Bromination of 1-hydroxyimidazoles. Synthesis and crystal structures

Article abstract of DOI:10.1515/znb-2012-0409

Bromination of 1-hydroxyimidazole 3-oxide and 1-hydroxy-2-methylimidazole 3-oxide using bromine in acetic acid gave 2-bromo-1,3-dihydroxyimidazole hydrobromide and 4,5-dibromo-1,3-dihydroxy-2-methylimidazole hydrobromide, respectively. In contrast, bromin

Full text of DOI:10.1515/znb-2012-0409

Bromination of 1-Hydroxyimidazoles. Synthesis and Crystal Structures
Gerhard Lausa, Klaus Wursta, Volker Kahlenbergb, and Herwig Schottenbergera
a Faculty of Chemistry and Pharmacy, University of Innsbruck, 6020 Innsbruck, Austria
b Institute of Mineralogy and Petrography, University of Innsbruck, 6020 Innsbruck, Austria
Reprint requests to Prof. Dr. Herwig Schottenberger. Fax: (+43) 512 507 2934.
E-mail: herwig.schottenberger@uibk.ac.at
Z. Naturforsch. 2012, 67b, 354 – 358; received January 28, 2012
Bromination of 1-hydroxyimidazole 3-oxide and 1-hydroxy-2-methylimidazole 3-oxide using
bromine in acetic acid gave 2-bromo-1,3-dihydroxyimidazole hydrobromide and 4,5-dibromo-1,3-di-
hydroxy-2-methylimidazole hydrobromide, respectively. In contrast, bromination in aqueous mixture
(acetic acid, methanol, dimethylformamide, tetrahydrofuran) yielded 2,4,5-tribromo-1-hydroxyimid-
azole. Crystal structures of four compounds were determined by X-ray diffraction.
Key words: Bromination, Crystal Structure, Imidazole, N-Oxide
Introduction
results. In our opinion, this situation demanded more
research.
Bromination of imidazole, first described in
1877 [1], gives 2,4,5-tribromoimidazole [2, 3]; the
fully brominated derivative is also obtained from 1-
methylimidazole [4, 5]. Different brominating agents
Results and Discussion
We examined the bromination of 1-hydroxyimid-
and systems are known to effect this transforma- azole-3-oxides in several solvents. The choice of sol-
tion [6 – 9]. Dibromo and monobromo compounds vents was limited by the solubility of these very polar
have been obtained by selective reduction of tri- compounds. We confirmed that the reported bromina-
bromo compounds using sodium sulfite [2, 3] or butyl- tion of 1 in acetic acid occurs solely at the 2-position
lithium [3]. Removal of the most reactive bromine to give crystalline 2-bromo-1,3-dihydroxyimidazolium
atom in position 2 by a Grignard reagent gave 4,5- bromide (2) as the sole product (Scheme 1). The yield
dibromo-1-methylimidazole in good yield [5]. These improved when the reaction was carried out in a more
compounds are valuable building blocks for the syn- concentrated solution and a longer reaction time was
thesis of polysubstituted imidazoles [10– 12]. Poly- allowed. Perbromination was not observed, even with
brominated imidazolium salts are also of interest as an excess of bromine. We found no difference when
constituents of high-density ionic liquids [13]. It is also glacial acetic acid was used instead of 96 % acetic
noteworthy that 2,4,5-tribromoimidazole is a natural acid. Treatment of the 2,4,5-triphenyl derivative with
product [14] and that trihaloimidazoles possess insec- bromine “in alkaline medium” [21] reportedly gave
ticidal activity [15]. Only a limited number of pertinent stable radicals [22]. However, the situation in the un-
crystal structures have been published [16].
substituted parent compound 1 can be expected to be
In contrast, oxidation of imidazoles by bromine has quite different.
been observed in aqueous solution [17] resulting in
complete fragmentation of the heterocyclic ring.
Astoundingly, bromination of 1 in aqueous mixtures
of acetic acid or other solvents (methanol, dimethyl-
1-(Benzyloxy)imidazole, a rare example of an im- formamide, tetrahydrofuran) yielded 2,4,5-tribromo-
idazole bearing an N-heteroatom substituent, was 1-hydroxyimidazole 3 in approximately 10 % yield.
brominated at all available positions [18]. We have re- Acetic acid procured the best yield (up to 17%). In
cently reported selective bromination in position 2 of pure water, a violent reaction was observed, and the
quaternary 1,3-(dialkyloxy)imidazolium salts [19, 20]. yield of 3 was very low (7 %). Severe degradation of
The bromination of related 1-hydroxyimidazole-3- the molecule occurred under these conditions. Ammo-
oxides has been described [21], but attempts to re- nium bromide and oxalic acid were identified as the
peat these experiments gave, in our hands, different final products (by 13C NMR, IR, reduction of KMnO4,
c
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G. Laus et al. · Bromination of 1-Hydroxyimidazoles
355
Fig. 1 (color online). Hydrogen bonding in the crystal struc-
ture of 2.
Scheme 1. a) Br2, AcOH; b) 3 Br2, AcOH/H2O (1 : 2);
c) HBr, MeOH.
and X-ray diffraction). Therefore, the modest yield is
understandable. The starting material, however, is in-
expensive, and the procedure is simple and yields 3 as
a crystalline product. Separation of main product and
byproducts was straightforward due to their comple-
mentary solubilities.
Fig. 2 (color online). Hydrogen bonding in the crystal struc-
ture of 3.
It is assumed that the first step of the reaction in-
volves oxidative cleavage of the N–O bond leading to
1-hydroxyimidazole, which is subsequently perbromi-
nated. This is principally a new synthesis of 1-hydr-
oxyimidazole, but not a practical one. This hypothesis
is supported by the fact that, under these conditions,
the parent compound 1-hydroxyimidazole, but not the
monobromo N-oxide 2, gives the deoxygenated and
perbrominated product 3 (Scheme 1). The observation,
that half an equivalent of bromine yielded the crys-
talline hydrobromide of the starting material, was sur-
prising at first but corroborates the picture of the mech-
anism. The protonated form of 1 did not react at all.
1
by H NMR (at least not in the solvent reported) or
elemental analysis. With both methods, the mixture
appeared to be a mono-brominated product. The au-
thors of the previous work therefore interpreted their
result as a mono-brominatedproduct. We identified the
components, however, by 13C NMR spectroscopy. Two
equivalents of bromine yielded pure 4,5-dibromo-1,3-
dihydroxyimidazoliumbromide (5), isolated in accept-
able yield. When water was used as the solvent, again
decomposition of the heterocyclic ring was observed.
Finally, the structure of the new product was
confirmed by X-ray diffraction. The crystal struc-
Furthermore, we disproved the reported [21] mono- tures of the new brominated imidazoles show the
bromination of 1-hydroxy-2-methylimidazole 3-oxide expected interionic and intermolecular interactions
(4). When treated with one equivalent of bromine in (Figs. 1 – 4). Thus, the 1,3-dihydroxyimidazolium
acetic acid, this compound rather gave a mixture of bromides 2 and 5 exhibit O–H···Br···H–O hydro-
di-brominated product and unchanged starting mate- gen bonds, 1-hydroxyimidazole hydrobromide 3·HBr
rial. This mixture, perfidiously, cannot be recognized shows O–H···Br···H–N, and 1-hydroxyimidazole 3
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356
G. Laus et al. · Bromination of 1-Hydroxyimidazoles
˚
Table 1. Hydrogen bonding geometries (A, deg) with estimated standard deviations in parentheses.
Compound
2a
Interaction
O1–H···Br2
O2–H···Br2
O1–H···Br4
N2–H···Br4
O1–H···N2
O1–H···Br1
O2–H···Br1
D–H
H···A
2.4(1)
D···A
D–H···A
139(10)
162(8)
168(6)
143(7)
180(9)
170(5)
163(6)
Symmetry code (A)
0.84(9)
0.83(8)
0.84(6)
0.90(6)
0.85(2)
0.83(3)
0.84(6)
3.106(7)
3.080(6)
3.127(7)
3.184(9)
2.681(7)
3.108(4)
3.060(4)
1/2+x, 1/2−y, 1/2+z
2.28(8)
2.30(6)
2.43(9)
1.83(2)
2.29(3)
2.25(6)
–
–
3a
x, 1+y, z
3
5a
1−x, −1/2+y, 1/2−z
1−x, 1/2+y, 1/2−z
–
1,3-Dihydroxyimidazolium bromide (1·HBr)
For spectroscopic comparison, this compound was pre-
pared from 4 and 48 % HBr. M. p., 1H NMR, IR and crystal
structure: see ref. [23]. – 13C NMR (75 MHz, [D4]MeOH):
δ = 119.6 (2C), 129.9 ppm.
2-Bromo-1,3-dihydroxyimidazolium bromide (2)
Bromine (5.1 mL, 100 mmol) was added dropwise to a
solution of 1-hydroxyimidazole-3-oxide (10.0 g, 100 mmol)
in glacial acetic acid (100 mL). The mixture was stirred
at ambient temperature for 24 h. The precipitate was fil-
tered off, washed with acetic acid (2 mL), twice with Et2O
(2×10 mL), and dried. Yield: 50 %. Single crystals were ob-
tained from MeOH at −20 ◦C. M. p. 180 ◦C (181 ◦C [21]). –
1H NMR (300 MHz, [D4]MeOH): δ = 7.97 (s, 2 H) ppm. –
13C NMR (75 MHz, [D4]MeOH): δ = 117.4, 120.8 (2C)
ppm. – IR (neat): ν = 3155 (w), 3136 (w), 2911 (w),
2850 (w), 2767 (m), 2688 (m), 2634 (br m), 1544 (w),
1515 (w), 1418 (w), 1316 (w), 1041 (m), 762 (w), 702 (m),
615 (s) cm−1. – C3H4Br2N2O2 (259.88): calcd. C 13.86,
H 1.55, N 10.78; found C 13.66, H 1.25, N 10.76.
Fig. 3 (color online). Hydrogen bonding in the crystal struc-
ture of 3·HBr.
Fig. 4 (color online). Hydrogen bonding in the crystal struc-
ture of 5.
2,4,5-Tribromo-1-hydroxyimidazole (3)
O–H···N contacts. The hydrogen bonding parameters
Bromine (15.4 mL, 300 mmol) was added dropwise to a
solution of 1-hydroxyimidazole-3-oxide (10.0 g, 100 mmol)
in a mixture of acetic acid (50 mL) and water (100 mL). The
mixture was stirred at ambient temperature for 24 h, then
kept at 5 ◦C for 1 h. The precipitate was filtered off, washed
with H2O (50 mL), and dried to constant weight. Yield: 5.3 g
(17 %). Single crystals were obtained from acetone/H2O.
M. p. 154 ◦C. – 13C NMR (75 MHz, [D4]MeOH): δ = 105.5,
112.9, 115.8 ppm. – IR (neat): ν = 2344 (br m), 1653 (w),
1527 (m), 1505 (s), 1378 (s), 1314 (s), 1226 (s), 1127 (m),
995 (s), 863 (m), 746 (m), 599 (m) cm−1. – C3HBr3N2O
are listed in Table 1.
Conclusion
The choice of solvent was found to be crucial for
the outcome of the bromination of 1-hydroxyimidaz-
ole 3-oxides. In aqueous solution, N–O bond cleavage
and severe degradation of the heterocyclic ring was
observed. Oxalic acid and ammonium bromide were
identified as the final products. The new tri- and di-
bromo derivatives are expected to open up interesting (320.76): calcd. C 11.23, H 0.31, N 8.73; found C 11.53,
H 0.27, N 8.75.
pathways in further imidazole chemistry.
2,4,5-Tribromo-1-hydroxyimidazole hydrobromide (3·HBr)
This compound was prepared from 3 and 48 % HBr
Experimental Section
NMR spectra were recorded with a Bruker AC 300 spec-
trometer. IR spectra were obtained with a Nicolet 5700 FT in MeOH. Hygroscopic single crystals were obtained from
instrument.
H2O. M. p. 199 ◦C. – 13C NMR (75 MHz, [D4]MeOH):
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G. Laus et al. · Bromination of 1-Hydroxyimidazoles
357
Table 2. Crystal data and numbers pertinent to data collection and structure refinement of 2, 3, 3·HBr, and 5.
Compound
Formula
2
3
3·HBr
5
C3H4Br2N2O2
259.90
0.3×0.05×0.04
monoclinic
Cc
13.4290(2)
4.2773(4)
12.8093(8)
90
102.818(4)
90
717.43(8)
4
2.41
11.2
488
C3HBr3N2O
320.76
C3H2Br4N2O
401.71
C4H5Br3N2O2
352.83
0.31×0.15×0.05
monoclinic
P21/c
7.4026(4)
10.7990(4)
11.8247(6)
90
104.733(3)
90
914.20(8)
4
Mr
Crystal size, mm3
Crystal system
Space group
0.12×0.04×0.04
orthorhombic
P212121
3.9509(2)
10.1324(4)
17.0987(7)
90
90
90
684.50(5)
4
3.11
0.25×0.11×0.03
triclinic
¯
P1
˚
a, A
6.0964(4)
7.1078(5)
11.3449(7)
76.010(4)
89.610(4)
70.580(4)
448.42(5)
2
˚
b, A
˚
c, A
α, deg
β, deg
γ, deg
3
˚
V, A
Z
Dcalcd, g cm−3
2.98
17.9
364
2.56
13.2
656
µ, mm−1
21.2
584
F(000), e
T, K
Radiation
233
MoKα
173
CuKα
233
MoKα
233
MoKα
hkl range
15, −5 → 4, 15
4, −10 → 12, 20
7, 8, 13
2633
1537
−8 → 9, 13, −14 → 10
Refl. measured
Refl. independent
Rint
2077
4238
5260
1224
0.042
1212
0.032
1765
0.063
0.055
Refl. observed
Restraints / parameters
R1 / wR2 [I ≥ 2σ(I)]
R1 / wR2 (all data)
x (Flack)
1160
4 / 91
0.034 / 0.076
0.037 / 0.078
0.48(3)
1.04
1180
1 / 85
0.030 / 0.074
0.031 / 0.075
−0.01(7)
1.11
1339
1539
2 / 100
0.066 / 0.184
0.072 / 0.192
–
2 / 109
0.043 / 0.111
0.050/ 0.114
–
Goodness of fit−3
1.06
1.07
˚
∆ρmax/min, e A
0.87 / −0.46
1.39 / −0.50
1.64 / −1.73
0.86 / −1.47
CCDC number
864100
864099
864101
864102
δ = 105.9, 112.4, 116.0 ppm. – IR (neat): ν = 2813 (w), tered off, washed with acetic acid (2 mL), twice with Et2O
2750 (w), 2702 (m), 2667 (m), 2600 (s), 2569 (s), 2525 (s), (2 × 10 mL), and dried. This crude product was dissolved
◦
2465 (m), 2369 (m), 1704 (m), 1555 (s), 1308 (m), 826 (s), in warm MeOH (ca. 12 mL) and kept at −20 C overnight.
753 (s) cm−1
.
The colorless product was collected by filtration, washed
with Et2O (10 mL), and dried to constant weight. Yield:
6.5 g (21 %). Single crystals were obtained from MeOH.
M. p. 183 ◦C (dec). – 1H NMR (300 MHz, [D4]MeOH):
δ = 2.68 (s, 3 H) ppm. – 13C NMR (75 MHz, [D4]MeOH):
δ = 8.9, 106.4 (2C), 142.4 ppm. – IR (neat): ν = 2981 (w),
2916 (w), 2806 (m), 2674 (br s), 1569 (m), 1452 (m),
1302 (m), 1145 (m), 1016 (m), 840 (m), 807 (w), 604 (s),
587 (s) cm−1. – C4H5Br3N2O2 (352.81): calcd. C 13.62,
H 1.43, N 7.94; found C 13.76, H 1.31, N 7.95.
1,3-Dihydroxy-2-methylimidazolium bromide (4·HBr)
For the purpose of spectroscopic comparison, this com-
poun◦d was prepared from 4 and 48 % HBr. M. p. 164 –
165 C. – 1H NMR (300 MHz, [D4]MeOH): δ = 2.62 (s,
3 H), 7.66 (s, 2 H) ppm. – 13C NMR (75 MHz, [D4]MeOH):
δ = 7.4, 118.0 (2C), 139.3 ppm. – IR (neat): ν = 3151 (w),
3111 (w), 3034 (w), 2958 (w), 2911 (w), 2805 (m), 2699 (s),
2647 (s), 2590 (s), 1595 (w), 1455 (m), 1356 (m), 1109 (s),
1053 (w), 1033 (w), 950 (w), 756 (m), 712 (s), 621 (s),
Crystal structure determinations
594 (s) cm−1
.
The crystal structures were determined using Nonius Kap-
paCCD and Oxford Diffraction Gemini-R Ultra diffractome-
ters with MoKα and CuKα radiation, respectively. Several φ
and ω scans were made to increase the number of redundant
4,5-Dibromo-1,3-dihydroxy-2-methylimidazolium
bromide (5)
Bromine (4.5 mL, 88 mmol) was added dropwise to a reflections, which were averaged previous to the refinement
solution of 1-hydroxy-2-methylimidazole-3-oxide (10.0 g, cycles. This procedure replaces in good approximation an
88 mmol) in acetic acid (100 mL). The mixture was stirred empirical absorption correction. The structures were solved
at ambient temperature for 27 h. The precipitate was fil- with direct methods and refined against F2 [24]. The struc-
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358
G. Laus et al. · Bromination of 1-Hydroxyimidazoles
ture of 2 was refined as racemic (inversion) twin with a batch
CCDC 864099–864102 contain the supplementary crys-
scale factor of 0.47 and checked for higher symmetry using tallographic data for this paper. These data can be obtained
the PLATON software [25]. The experimental conditions and free of charge from The Cambridge Crystallographic Data
crystallographic data are summarized in Table 2.
Centre via www.ccdc.cam.ac.uk/data request/cif.
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