C-N bond formation followed by N-Cl bond breaking. One more and unexpected case of the formation of a hydroxamic group via heterolytic bond cleavage

Article abstract of DOI:10.1016/j.tetlet.2003.11.069

An unexpected and previously unknown reaction sequence in the interactions of the acyl halides with nitrosobenzenes, which involves carbon-nitrogen bond formation followed by heterolytic nitrogen-chlorine bond cleavage giving the corresponding unsubstituted N-phenylalkylhydroxamic acids (or N-phenylarylhydroxamic acids) and chlorine as the products has been observed. The kinetic and other evidence obtained suggest that the carbon-nitrogen bond formation is the consequence of a nucleophilic interaction of an N-phenylchlorohydroxylamine intermediate, formed in the first reaction step, with the acyl halide in the second step of the complex sequence, which leads to an N-acyl-N-chlorophenylhydroxylamine cation intermediate. The key reaction step involves the interaction of an N-acyl-N-chlorophenylhydroxylamine cation intermediate with chloride ion, which leads to the N-Cl heterolytic bond cleavage and the final formation of the hydroxamic group and a molecule of chlorine.

Full text of DOI:10.1016/j.tetlet.2003.11.069

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 699–702
C–N bond formation followed by N–Cl bond breaking.
One more and unexpected case of the formation of a
hydroxamic group via heterolytic bond cleavage
Ivana Vinkovi ꢀc Vr ꢁc ek, Viktor Pilepi ꢀc and Stanko Ur ꢁs i ꢀc *
Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kova ꢁc i ꢀc a 1., 10000 Zagreb, Croatia
Received 30 September 2003; revised 6 November 2003; accepted 14 November 2003
Abstract—An unexpected and previously unknown reaction sequence in the interactions of the acyl halides with nitrosobenzenes,
which involves carbon–nitrogen bond formation followed by heterolytic nitrogen–chlorine bond cleavage giving the corresponding
unsubstituted N-phenylalkylhydroxamic acids (or N-phenylarylhydroxamic acids) and chlorine as the products has been observed.
The kinetic and other evidence obtained suggest that the carbon–nitrogen bond formation is the consequence of a nucleophilic
interaction of an N-phenylchlorohydroxylamine intermediate, formed in the first reaction step, with the acyl halide in the second
step of the complex sequence, which leads to an N-acyl-N-chlorophenylhydroxylamine cation intermediate. The key reaction step
involves the interaction of an N-acyl-N-chlorophenylhydroxylamine cation intermediate with chloride ion, which leads to the N–Cl
heterolytic bond cleavage and the final formation of the hydroxamic group and a molecule of chlorine.
ꢀ
2003 Elsevier Ltd. All rights reserved.
Many important processes in organic chemistry and
biochemistry involve C–N bond formation as the fun-
acids belong to a class of compounds of great bio-
medicinal and industrial significance.
10;11
1
;2
damental reaction step.
Interactions of nitrogen
nucleophiles with a carbonyl group involving carbon–
nitrogen bond formation probably take the position of
central significance among these processes. The inter-
actions of the C-nitroso group with the carbonyl group
of some aldehydes and a-oxo acids present a rather
special case among the processes involving the interac-
tions of nitrogen nucleophiles and carbonyl groups and
We report here the observation of an unprecedented
case of the formation of a hydroxamic group resulting
from an unexpected and previously unknown reaction
sequence in the interactions of the acyl halides with
nitrosobenzenes, which involves carbon–nitrogen bond
formation followed by heterolytic nitrogen–chlorine
bond cleavage. The final products in the complex reac-
tion are the corresponding unsubstituted N-phenylalkyl
and N-phenylarylhydroxamic acids and chlorine
(Scheme 1). The final formation of the hydroxamic
group at the expense of the oxidation of chlorine in a
3–9
we have been interested in this field for some time.
The reactions are complex, and ordinarily the first step
involves carbon–nitrogen bond formation while the final
products are the corresponding hydroxamic acids. The
O
O
R
OH
O
R
OH
.
. OH
O
HO
Cl
O
+
-
Cl
+
N
N
N
Cl
N
Cl
R
N
R
Cl
-
Cl
+
-
+
H Cl
+
Cl2
1
2
3
4
5
Scheme 1.
Keywords: C-Nitroso group; Acyl chlorides; Hydroxamates; N–Cl bond; Kinetics; Mechanism.
*
Corresponding author. Tel.: +385-1-481-8306; fax: +385-1-485-6201; e-mail: stu@pharma.hr
0
040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.069

700
I. Vinkovi ꢀc Vr ꢁc ek et al. / Tetrahedron Letters 45 (2004) 699–702
reaction has never previously been observed. The above-
mentioned formation of hydroxamic acids via the
nucleophilic interaction of a C-nitroso group with the
5
4
3
2
1
0
100
80
4–6
3;4;6
carbonyl group of aldehydes
involves heterolytic C–H or C–C bond cleavage (proton
and a-oxo acids
5;7
3;4;6
transfer from the carbon or decarboxylation ) at the
carbonyl group to give the electron pair needed for the
final formation of the hydroxamic group. Such a het-
erolytic bond cleavage however cannot be expected in
the case of acyl chlorides.
60
k
40
12
However, in the recently reported interaction of acyl
chlorides with nitrosobenzene, the electron pair needed
in that key step for the final formation of the hydroxa-
mic group arises by proton transfer from the para-
position of the phenyl moiety interconnected with the
addition of the chloride ion at the same carbon, which
leads to the completion of the incipient hydroxamic
group. As a consequence, the only products in the
reaction are the corresponding substituted N-p-chloro-
phenylalkyl or N-p-chlorophenylaryl hydroxamic acids.
In contrast, the products in the interaction reported here
are the corresponding unsubstituted N-p-phenylalkyl or
N-p-phenylarylhydroxamic acids. We have observed the
following:
20
0
0.3
0
0.1
0.2
-3
[C H NO] /mol dm
6
5
Figure 1. Dependence of the observed rate constants for the formation
of unsubstituted N-phenylacetohydroxamic acid on the concentration
of nitrosobenzene in excess (solid circles) along with the yield obtained of
the unsubstituted acid (solid triangles, right-hand vertical axis) at
ꢁ
3
ꢁ3
2
5 ꢁC. Acetyl chloride and HCl were 5 · 10
and 1.67 · 10 M,
respectively, throughout. Pseudo-first-order rate constants were
determined using an HPLC system (Spectra Physics) and are the
average of several runs. Good first-order kinetics were obtained for 3–5
half lives. The appropriate aliquots of the reaction mixture were
(
1) Unsubstituted N-phenylalkyl and N-phenyl-
arylhydroxamic acids (5 in Scheme 1) and chlorine
bromine in the case of acyl bromides) were the products
of the interactions of the acyl halides and nitrosobenz-
(
diluted with mobile phase buffer (NH
4
HCOO buffer pH 3.5:methanol,
4
0:60, 60:40, or 70:30) to ensure the reaction was stopped and then
;
à
ene in pure acetonitrile providing that the nitroso
compound was present in a large excess over HCl in the
purified by chromatography on a Restek UltraIBD HPLC column and
detected by the monitoring of absorbance at 254 nm. The amounts of
the product hydroxamic acids were determined using the standard
samples of the corresponding acid and p-nitrotoluene or m-nitrotolu-
ene as the internal standards. Ordinarily, the overall yield of both
unsubstituted and the corresponding substituted acid were as high as
§
reaction mixture. Thus, for example, at the ratio
[
PhNO]/[HCl] of ꢀ180, and [PhNO] ¼ 0.3 M, the yield of
unsubstituted N-phenylalkylhydroxamic acids was 98%,
while only 1% of the corresponding p-chloro substituted
acid was formed, as evidenced by HPLC (see also Fig.
9
5% or more.
1
).
addition, the presence of an electron-withdrawing group
on the nitrogen of the N-acyl-N-chlorophenylhydroxyl-
amine cationic intermediate possibly enhances the
charge separation between the nitrogen and chlorine of
that N–Cl bond.
(2) The formation of chlorine in the reaction was sub-
stantiated both qualitatively and quantitatively using
ꢁ
–
the fast redox reaction with I in chloroform. The
known phenomenon of some positive charge on the
13;14
chlorine in an N–Cl bond
may be significant here. In
(3) The observed pseudo-first-order rate constants for
the formation of N-phenylacetohydroxamic acid depend
linearly on the concentration of nitrosobenzene in excess
(Fig. 1). The corresponding linear dependence on the
Acetonitrile (99.9%, HPLC grade) and an acetonitrile solution of dry
HCl were used in all the experiments.
à
For example,
interaction of 0.1 M of nitrosobenzene with 0.005 M HCl and
.01 M of acetyl chloride in acetonitrile for 1 h gave, after working-
up with aqueous NaHCO , extraction with dichloromethane, drying,
and purification (TLC or HPLC) N-phenylacetohydroxamic acid (as
a simple preparative procedure, which includes
HCl concentration in the reaction was obtained (Figs. 2
and 3 inset). Under the conditions employed, the rate
dependencies obtained for the formation of unsubsti-
tuted N-phenylacetohydroxamic acid should be consis-
tent with the rate law: kobs ¼ k [PhNO][HCl]. At constant
concentration of the nitroso compound in excess, the
fraction of the unsubstituted N-phenylacetohydroxamic
acid versus corresponding substituted N-p-chloro-
phenylacetohydroxamic acid increases as the observed
rate constant for the formation of the unsubstituted acid
increases (see Fig. 2). This finding is consistent with the
existence of two concurrent processes.
0
3
1
13
substantiated by H, see, for example, Ref. 15, and C NMR
spectroscopy) in 92% yield.
The only products we observed under the conditions applied in the
§
12
previous kinetic investigation of the interaction, where the range of
concentration of nitrosobenzene applied was necessarily determined
by the magnitude of molar absorbance of nitrosobenzenes and the
limitations of available spectroscopic method, were the correspond-
ing N-p-chlorophenylalkylhydroxamic acids.
–
ꢁ
The molar absorbance coefficient of the I complex in chloroform is
4
3
2.72 · 10 at 364 nm. As the source of iodide ions, tetraethylammo-
nium iodide was used. At the ratio of iodide/chlorine of 250 used in
the procedure, the oxidation of the iodide is almost instantaneous.
(4) A kinetic deuterium isotope effect kobs(HCl)/
k
obs(DCl) of 0.81 (0.02) for the formation of the

I. Vinkovi ꢀc Vr ꢁc ek et al. / Tetrahedron Letters 45 (2004) 699–702
100
701
2
1
1
0
5
0
8
6
4
2
0
1
0
5
0
8
6
0
0
k
0
0.5
1
1.5
/mol dm-3
2
3
2
0
0
3
1
0 [HCl]
calc
k
k
40
k
5
0
10
0
2
0
0
0.01
0.02
0.03
[
HCl] / mol dm-3
0
0
0.001
0.002
0.003
0.004
0
0.01
0.02
3
0.03
[
HCl]calc /mol dm-3
[
CH COCl] /mol dm-
3
Figure 2. Dependence of the observed rate constants for the formation
of unsubstituted N-phenylacetohydroxamic acid on the effective con-
centration of HCl (solid circles) along with the obtained yield of the
unsubstituted acid (solid triangles, right-hand vertical axis). At 25 ꢁC.
The effective concentrations of HCl were calculated from the corre-
Figure 3. Change of the observed rate constants for the formation of
unsubstituted N-phenylacetohydroxamic acid on the increase in the
concentration of acetyl chloride in excess with regard to the HCl
concentration. Concentrations of nitrosobenzene and HCl were 0.200
and 0.0033 M, respectively, throughout. Inset: the corresponding
dependence of the same observed rate constants on the calculated
effective concentration of HCl (see text). Note that the order of
appearance of the rate constants is now reversed to show no depen-
dence on the acetyl chloride concentration.
ꢁ1
sponding total concentrations using the value of 450 M for the
association constant between HCl and acetyl chloride in 99.9% ace-
tonitrile (see text). Concentrations of nitrosobenzene and acetyl chlo-
ride were 0.200 and 0.010 M, respectively, throughout. Rate constants
were determined as described above (see Fig. 1). Inset: Dependence of
the observed rate constants for the formation of unsubstituted
N-phenylacetohydroxamic acid on the concentration of HCl in excess
over acetyl chloride. Concentrations of nitrosobenzene and acetyl
chloride were 0.050 and 0.003 M, respectively, throughout.
3–9;17
phile,
nitrosobenzene does not react with acyl
halides in the absence of HCl (or HBr), which suggests
that the other nucleophile should be involved in the
C–N bond formation. However, the excess of halide
over HCl causes a reduction of the apparent rate con-
stant (Fig. 3). Probably, the apparent decrease is caused
unsubstituted N-phenylacetohydroxamic acid in the
complex reaction was observed. This result suggests the
involvement of a proton transfer in the process and
could support the formation of an N-chloro-
**
by the formation of an association between the acyl
halide and HCl, which in turn decreases the effective
concentration of the acid. Starting from this assump-
tion, an estimate based on the kinetic results (see Fig. 3)
12
phenylhydroxylamine intermediate 2 from the acyl
halide and the nitroso compound, assuming that the
well known difference in the affinities of a weakly basic
ꢁ1
gave, for the association constant, a value of 450 M .
16
substrate toward the proton and its isotope existed in
This value is in quite a good agreement with one
obtained by comparison of the slopes of linear plots of
Figures 1 and 3.
||
this case. The linear dependencies (Figs. 1 and 2) of the
observed rate constants on the concentrations of nitroso
compound and HCl could also be used in support of the
proposed formation of the intermediate 2 in the process.
3
(6) Substituted nitrosobenzenes (p-CH , p-Br, p-Cl,
m-Cl) enter the reaction giving the corresponding
substituted N-phenylhydroxamic acids. Thus, p-methyl-
nitrosobenzene gave p-methylphenylacetohydroxamic
acid in 91% yield. This observation is fully consistent
with the proposed mechanism (Scheme 1) since the
(
5) Taking into account the results summarized by
Figures 1–3 it seems reasonable to assert that under the
conditions employed, the rate constants for the forma-
tion of the unsubstituted N-phenylacetohydroxamic acid
in the reaction do not depend on the concentration of
acetyl chloride. The finding would be consistent with a
fast nucleophilic interaction of the intermediate 2 with
the acyl halide or possibly with protonated acyl halide.
Although the C-nitroso group could act as a nucleo-
12
earlier described concurrent process of substitution by
halide ion in the para-position and the formation of
corresponding p-chlorophenylacetohydroxamic acid
was not possible in this case.
||
Assuming an unfavorable equilibrium for the formation of
N-chlorophenylhydroxylamine intermediate (which would be in line
with our spectroscopic evidence since no change in the spectra of the
nitroso compound on the addition of HCl in acetonitrile was
observed) the linear dependence of the observed rate constants on the
concentration of nitroso compound in excess would be expected.
**
At present, it is difficult to give any precise account about the nature
of the association between acetyl chloride and HCl in dry aceto-
nitrile. We note however that in a separate investigation we have
observed that formaldehyde and HCl in dry acetonitrile associate
4
ꢁ1
with a constant of the order of 10 M
.

702
I. Vinkovi ꢀc Vr ꢁc ek et al. / Tetrahedron Letters 45 (2004) 699–702
(
7) Substituted N-p-chlorophenylalkylhydroxamic acids
alkylhydroxamic acids follows a completely different
reaction pathway subsequently.
or N-p-bromophenylalkylhydroxamic acids were formed
in the interaction of the corresponding unsubstituted
acids and chlorine or bromine in acetonitrile, The
finding is in support of the mechanism proposed in
Scheme 1. The reaction should involve the reverse of the
key reaction step of the process of formation of the cor-
responding unsubstituted hydroxamic acids, that is, the
N–Cl heterolytic bond breaking followed by the forma-
tion of chlorine and unsubstituted hydroxamic acid.
Acknowledgements
We thank Prof. S. Rendi ꢀc for kindly allowing us to use
the Spectra Physics HPLC facility and the Ministry of
Science and Technology of the Republic of Croatia for
financial support (project 006-431).
The picture that emerges from the evidence (Scheme 1) is
a complex process, which starts with an initial addition
giving chlorophenylhydroxylamine 2. The intermediate
reacts further in a relatively fast step with the acyl halide
giving the corresponding N-acyl-N-chlorophenylhydr-
oxylamine cation intermediate 3. This intermediate
undergoes heterolytic N–Cl bond cleavage mediated by
References and notes
1
. Smith, M. B.; March, J. MarchÕs Advanced Organic
Chemistry, 5th ed.; Wiley-Interscience, New York, NY,
2001; Chapter 16.
2. Berg, J. M.; Stryer, L.; Tymoczko, J. L. Biochemistry, 5th
ed.; W. H. Freeman, New York, NY, 2002; Chapter 3.
3. Ur
ꢁs i ꢀc , S.; Vr ꢁc ek, V.; Gabri ꢁc evi ꢀc , M.; Zorc, B. J. Chem.
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J. Chem. Soc., Perkin Trans. 2 1993, 509–514.
þ
ꢁ
àà
chloride ion (from the H Cl ion pair or possibly the
ꢁ
Cl ion resulting from the nucleophilic interaction of
4
acyl chloride with the chlorophenylhydroxylamine),
which leads to the formation of the unsubstituted
hydroxamic acid and chlorine as the products. This
process is much faster than the concurrent process of the
formation of the hydroxamic group via the substitution
of chloride ion at the para-position of the phenyl moiety
interconnected with the proton transfer from the same
position. Therefore, at the high ratios of [nitroso com-
5
6
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7
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J. Chem. Soc., Perkin Trans. 2 1999, 1295–1297.
8. Lovrek, M.; Pilepi ꢀc , V.; Ur ꢁs i ꢀc , S. Croat. Chem. Acta 2000,
73, 715–731.
þ
ꢁ
9. Pilepi
c, V.; Ur ꢁs i ꢀc , S. J. Mol. Struct. (THEOCHEM) 2001,
ꢀ
pound]/[H Cl ] almost all the HCl is consumed in the
formation of the unsubstituted N-phenylalkylhydroxa-
538, 43–49.
0. Dooley, C. M.; Devocelle, M.; McLoughlin, B.; Nolan,
K. B.; Fitzgerald, D. J.; Sharkey, C. T. Mol. Pharmacol.
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1. Parkin, E. T.; Trew, A.; Christie, G.; Faller, A.; Mayer,
1
1
1
2
mic (or N-phenylarylhydroxamic) acids and Cl and the
lack of HCl prevents (except to the small extent) the
slower concurrent reaction of the formation of ring-
chlorinated hydroxamic acid. When excess of HCl is
present this concurrent process becomes important. The
experiment in which ring-chlorinated hydroxamic acid
was obtained from unchlorinated hydroxamic acid and
R.; Turner, A. J.; Hooper, N. M. Biochemistry 2002, 41,
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4
2. Pilepic, V.; Lovrek, M.; Vikic-Topic, D.; Ursic, S. Tetra-
ꢀ
hedron Lett. 2001, 42, 8519–8522.
ꢀ
ꢀ
ꢁ ꢀ
Cl
3
2
(see above) suggests that the reaction sequence
fi 4 fi 5 (Scheme 1) should be reversible. If this is the
13. Matte, D.; Solastiouk, A.; Merlin, X. D. Can. J. Chem.
1989, 67, 786–793.
1
1
1
4. Poleshchuk, K.; Makiej, M.; Ostafin, B. N. Magn. Reson.
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5. Sakamoto, Y.; Yoshioka, T.; Uematsu, T. J. Org. Chem.
case, the key intermediate 3 arises also from the reverse
of 3 fi 4 fi 5 path, which in presence of HCl also con-
tributes the ring-chlorination process at the para-posi-
tion. Following the evidence obtained it seems
reasonable to conclude that the intermediates involved
in the first and second steps should be the same as those
proposed to be involved in the previously investigated
1
989, 54, 4449–4453.
6. See for example in: Isaacs, N. S. Physical Organic
Chemistry. 2nd ed. Longmann, Harlow, UK, 1995; p 389.
7. Zuman, P.; Shah, B. Chem. Rev. 1994, 94, 1621–1641.
8. See in: Izutsu, K. Acid–Base Dissociation Constants in
Dipolar Aprotic Solvents; Blackwell Scientific Publications:
Oxford, 1990.
1
1
12
formation of N-p-chlorophenylalkylhydroxamic acids
while the formation of the unsubstituted N-phenyl-
For example, performing the reaction for 40 min at 25 ꢁC in a
solution containing 0.01 M Cl and 0.001 M N-phenylacetohydrox-
2
amic acid in acetonitrile, HPLC analysis showed that a 4:6 mixture
of N-p-chlorophenylacetohydroxamic acid and the starting unsub-
stituted N-phenylacetohydroxamic acid were obtained. In a control
2
experiment, no change in the spectra of 0.01 M Cl and 0.0001 M
nitrosobenzene was observed for a period of at least three half lives
of the corresponding reaction of nitroso compound with acetyl
chloride and HCl. Also, the HPLC evidence with regard to the
standard reaction conditions do not show appearance of any other
products than hydroxamic acids.
àà
18
HCl is considered to be an ionic pair in 99.9% acetonitrile.