatography of the dimethyiesters on ChirasilVal [5, 6], a chiral stationary phase for gas liquid
chromatography (see Fig. 1). Optically active 2 a and
the m eso form showed sufficient difference in chem i­
cal shifts in the 'H NM R spectra to allow' the deter­
mination of the amount of the meso-form present in
optically active 2 a (see Fig. 2).
Starting from optical active L-a-bromopropionic
acid with an optical purity in excess of 95% [7]. D .D N-hydroxy-a,a'-im inodipropionic acid (2 a ) was ob ­
tained. The product contained only about 9% of the
m eso-isom er as shown by 'H NMR spectroscopy and
gas chromatography. The L.L-form of com pound 2 a
was not detectable by gas chromatography. Further
purification by preparative HPLC was not necessary.
Determ ination of the absolute configuration of com ­
pound 2 a was possible by its reduction to a ,a'-im in o-
Fig. 2. 'H NM R spectra o f D .D -N -h ydroxy-a, a'-im inodipropionic acid with 9 % of the m eso-isom er present (90 M H z. D ;0 ) .
361
E. K ocher al. • Synthesis o f N ew Com plexons
dipropionic acid with zinc/acetic acid. The configura­
tion o f this compound was already determined in
1942 [8] (see also ref. [3]).
Yield: 1.66 g (11.4 m mol) = 81% d.Th. White
powder, Fp. 136 °C.
E xp erim en tal
IR (KBr): 3420 (O H ), 3240 (N H ), 2930 (C H ),
1600 (C O ), 1585 (C O O - st as), 1420 (COO~ st
sym) cm -1.
' 'H NM R (D ;0 ) : Ö = 3.85 (s); (R ef. 3-(Trimethylsilyl)propionic acid, sodium salt).
FD-M S: m/e 150 (100% , M + l ) , 149 (M +).
The product had a purity of 9 8 .0 ± 1 % , determ i­
nated by titration against standard 0.1 N NaOH
using phenolphthalein as indicator.
D .L -a-Brom opropionic acid, bromoacetic acid
and hydroxylamine hydrochloride were com m er­
cially available products. Lewatit S-100 ion exchange
resin was purchased from Bayer AG and purified by
standard procedures. L-a-Brom opropionic acid was
obtained from L-alanine according to Fu and co­
workers [9).
Elem entary analysis: C4H 7N O 5 M G 149.10
Calcd
C 32.22 H 4.73 N 9.39,
Found C 31.97 H 4.58 N 9.14.
N -H ydroxyim inodiacetic acid
6.95 g (0.1 m ol) hydroxylamine hydrochloride and
34.7 g (0.25 mol) bromoacetic acid were dissolved in
200 ml o f water. The reaction mixture was kept at
room tem perature and titrated automatically (Impulsomat E 473 Metrohm, Herisau, Schweiz) to a
pH of 7 using 10% sodium hydroxide solution.
A fter 6 h the reaction mixture was acidified to
pH 4 and 21.35 g (0.1 mol) zinc acetate dihydrate
was added. A fter standing over night at room tem ­
perature the zinc complex of N-hydroxyiminodiacetic acid was collected and dried over diphosphorus
pentoxide.
Yield: 12.1 g (56.7 mmol) = 56.7% d.Th. White
powder; Fp. > 2 5 0 °C.
Elem entary analysis: ZnC 4H^NO^ M G 212.46
Calcd
C 22.61 H 2.37 N 6.59 Zn 30.77.
Found C 22.59 H 2.50 N 6.38 Zn 29.20.
Zn was determined by dissolving the salt in con­
centrated nitric acid and titration with ethylenediamine tetraacetic acid [10].
IR (KBr): 3420 (O H ), 3240 (N H ), 2930 (C H ),
1655 and 1580 (CO ) cm"1.
N -H yd ro x y-a ,a '-im in o d ip ro p io n ic acid
A nalogous to the procedure previously described
0.05 mol o f N H .O H x H C l and 0.15 mol D,L-2brom opropionic acid were allowed to react for 24 h
at 40 °C and the zinc com plex precipitated.
Yield: 6.70 g (27.9 m m ol) = 55.7% d.Th. Fp.
> 2 5 0 °C.
Elem entary analysis: Z n C 0H^NO<; M G 240.52
Calcd
C 29.96 H 3.77 N 5.82 Zn 27.18,
Found C 29.66 H 3.84 N 5.72 Zn 26.50.
IR (KBr): 3420 (O H ), 3200 (N H ), 2950 (C H ),
1660 (C O ), 1590 and 1440 ( C O O ) c m '1.
The metal-free com pound was obtained by
chromatography on D ow ex 50 W X 8 H T:
Elem entary analysis: C^HnNOs M G 177.16
Calcd
C 40.45 H 6.79 N 7.86,
Found C 40.27 H 6.58 N 7.68.
IR (KBr): 3400 (O H ), 2995 (C H ) and 1750 (CO)
cm -1.
‘H N M R (D .O ): Ö = 4.12 (m eso) and 4.05
( D ,D + L,L) (q, J = 1 Hz; 2 H , C H ,-C H ) , 1.46
(m eso) and 1.43 (D .D + L.L) (d, J = 7 Hz; 6 H.
C H ?—CH ); (R ef. 3-(Trim ethylsilyl)propionic acid,
Chrom atography on lon-exchange Resin
sodium salt).
Lew atit S 100
FD-M S: m /e 178 (100% M + l) and 177 (M +).
(Instead o f Lewatit S 100 also Dowex 50 W X 8
The substance had a purity o f 95% determined by
5 0 —100 mesh from Serva Fein Biochem ica, H eidel­ titration against standard 0.1 N N aO H solution.
berg, FR G , can be used.)
Optically
active
L,L-N -hydroxy-a,a'-im inodi3.00
g (14.1 mmol) of the zinc complex from the propionic acid showed [a]o = —25.8° (c = l , H :0 )
above reaction were dissolved in 25 ml of water by
(uncorrected. 9% m eso-isom er present).
dropwise addition of concentrated hydrochlorid acid.
The solution was loaded on a column (2 .5 x 3 0 cm)
containing strongly acidic cation exchange resin
(Lewatit S 100) and eluted with 0.2 N sodium hy­
One of us (E. K .) is grateful for the support from
droxide solution. The fraction containing the product
the Herm ann-Schlosser-Stiftung, Frankfurt.
was concentrated to a volume of 100 ml and freeze
W e thank Mr. G. J. N icholson for his help in gas
dried.
chromatographic analyses.
362
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[5] E. Bayer. Z. Naturforsch. 3 8 b , 1281 (1983).
[6] Chirasil-Val-Capillaries are available from Chrom­
pack. M iddelburg. H olland.
E. Koch et al. ■Synthesis o f New C om plexons
[7] E. Koch. G. J. Nicholson, and E. Bayer. H RC & CC
7, 398 (1984).
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