Reaction of N,N-dialkylcarboxamides with halogens

Article abstract of DOI:10.1023/A:1013146630045

N,N-Dialkylcarboxamides react with halogens in the absence of water to form complexes which are likely to have an ionic structure with the Hlg⁺ ion coordinated at the carbonyl oxygen atom. These products can be isolated as individual compounds.

Full text of DOI:10.1023/A:1013146630045

Russian Journal of Organic Chemistry, Vol. 37, No. 9, 2001, pp. 1210 1219. Translated from Zhurnal Organicheskoi Khimii, Vol. 37, No. 9, 2001,
pp. 1276 1286.
Original Russian Text Copyright
2001 by Burakov, Kanibolotskii, Osichenko, Mikhailov, Savelova, Kosmynin.
Reaction of N,N-Dialkylcarboxamides with Halogens
N. I. Burakov, A. L. Kanibolotskii, G. Yu. Osichenko, V. A. Mikhailov,
V. A. Savelova, and V. V. Kosmynin
Litvinenko Institute of Physical Organic and Coal Chemistry, National Academy of Sciences of Ukraine,
ul. R. Luxemburg 70, Donetsk, 340114 Ukraine
e-mail: bni@newmail.ru
Received July 13, 1999
Abstract N,N-Dialkylcarboxamides react with halogens in the absence of water to form complexes which
+
are likely to have an ionic structure with the Hlg ion coordinated at the carbonyl oxygen atom. These
products can be isolated as individual compounds. Complexes with bromine undergo further transformations
to afford bis-dialkylamide hydrogen tribromide and the corresponding -bromo amide. When the reaction
is carried out in the presence of water, the products are only bis-dialkylamide hydrogen tribromides; here,
the N-alkyl groups act as a source of protons.
The reaction of N,N-dialkylcarboxamides with
halogen was the subject of numerous studies. Accord-
ing to Gur’yanova et al. [1], such reaction in weakly
polar media is reversible, and it yields 1:1 molecular
complexes. The complex formation constants of di-
methylformamide (DMF) [2], dimethylacetamide
DMA chlorine [12], DMA bromine [13], and
HMPA bromine complexes [14] has been reported.
The complexes DMF Br and DMF Cl were charac-
2
2
1
31
terized by UV, IR, and H NMR spectra [13];
P
NMR spectra and results of conductomertric measure-
ments were reported for the complex HMPA Br [14].
2
(
DMA) [3], tetramethylurea [4], and N,N-dimethyl-
benzamide [5] with iodine in carbon tetrachloride at
5 C range from 2 to 7 l/mol. Bromine is a less active
These complexes were assigned [11 14] ionic struc-
+
ture with a [ O Br] Br fragment.
2
Halogen complexes with amides can be used in
organic synthesis. The bromine complex with DMA
was used to brominate isoxazolidinones [15], and the
complexing agent than iodine toward DMF, whereas
iodine chloride is more active [6]. It is assumed that
the site of halogen coordination is the carbonyl
oxygen atom [2]. In a more polar solvent, methylene
chloride, the complex formation constant of iodine
with DMF [7] and DMA [8] is slightly smaller than
in carbon tetrachloride; in less polar heptane the
complex formation constant of iodine with tetra-
HMPA Br complex was used to convert an alcohol
2
aldehyde mixture into the corresponding ester [16].
In the two cases, neither the complexes were isolated
nor their structure was discussed. More frequently,
the possibility for complex formation of dialkyl-
carboxamides with halogens is merely neglected, e.g.,
in the halogenation of poorly soluble compounds in
dialkylamides as media possessing a strong dissolving
power. Sometimes, the processes were carried out
under fairly severe conditions. For instance, the
chlorination of pyrazines was performed in DMF at
methylurea [9] is somewhat greater than in CCl4
(
19 l/mol). Judging by the Kass values, bromine and
iodine form fairly weak complexes with N,N-dialkyl-
carboxamides. This is clearly seen when comparing
with their thio analogs, N,N-dimethyl(thioacetamide)
[
10] and N,N,N ,N -tetramethylthiourea [9] whose
45 80 C [17], 4-nitroimidazoles were brominated in
Kass values for complex formation with iodine in
DMF at 60 70 C [18], and imidazo[2,1-b]thiazoles,
at 80 C [19]. There are a number of examples which
suggest as if dialkylcarboxamides are relatively stable
toward halogens and their interaction is limited to
formation of complexes without rupture of existing
covalent bonds and formation of new bonds. How-
ever, polarographic study of bromine solutions in
DMF [20] has shown that even at room temperature
CCl [10] and heptane [9] exceed those found for
4
amides [3, 4] by 2 3 orders of magnitude.
The conclusion that the above complexes are weak
contradicts published data according to which com-
plexes of dialkylcarboxamides with halogens can be
isolated as individual compounds. For example, the
isolation of DMF bromine [11], DMF chlorine [12],
1
070-4280/01/3709-1210$25.00 2001 MAIK Nauka/Interperiodica

REACTION OF N,N-DIALKYLCARBOXAMIDES WITH HALOGENS
1211
the total amount of bromine is gradually reduced
a number of N,N-dialkylcarboxamides toward bromine
and of some dialkylamides toward iodine and inter-
halogen compounds. The results of previous studies
led us to conclude that complexes of amides with
iodine and interhalogen compounds are stronger than
to Br ion. It was presumed that dimethylformamide
3
molecule is thus oxidized to radical cation whose
further transformations were not examined. Later on,
Mikhailov [21] found that the reaction of DMF with
bromine is accompanied by profound transformations those with bromine (here, the lower degree of dis-
of the former and that the reaction course and product
composition depend on the presence or absence of
water in the system. Analogous products are formed
in the reaction of DMF with iodine trichloride [22].
Profound transformations were also observed in the
reactions of DMA with bromine [23, 24] and iodine
chloride [25] and of HMPA with chlorine [26] and
sociation is meant). Therefore, complexes with iodine
and interhalogen compounds should be isolable
a priori, provided that the corresponding complex
with bromine is stable. The reactions of dialkylamides
with halogens were carried out as follows. To a solu-
tion of appropriate amide in a thoroughly dehydrated
inert solvent (the reactions with liquid amides were
bromine [27]. Our experience shows that these reac- sometimes carried out without a solvent) we added
tions are strongly exothermic and that the main dif-
ficulty is not to initiate the process but to keep its
quiet running.
We can conclude that there is a large divergence
in published data on the reaction of halogens with
N,N-dialkylcarboxamides:
a solution of halogen (bromine was added with no
solvent), in some cases at reduced temperature. The
product was separated, and the concentration of halo-
gen and hydrogen halide was determined by iodo-
metric titration. Obviously, a stable complex should
be characterized by a concentration of halogen close
to stoichiometric and zero concentration of hydrogen
halide. The details are given in Experimental, and
the results, in Table 1.
(1) The interaction is such a weak that it could
be neglected, and dialkylamides can be used as sol-
vents for halogenation reactions;
Among the examined amides, compounds I and II
are the most nucleophilic; they are characterized by
the greatest proton affinities (judging by the PA
values from [28, 29]), the strongest ability to form
hydrogen bonds (KHB [30]), and high heat of mixing
with bromine [31]. Amides I and II react with Br2
at room (or even lower) temperature to afford red
orange viscous oily products which differ visually
(
2) Formation of weak molecular complexes;
(3) Formation of stable isolable complexes in
which the carboxamide skeleton remains unchanged;
4) Vigorous reaction leading to essential trans-
(
formation of the amide structure.
A plausible explanation is that halogen complexes
or adducts) with dialkylamides are actually formed
(
but they are only intermediates in further transforma- from the initial amides and bromine. The products
tions. Then, the stability of intermediate complexes
can be considered in two aspects: first, as a high
degree of association of halogen and dialkylamide. In
this case, the greater the nucleophilicity (or basicity,
or donor number) of amide and the greater the electro-
philicity of halogen, the stronger is the complex (its
formation constant is greater, and the degree of dis-
sociation into initial components is lower). The other
aspect is a weak ability of the complex to undergo
further transformations; this process may be governed
by other factors, e.g., ready elimination of hydrogen.
The number of such assumptions is unlimited unless
fine details of the structure of complexes and
mechanism of their further transformations are known.
Clearly, the role of halogen dialkylamide complexes
as possible intermediates may be substantiated by
contain a lot of hydrogen bromide. Presumably, the
amide Br complex (if it is formed) undergoes fast
2
further transformations. Less basic amides III VII
[32] behave similarly. A reason for fast transforma-
tions of the complexes may be liquid state of the
primary adduct. N-Methylpyrrolidinone (VIII) gives
a solid product with bromine, but it contains a lot
of HBr. DMF (IX) and DMA (X) react with bromine
at low temperature in solution (or without a solvent)
to afford a red orange solid low-melting product
Scheme 1.
(1) isolation of halogen dialkylamide complexes
which are stable under standard conditions and (2) by
performing their further transformations.
With the goal of obtaining relatively stable but
reactive complexes we examined the behavior of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 9 2001

1
212
BURAKOV et al.
Table 1. Reaction of bromine with dialkylamides
Reaction conditions
Dialkylamide
Concentration, %
Aggregate state
of the product
Isolation
procedurea
solvent
temperature,
C
Br2
HBr
N,N,N ,N -Tetramethyl-
urea (I)
HMPA (II)
15
30
1
20
10
Liquid
Liquid
Liquid
42 46
35
25
30
46
9 18
7.0
12.0
9.8
f
c
f
c
f
CCl4
Heptane
N,N-Dimethylpivalamide
1.5
(
III)
N-Acetylpiperidine (IV)
N-Acetylmorpholine (V)
N,N-Dimethylbenzamide
20
5
Liquidb
Liquid
Liquid
45
34
39
38
35
32
41
4.4
11.0
3.7
1.5
3.0
f
a
f
a
f
Chloroform
Chloroform
Chloroform
20
10
20
15
15
(
VI)
N-Benzoylpiperidine
VII)
N-Methylpyrrolidinone
VIII)
Liquid
(
1.5
11.0
a
d
Solid
(
DMF (IX)
10
60
15
40
30
20
20
20
35
20
Low-melting solid
Glassy material
59
50
53
49
45
35
45
32
43
37
2.4
0.5
0.2
0.1
0.5
16.0
0.8
14.0
0.4
f
a
f
a
a
d
e
d
e
d
Chloroform
DMA (X)
Chloroform
CCl4
Chloroform
Chloroform
Chloroform
Chloroform
Chloroform
N,N -Diformylpiperazine
Solid
Solid
Solid
Solid
Solid
Solid
(XI)
N,N -Dipropionylpipera-
zine (XII)
N,N -Dipivaloylpipera-
zine (XIII)
N,N -Bis(dimethylcarba-
moyl)piperazine (XIV)
N,N -Dibenzoylpipera-
zine (XV)
6.6
Chloroform
Chloroform
Chloroform
20
20
20
34
6.2
46
13.0
0
d
e
e
N,N -Diacetylpiperazine
0
(XVI)
a
See Experimental.
Solidifies on storage as a result of further transformations.
b
(
DMF) or a glassy material (DMA) with a high con-
undergoes the same transformations as does DMA in
the reaction with bromine [24]: It is converted into
tribromide XVIII and N,N -bis(bromoacetyl)pipera-
centration of bromine and low concentration of HBr.
The concentration of hydrogen bromide rapidly in-
creases on storage at room temperature. Encouraging zine (XIX) (Scheme 2). Structurally related N,N -di-
results were obtained in the series of N,N -bisacylated
piperazine derivatives. All N,N -diacylpiperazines
XI XVI gave solid products in reaction with bromine.
The data in Table 1 show that at least one of the
examined dialkylamides, N,N -diacetylpiperazine
propionylpiperazine (XII) forms with bromine less
stable complex XX; but the latter undergoes analogous
transformations (Scheme 3). The yield of compound
XXI was low, and it was not isolated as individual
1
product. The H NMR spectrum of the residue ob-
(
XVI), forms complex XVII with bromine, which is
tained by evaporation of the extract (after washing
of the reaction mixture with chloroform) contained
signals from the initial amide and -bromo derivative.
stable at room temperature (Scheme 1). On keeping
in carbon tetrachloride or chloroform, complex XVII
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 9 2001

REACTION OF N,N-DIALKYLCARBOXAMIDES WITH HALOGENS
1213
Scheme 2.
The extremely low solubility of complexes XVIII
and XXII suggests that they have a polymeric ionic
structure (see above).
As expected, amides capable of forming stable
complexes with bromine also give stable complexes
with iodine and interhalogen compounds. Diacetyl-
piperazine XVI and iodine form 1:1 complex XXIII.
The latter loses halogen on heating before melting.
Interhalogen compounds, iodine chloride and iodine
bromide react with amide XVI to form 2:1 com-
plexes. N,N -Bispropionylpiperazine (XII) reacts in
a similar way (Scheme 5).
Scheme 3.
Scheme 5.
XXIV, R = Et, X = Cl; XXV, R = Et, X = Br;
XXVI, R = Me, X = Cl; XXVII, R = Me, X = Br.
Table 2 lists the yields, physical properties, and
elemental analyses of compounds XVII, XVIII, and
XXII XXVII. Hassel and Romming [33] noted
an analogous difference in the stoichiometry of com-
plexes formed by a difunctional nucleophile (dioxane)
with bromine, iodine, and interhalogen compounds.
The IR spectrum of XVII in Nujol resembles that
of the free ligand with the difference that the carbonyl
stretching vibration band of the complex is displaced
toward lower frequencies. The main IR absorption
bands of complex XVII, diacetylpiperazine XVI, and
tribromide XVIII are compared in Table 3. We
previously showed [24] that bis(dimethylacetamide)
hydrogen tribromide, which is structurally related to
XVIII, is protonated at the carbonyl oxygen atom,
which is typical for carboxamides [34]. Presumably,
the proton in XVIII is also coordinated at the car-
bonyl group. As a result, the C O stretching vibration
band shifts to lower frequencies, as compared to the
nonprotonated amide. A similar shift of the carbonyl
band is observed in the IR spectrum of XVII.
H-Complexes XVIII and XXII were also synthesized
by independent procedure from the corresponding
amide, hydrogen bromide, and bromine (Scheme 4).
Scheme 4.
XVI, XVIII, R = Me; XII, XXII, R = Et.
Complex XVIII shows in the IR spectrum a broad
diffuse band typical of compounds having a short
symmetrical O H O bond. An analogous band
was observed in the IR spectrum of bis(dimethylacet-
amide) hydrogen tribromide complex. Probably,
vibrations in the above fragment are anharmonic [35].
1
13
The H and C NMR spectra of XVII in chloro-
form (Table 4) differ from those of parent amide XVI
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 9 2001

1
214
Table 2. Yields, melting points, colors, and elemental analyses of compounds XVII, XVIII, and XXII XXVII
Found, % Calculated, %
BURAKOV et al.
Comp. Yield,
mp,
C
Color
Formula
no.
%
C
H
N
Hlga
48.66 C H Br N O
2 2 2
C
H
N
Hlg
b
XVII
70
69
70
Yellow
orange
Violet
27.49 4.56 8.51
22.73 3.42 6.80
19.48 2.92 5.66
16.47 2.51 4.75
22.95 3.59 5.37
19.93 3.19 4.50
23.85 3.75 6.85
27.40 4.48 6.03
29.12 4.28 8.49 48.42
22.66 3.33 6.61 59.86
19.41 2.85 5.66 65.61
16.46 2.42 4.80 70.85
22.97 3.47 5.36 62.09
19.63 2.97 4.58 67.60
23.38 3.68 6.82 58.33
27.36 4.36 6.38 54.61
6
14
(48.45)
59.75 C H I N O
14 2 2 2
60.00)
65.62 C H Cl I N O
14 2 2 2 2
b
XXIII
XXVI
8
(
120 122 Light
yellow
100 102 Orange
8
(65.82)
XXVII 56
70.85 C H Br I N O
8 14 2 2 2 2
(
70.87)
61.93 C H Cl I N O
0 18 2 2 2 2
XXIV
XXV
84
93
81 83 Light
yellow
60 62 Orange
1
(62.08)
66.84 C H Br I N O
1
0
18 2 2
2
2
2
(
66.88)
57.81 C H Br N O
XVIIIc 72
183 184 Yellow
orange
168 170 Yellow
orange
8
15
3 2
(37.70)
XXIId
64
54.70 C H Br N O
10 19 3 2 2
(36.00)
a
Total halogen; in parentheses is given the active halogen concentration.
Loses halogen on heating.
Found, %: HHlg 19.95.
b
c
d
Found, %: HHlg 18.50.
Table 3. IR spectra of complexes XVII and XVIII and free ligand XVI
Comp.
no.
,
cm 1
XVI
XVII
1650 (C O) 1281
1635 (C O) 1283
1250
1252
1006
1005
1009
980
984
945
727 624 590 539 458
727 627 589 540 454
631 571
XVIII 1655 (C O) 1285
1170
1095
1033
by a slight downfield shift of all signals. On storage
of a solution of complex XVII in acetonitrile (even
specially purified from reducing impurities), hydrogen
bromide accumulates in the mixture at an appreciable
rate. This process strongly hampers UV spectroscopic
and conductometric studies of XVII in solution.
Stable complexes of dipropionylpiperazine with iodine
bromide (XXV) and iodine chloride (XXIV) are much
better soluble. The equivalent electric conductivity
of solutions of complex XXV in acetonitrile in the
absorption bands at
227 (XXIV) and 256 nm
(XXV). Their position differs from the position of
bands of initial interhalogen compounds and amides
but is typical of [ICl ] and [IBr ] ions [36]. Counter-
2
2
ions are likely to be iodine cations coordinated to two
carbonyl groups of two dipropionylpiperazine mole-
cules. The color of the solid complexes corresponds
to the color of salts having ICl and IBr anions. In
addition, diacetylpiperazine complexes with iodine
chloride and iodine bromide are very poorly soluble
in most moderately polar solvents. In this respect,
they resemble the corresponding H-complexes of
diacylpiperazines. An analogous stoichiometry and
low solubility of the 1,4-diazabicyclo[2.2.2]octane
complex with bromine [37] and of the 4,4-bipyridine
2
2
2
3
range of concentrations from 10 to 10 M is about
2
1
8
cm mol , and it shows a weak concentration
dependence. These data indicate that complexes
XXIV and XXV in solution exist as ionic species.
The UV spectra of acetonitrile solutions contain
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 9 2001

REACTION OF N,N-DIALKYLCARBOXAMIDES WITH HALOGENS
1215
complex with iodine chloride [38] were previously
interpreted as factors indicating an ionic polymeric
an O Br bond is hindered or impossible, the reaction
with bromine follows a different pathway. Complex
structure of these hypervalent compounds. We can XVII cannot be obtained by reaction of diacetyl-
conclude that solid complexes XXIV XXVII exist as
ionic crystals in which one iodine cation is surrounded
by two halves of two different diacylpiperazine gen bonding with water molecules. Nevertheless, the
molecules as shown below:
piperazine with bromine in the presence of water.
Here, the carbonyl group is deactivated due to hydro-
reaction with bromine does occur, and the major
product is diacetylpiperazine hydrogen tribromide
complex XVIII which is formed in high yield. The
yields of the other products are very small, so that
they can be neither isolated nor characterized. The
1
H NMR spectrum of the oily residue obtained by
washing of the reaction mixture with chloroform and
subsequent evaporation of the extract contains no
signals assignable to bromoacetyl group protons.
Also, there are no signals typical of piperazine ring
which is likely to decompose giving rise to protons.
Under these conditions, the first (or one of the first)
stage of oxidation of an organic substrate is the same
as in the halogenation of acyclic dialkylcarboxamides
Complexes of diacetylpiperazine with bromine and
iodine (compounds XVII and XXIII) have a different
stoichiometry, but their color resembles the color of
salts formed by Br and I ions. Presumably, com-
plexes XVII and XXIII have an analogous structure
in which the halogen cation coordinates to two
whole diacylpiperazine molecules. Taking into
account that compounds XVII and XXIII have no
sharp melting point but lose the halogen on heating
to give the initial amide, molecular structure of these
complexes is also possible. In this case, polymeric
molecular structure with bridging halogen atoms can
be assumed (like that described by Hassel for the
dioxane bromine complex [33]):
3
3
[
24], which involves intermediate formation of
iminium salt (Scheme 6).
Scheme 6.
Its further transformations remain unclear. The
extremely low yield of organic products in the
bromination in the presence of water indicates that
the most probable reaction path is profound decom-
position of the piperazine ring via oxidation and
hydrolysis. Halogen binding to the carbonyl group
may also be hindered for steric reasons, as, e.g., in
the case of N,N -dipivaloylpiperazine (XIII). Pival-
amides are characterized by reduced barrier to rotation
about the C N bond [34] and reduced conjugation
between the lone electron pair on the nitrogen and
double C O bond. As a result, pivalamides behave
largely as amines rather than amides (i.e., as N-nuc-
leophiles rather than O-nucleophiles). Therefore, the
reaction of N,N -dipivaloylpiperazine with bromine
leads to fast decomposition of the piperazine ring.
N,N -Diacetylpiperazine hydrogen tribromide com-
plex XVIII is a convenient reagent for acid-catalyzed
bromination of acidophobic compounds due to high
concentration of active bromine, stability on pro-
longed storage, safe handling, and low solubility
in most organic solvents. The reactions of complex
XVIII with acetyl-substituted furan and thiophene
derivatives XXVIII and XXIX smoothly afforded the
XVII, X = Br; XXIII, X = I.
Naturally, the available data are insufficient to
unambiguously choose between the molecular and
ionic structure of diacylpiperazine complexes with
halogens; the problem calls for a special investigation.
However, it is clear that dialkylamide complexes with
halogens do exist and that under certain conditions
they can be isolated as individual compounds. It is
also clear that the halogen atom coordinates at the
carbonyl oxygen atom and that just these complexes
are intermediates in the bromination of amide at the
acyl moiety. When the formation of complexes with
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 9 2001

1
216
BURAKOV et al.
corresponding bromoacetyl-substituted compounds
XXX and XXXI (Scheme 7).
and water, dried over calcium chloride, and distilled
over phosphoric anhydride. Carbon tetrachloride was
distilled over P O . Only freshly distilled solvents
2
5
Scheme 7.
were used. Acetyl chloride, benzoyl chloride, dioxane,
methanol, ethanol, and ethyl acetate were purified by
simple distillation. Dimethylformamide, dimethylacet-
amide, tetramethylurea, dimethylpivalamide, triethyl-
amine, piperidine, morpholine, and pivalic acid were
purified by distillation through a 20-cm Vigreaux
column. Hexamethylphosphoramide and N-methylpyr-
rolidinone were distilled under reduced pressure.
Tertiary benzamides, as well as cyclic amides, namely
N-acetylpiperidine, N-acetylmorpholine, N,N -diacetyl-
piperazine, N,N -dipropionylpiperazine, N,N -dipiva-
loylpiperazine, N,N -dibenzoylpiperazine, and N,N -
bis(dimethylcarbamoyl)piperazine (mp 130 132 C
[39]) were synthesized by acylation of the correspond-
ing amines according to standard procedures [40].
XXVIII, XXX, Ht = 4-methyl-2-furyl;
XXIX, XXXI, Ht = 2-thienyl.
The structure of bromoketones XXX and XXXI
1
13
was proved by the H and C NMR spectra and by
their transformation into aminothiazoles via reaction
with thiourea (Scheme 8).
Scheme 8.
Iodine bromide and iodine chloride were prepared
by known methods [41]. Molecular bromine of chem-
ically pure grade was distilled over P O . Initial
2
5
crystalline ligands were kept for 1 h under reduced
pressure (0.1 mm) near melting point prior to reaction
with bromine. Liquid organic nucleophiles were dis-
tilled just before use.
XXX, XXXII, Ht = 4-methyl-2-furyl;
XXXI, XXXIII, Ht = 2-thienyl.
The possibility for formation of a stable complex
was checked as follows. A flask was charged with
an amide, appropriate solvent was added (if neces-
sary), and bromine was added dropwise (1.1 equiv).
The product was separated and analyzed for bromine
and hydrogen bromide. The products were isolated
by the procedures given below (cf. Table 1): (a) the
solvent was removed under reduced pressure (water-
jet pump); (b) the solvent was partially distilled off,
and the precipitate was filtered off; (c) liquid adduct
was separated using a separatory funnel and was dried
under reduced pressure (water-jet pump); (d) the
precipitate was filtered off and dried under reduced
pressure; (e) the precipitate was filtered off but was
not dried; and (f) when the reaction was carried out
without a solvent, the reaction mixture was directly
analyzed by iodometric titration. Table 1 summarizes
the reaction conditions, product isolation procedure,
and also the concentrations of active bromine and
hydrogen bromide in the adduct.
EXPERIMENTAL
Spectrophotometric data were obtained using
Specord UV-Vis, Specord M40, and SF-26 spectro-
photometers. The IR spectra were measured on
1
a UR-20 spectrometer. The H NMR spectra were
recorded on Tesla BS-467 (60 MHz) and Varian
Gemini-200 (200 MHz) instruments; the C NMR
spectra were run on a Gemini-200 spectrometer at
0.3 MHz; tetramethylsilane or hexamethyldisiloxane
was used as internal reference.
The concentration of water in liquid amides was
monitored by GLC on an LKhM-8MD chromatograph
equipped with a thermal conductivity detector; carrier
gas helium, 3 2000-mm column packed with
Versamide 900 on Inerton N-AW (0.16 0.20 mm).
The bromination products were identified by HPLC
using a GPTs chromatograph equipped with an RIDK-
1
3
5
1
02 differential refractometer as detector; 3 150-mm
N,N -Diacetylpiperazine bromine complex
XVII). To a solution of 8.5 g (50 mmol) of anhy-
column packed with Separon C18; eluent methanol
water, 7:3. The concentrations of active halogen and
acids were determined by iodometric titration using
(
drous diacetylpiperazine in 50 ml of chloroform we
added dropwise 5.2 ml (100 mmol) of bromine.
Chloroform was partially distilled off (until a solid
precipitated) under reduced pressure (water-jet pump),
and the precipitate was filtered off. Yield 11.5 g
(70%). The product was a 1:1 complex. We failed
a 0.01 M solution of Na S O .
2
2
3
Acetonitrile was purified by the known procedure
27]. Chloroform was washed with concentrated sul-
[
furic acid, a saturated solution of sodium carbonate,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 9 2001

REACTION OF N,N-DIALKYLCARBOXAMIDES WITH HALOGENS
1217
to obtain a 2:1 complex of bromine with diacetyl-
piperazine, stable under standard conditions.
N,N -Diacetylpiperazine iodine complex (XXIII).
To a solution of 0.25 g (1.5 mmol) of diacetylpipera-
zine in 2 ml of methanol we added a solution of
Further transformations of the N,N -diacetyl-
piperazine bromine complex (XVII). A mixture of
11.5 g (34.9 mmol) of complex XVII with carbon
tetrachloride was stirred for 5 days. The precipitate
was filtered off, washed with chloroform, and dried.
Yield of complex XXII 7.6 g. Its physical properties,
elemental composition, and spectroscopic data coin-
cided with those of a product obtained from N,N -di-
acetylpiperazine, HBr, and bromine. The filtrate was
evaporated on a rotary evaporator to isolate 2.65 g of
N,N -bis(bromoacetyl)piperazine (XIX). It was washed
0
.37 g (1.5 mmol) of iodine in methanol. The solvent
was removed under reduced pressure (water-jet pump)
to obtain 0.43 g (69%) of complex XXIII as violet
crystals. Like the bromine complex, the product lost
halogen on heating and became colorless before
melting.
N,N -Diacetylpiperazine reacted with interhalogen
compounds to form 1:2 complexes. Our attempts to
obtain 1:1 complex by the above procedure gave
a mixture of the 1:2 complex and the initial amide,
which precipitated from the chloroform solution.
with water and recrystallized from benzene; colorless
1
prisms, mp 156 158 C. H NMR spectrum (CDCl ),
3
,
ppm: 3.3 4.0 m (8H, NCH CH ), 3.86 s (4H,
2 2
1
3
COCH Br). C NMR spectrum (CDCl3), C, ppm:
2
2
5.42, 41.88, 46.24. Found, %: C 28.25; H 3.51;
Br 49.81; N 8.21. C H Br N O . Calculated, %:
8
12
2
2
2
N,N -Diacetylpiperazine iodine chloride complex
XXVI). To a solution of 0.5 g (2.9 mmol) of N,N -di-
C 29.29; H 3.69; Br 48.72; N 8.54.
When the reaction of N,N -diacetylpiperazine with
bromine was carried out at a reactant ratio of 2:3 or
(
acetylpiperazine in 3 ml of chloroform we added
a solution of 0.942 g (5.8 mmol) of iodine chloride
in 4 ml of chloroform. A yellow solid precipitated
immediately and was filtered off and dried on a filter.
Yield 1 g (70%).
The complex of iodine bromide with N,N -diacetyl-
piperazine (XXVII) was synthesized in a similar way.
N,N -Dipropionylpiperazine complexes with
iodine chloride and iodine bromide XXIV and
XXV were synthesized in a similar way, but to isolate
the products it was necessary to remove the solvent
almost to dryness, for the complexes are much more
readily soluble in chloroform.
N,N -Diacetylpiperazine hydrogen tribromide
complex (XVIII). To a solution of 1 g (5.9 mmol)
of amide I in 5 ml of water we added a mixture of
1
:2, as well as on increasing the reaction time and
using chloroform as solvent, the yield of compound
XIX did not increase considerably, but the yield
of H-complex XXVIII slightly increased.
Reaction of N,N -diacetylpiperazine (XVI) with
bromine in the presence of water. To a solution of
5
.25 g (30.9 mmol) of amide XVI in 35 ml of water-
saturated chloroform we added 2.45 ml (46.3 mmol)
of bromine, and the mixture was kept for 2 days at
2
0 C. The first portion of product XVIII (6.58 g)
was filtered off and, after 3 days, the second portion
4.15 g) was separated. The filtrate was evaporated
(
on a rotary evaporator. The residue (0.45 g) was
a mixture of an oily material containing some crystals
1
of amide XVI. H NMR spectrum of the oily product
0
0
.83 ml of 41% hydrobromic acid (5.8 mmol) and
.3 ml (5.8 mmol) of bromine. The precipitate was
(
3
CDCl ), , ppm: 0.92 1.12 m, 1.86 s, 1.96 s, 1.98 s,
.20 3.55 m, 4.73 s, 5.95 s, 6.00 s.
3
filtered off, washed, and dried. We isolated 1.75 g
73%) of a yellow finely crystalline product with
Reaction of bromine with N,N -dipropionyl-
(
piperazine (XII). To a solution of 8.5 g (43 mmol)
of dipropionylpiperazine in 50 ml of chloroform we
added dropwise with stirring over a period of 30 min
mp 183 184 C, which was poorly soluble in most
moderately polar organic solvents.
N,N -Dipropionylpiperazine hydrogen tri-
bromide complex (XXII) was obtained in a similar
way.
3
ml (57 mmol) of bromine. The mixture was stirred
for 7 days at room temperature, and the precipitate
of complex XXII was filtered off and dried. Yield
The yields, properties, amd elemental analyses of
the newly synthesized complexes of N,N -diacetyl-
and N,N -dipropionylpiperazine with halogens, as well
as of the corresponding H-complexes, are given in
Table 2. The chemical shift of the bridging proton
12.8 g, yellow finely crystalline substance with
1
mp 168 170 C. H NMR spectrum (DMSO-d ), ,
6
3
ppm: 0.96 t (6H, COCH CH , J = 7.56 Hz), 2.30 q
(4H, COCH CH , J = 7.5 Hz), 3.27 3.61 m (8H,
2
3
3
2
3
NCH CH ), 10 br.s (1H, HBr). UV spectrum:
2
2
max
1
in the H NMR spectra of the complexes depends on
270 nm (absorption of Br ion). Concentration of
3
the concentration and solvent preparation procedure;
its signal is usually observed as a narrow singlet in
active bromine 35% (calculated 36.86%), HBr 18.50%
(calculated 18.44%). The filtrate was evaporated
on a rotary evaporator to obtain 0.8 g of an oily
the region
14.5 18.0 ppm.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 9 2001

1
218
BURAKOV et al.
Table 4. 1H and 13C NMR spectra of N,N -diacetylpiperazine (XVI) and its complexes XVII and XVIII
,
ppm
C, ppm
NCH2
Comp.
no.
CH CO
NCH2
CH CO
CH CO
3
3
3
XVI
XVII
XVIII
2.02
2.10
2.00
3.32 3.58 m
3.40 3.70 m
3.26 3.59 m
21.17
21.24
40.90
41.01
41.11
41.22
45.72
45.81
45.99
46.07
169.04
169.22
a
a
1
The H NMR spectrum of complex XVIII was recorded in DMSO-d6.
substance containing 1.40% of acid (HBr) and 5.48%
tion into 2-aminothiazoles according to Hantzsch (via
reaction with thiourea).
1
of active bromine. H NMR spectrum (CDCl ), ,
3
ppm: 1.16 t (J = 7.7 Hz), 1.82 d (J = 7.7 Hz), 2.44 q
2
-Amino-4-(2-thienyl)thiazole hydrobromide
(J = 7.7 Hz), 3.23 4.01 m, 4.52 q (J = 7.7 Hz).
monohydrate (XXXIII). To a solution of 0.8 g
(10.5 mmol) of thiourea in 10 ml of methanol we
added 1.7 g (8.3 mmol) of 2-bromoacetylthiophene.
After 24 h, methanol was distilled off from the mix-
ture, and the residue was recrystallized from 5 ml
of water. Yield 1.6 g (73%); bright yellow crystals,
mp 104 106 C. H NMR spectrum (DMSO-d ), ,
ppm: 7.07 s (1H, thiazole), 7.2 t (1H, 4-H, J = 3.7,
J(1) = 5.0 Hz), 7.6 d (1H, 5-H, J = 3.7, J = 1 Hz),
2-Bromoacetyl-5-methylfuran (XXX). To a solu-
tion of 5.3 g (42.7 mmol) of 2-acetyl-5-methylfuran
in 25 ml of methanol we added 18 g (43 mmol) of
compound XVIII, and the mixture was heated with
stirring to 40 C. The undissolved red orange precip-
itate of XVIII turned colorless, indicating that the
reaction came to completion. The mixture was diluted
with 25 ml of water and extracted with ether
1
6
3
(1)
3
3
4
(4 20 ml), and the extract was dried over anhydrous
3
4
7
.7 d (1H, 3-H, J = 5.06, J = 1 Hz). Found, %:
calcium chloride. The extract was evaporated on
a rotary evaporator to leave a dark oily residue which
crystallized on storage. Yield 7.2 g (83%). The prod-
uct contained no less than 87% of the main substance;
the major impurities were unchanged initial com-
pound XXVIII (6%) and, assumingly, 2-dibromo-
acetyl-5-methylfuran (7%). The product was distilled
under reduced pressure (71 73 C/0.1 mm; oil pump
with a trap cooled by liquid nitrogen) to obtain
a yellow viscous liquid which crystallized on storage
to afford light yellow crystals with mp 56 58 C.
C 29.87; H 3.24; Br 27.62; N 9.61; S 22.89.
C H BrN OS . Calculated, %: C 29.89; H 3.22;
Br 28.42; N 9.96; S 22.80.
7
9
2
2
2
-Amino-4-(4-methyl-2-furyl)thiazole hydro-
bromide monohydrate (XXXII) was synthesized in
a similar way. Light brown crystals (from water).
1
H NMR spectrum (DMSO-d ), , ppm: 2.34 s (3H,
6
3
CH ), 6.25 d (1H, 4-H, J = 1.5 Hz), 6.8 d (1H, 3-H,
3
3
J = 1.5 Hz), 6.9 s (1H, thiazole). Found, %: C 34.82;
H 3.44; Br 28.03; N 10.33; S 11.24. C H BrN O S.
8
11
2
2
1
Calculated, %: C 34.42; H 3.97; Br 28.60; N 10.03;
S 11.49.
H NMR spectrum (CDCl3), , ppm: 2.41 s (3H,
3
CH ), 4.26 s (2H, CH Br), 6.22 d (1H, 4-H, J =
3
3
2
3
13
.4 Hz), 7.50 d (1H, 3-H, J = 3.4 Hz). C NMR
spectrum (CDCl3), C, ppm: 13.80, 29.66, 109.44,
20.97, 148.74, 158.81, 179.21.
-Bromoacetylthiophene (XXXI) was synthesized
REFERENCES
1
1
2
.
.
Gur’yanova, E.N., Gol’dshtein, I.P., and Romm, N.P.,
Donorno-aktseptornaya svyaz’ (Donor Acceptor
Bond), Moscow: Khimiya, 1973.
2
in a similar way using acetic acid as solvent. Light
yellow liquid, yield 95%, bp 120 124 C (1 mm);
published data [42]: bp 95 98 C (1 mm). The product
crystallized on storage; yellow crystals, mp 33 35 C.
Drago, R.S., Wenz, D.A., and Carlson, R.L., J. Am.
Chem. Soc., 1962, vol. 84, no. 7, pp. 1106 1109.
1
H NMR spectrum (CDCl3), , ppm: 4.41 s (2H,
3. Drago, R.S., Carlson, R.L., Rose, N.J., and
Wenz, D.A., J. Am. Chem. Soc., 1961, vol. 83, no. 17,
pp. 3572 3575.
CH Br), 7.07 7.15 m (1H, 4-H), 7.70 d (1H, 5-H),
2
7
.78 d (1H, 3-H). Compound XXXI was not analyzed
for elemental composition because of its high volatil-
ity and strong lacrimatory properties.
4. Middaugh, R.L., Drago, R.S., and Niedzielskj, R.J.,
J. Am. Chem. Soc., 1964, vol. 86, no. 2, pp. 388 392.
The structure of compounds XXX and XXXI as
bromo ketones was confirmed by their transforma-
5. Carlson, R.L. and Drago, R.S., J. Am. Chem. Soc.,
-
1963, vol. 85, no. 5, pp. 505 508.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 9 2001

REACTION OF N,N-DIALKYLCARBOXAMIDES WITH HALOGENS
1219
6
7
8
.
.
.
Drago, R.S. and Wenz, D.A., J. Am. Chem. Soc.,
962, vol. 84, no. 4, pp. 526 528.
Tsubomura, H. and Lang, R.P., J. Am. Chem. Soc.,
961, vol. 83, no. 9, pp. 2085 2092.
25. Gubin, A.I., Buranbaev, M.Zh., Pugina, E.G., Kosty-
nyuk, V.P., and Il’in, A.I., Kristallografiya, 1990,
vol. 35, no. 1, pp. 218 219.
1
1
26. Poignant, S. and Gauvreau, J.R., Can. J. Chem.,
1
980, vol. 58, no. 9, pp. 946 952.
Drago, R.S., Bolles, T.F., and Niedzielskj, R.J.,
J. Am. Chem. Soc., 1966, vol. 88, no. 12, pp. 2717
27. Kanibolotskii, A.L., Mikhailov, V.A., and Savelo-
va, V.A., Zh. Org. Khim., 1993, vol. 29, no. 6,
pp. 1105 1110.
2
721.
9
.
Lang, R.P., J. Phys. Chem., 1968, vol. 72, no. 6,
2
2
3
3
8. Koppel’, I.A., Mel’der, U.Kh., and Pikver, R.I.,
Reakts. Sposobn. Org. Soedin., 1980, vol. 17, no. 4,
pp. 460 497.
pp. 2129 2135.
1
1
0. Niedzielskj, R.J., Drago, R.S., and Middaugh, R.L.,
J. Am. Chem. Soc., 1964, vol. 86, no. 2, pp. 388 392.
9. Bollinger, J.C., Houriet, R., Kern, C.W., Perret, D.,
1. Petrosyan, V.A., Sarkisyan, E.S., Gorbuleva, E.A.,
Abramyan, L.A., and Akopyan, G.V., Arm. Khim.
Zh., 1977, vol. 30, no. 6, p. 527.
Weber, J., and Yvernaut, T., J. Am. Chem. Soc.,
1
985, vol. 107, no. 19, pp. 5352 5358.
0. Le Questel, J., Laurence, C., Lachkar, A., and
Helbert, M., J. Chem. Soc., Perkin Trans. 2, 1992,
no. 12, pp. 2091 2094.
1
1
1
2. Akopyan, G.V., Petrosyan, V.A., Mirakyan, S.M.,
and Martirosyan, G.T., Arm. Khim. Zh., 1981,
vol. 34, no. 1, pp. 28 33.
1. Tsvetkov, V.G., Kupriyanov, V.F., Novoselova, N.V.,
amd Klimin, B.V., Zh. Obshch. Khim., 1977, vol. 47,
no. 4, pp. 729 731.
3. Petrosyan, V.A., Mirzakhanyan, S.G., Mkryan, G.G.,
Arustamyan, S.A., and Martirosyan, G.T., Arm.
Khim. Zh., 1989, vol. 42, no. 2, pp. 120 125.
3
3
3
3
2. Bagno, A., Lovato, G., and Scorrano, G., J. Chem.
Soc., Perkin Trans. 2, 1993, no. 6, pp. 1091 1098.
4. Petrosyan, V.A., Mirzakhanyan, S.G., Matevo-
syan, M.V., Botnyakova, A.I., and Grigoryan, E.A.,
Arm. Khim. Zh., 1989, vol. 42, no. 8, pp. 535 537.
3. Hassel, O. and Romming, C., Quart. Rev., 1962,
vol. 16, no. 1, pp. 1 18.
1
1
1
1
5. Kim, K., Pyu, E.K., and Seo, Y., Tetrahedron Lett.,
4. Stewart, W.E. and Siddall, T.H., Chem. Rev., 1970,
1
990, vol. 31, no. 35, pp. 5043 5044.
vol. 70, no. 5, pp. 517 560.
6. Al Neirabeyeh, M. and Pujol, M.D., Tetrahedron
Lett., 1990, vol. 31, no. 16, pp. 2273 2276.
5. Tarakanova, E.G., Yukhnevich, G.V., and Viga-
sin, A.A., Khim. Fiz., 1992, vol. 11, no. 5, pp. 608
6
7. Rao, A.K.S.B., Gundu Rao, C., and Singh, B.B.,
26.
6. Popov, A.I. and Swensen, R.F., J. Am. Chem. Soc.,
955, vol. 77, no. 14, pp. 3724 3726.
J. Org. Chem., 1992, vol. 57, no. 11, pp. 3240 3242.
3
3
8. Yaroslavsky, C., Bracha, P., and Classer, P.,
1
J. Heterocycl. Chem., 1989, vol. 26, no. 6, pp. 1649
7. Blair, L.K., Parris, K.D., Hii, P.S., and Brock, C.P.,
1
654.
J. Am. Chem. Soc., 1983, vol. 105, no. 11, pp. 3649
1
9. O’Daly, M.A., Hopkinson, C.P., Meakins, G.D., and
3
653.
Raybould, A.J., J. Chem. Soc., Perkin Trans. 1,
3
8. Popov, A.I., Marshall, J.C., Stute, F.B., and
Person, W.B., J. Am. Chem. Soc., 1961, vol. 83,
no. 20, pp. 3586 3590.
1
991, no. 4, pp. 855 860.
0. Matsui, Y. and Date, Y., Bull. Chem. Soc. Jpn.,
970, vol. 43, no. 9, pp. 2828 2835.
2
2
2
1
3
4
9. Beilsteins Handbuch der organischen Chemie, H,
1. Mikhailov, V.A., Ukr. Khim. Zh., 1990, vol. 56,
vol. 23, p. 12.
no. 7, pp. 765 766.
0. Weygand Hilgetag Organisch-chemische Experimen-
tierkunst, Leipzig: Barth, 1964, 3rd ed. Translated
under the title Metody eksperimenta v organicheskoi
khimii, Moscow: Khimiya, 1968, pp. 445 458.
2. Gubin, A.I., Il’in, A.I., Pugina, E.G., Kosty-
nyuk, V.P., and Buranbaev, M.Zh., Kristallografiya,
1
990, vol. 35, no. 2, pp. 501 503.
2
2
3. Gubin, A.I., Buranbaev, M.Zh., Kostynyuk, V.P.,
Kopot’, O.I., and Il’in, A.I., Kristallografiya, 1988,
vol. 33, no. 6, pp. 1393 1395.
41. Brauer, G., Handbuch der Praparativen anorgani-
schen Chemie, Stuttgart: Enke, 1981. Translated
under the title Rukovodstvo po neorganicheskomu
sintezu, Moscow: Mir, 1985, pp. 339 341.
4. Mikhailov, V.A., Yufit, D.S., and Struchkov, Yu.T.,
Zh. Obshch. Khim., 1992, vol. 62, no. 2, pp. 399
42. Kipnis, F., Soloway, H., and Ornfelt, J., J. Am.
Chem. Soc., 1949, vol. 71, no. 1, pp. 10 11.
4
05.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 9 2001