An unusual case of carbon-nitrogen bond formation. Reactivity of a C-nitroso group toward acyl chlorides

Article abstract of DOI:10.1016/S0040-4039(01)01812-3

Acyl chlorides react with nitrosobenzene in 99.9% acetonitrile and in the presence of catalytic amounts of HCl giving the corresponding N-p-chlorophenylhydroxamic acids. The spectroscopic and kinetic evidence obtained indicates that the reaction is initia

Full text of DOI:10.1016/S0040-4039(01)01812-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8519–8522
An unusual case of carbonꢀnitrogen bond formation. Reactivity
of a C-nitroso group toward acyl chlorides
Viktor Pilepic´,a Monika Lovrek,a Drazˇen Vikic´-Topic´b and Stanko Ursˇic´a,*
aFaculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovacˇic´a 1, 10000 Zagreb, Croatia
bRugjer Bosˇkovic´ Institute, NMR Center, PO Box 180, 10002 Zagreb, Croatia
Received 3 August 2001; accepted 21 September 2001
Abstract—Acyl chlorides react with nitrosobenzene in 99.9% acetonitrile and in the presence of catalytic amounts of HCl giving
the corresponding N-p-chlorophenylhydroxamic acids. The spectroscopic and kinetic evidence obtained indicates that the reaction
is initiated by the formation of an N-chlorohydroxylamine intermediate from nitrosobenzene and hydrochloride in the first, slow
step of the process. The nucleophilic N-chlorohydroxylamine intermediate reacts with acyl chloride (or possibly an acyl
cation–chloride ion pair) to give the addition acylnitroso intermediate which undergoes to nucleophilic attack by chloride ion at
the para position of the phenyl moiety and, after proton transfer from carbon, the corresponding N-p-chlorophenylhydroxamic
acid is formed. © 2001 Elsevier Science Ltd. All rights reserved.
Formation of a carbonꢀnitrogen bond is among the
most important fundamental processes in organic
chemistry and biochemistry. For example, many impor-
tant chemical and biochemical processes are initiated by
the addition of a nitrogen nucleophile to a carbonyl
group.1,2 Recently, we have investigated a more special
case of the nucleophilic interaction of a C-nitroso
group with the carbonyl group of some aldehydes and
a-oxo acids.3–9 The interactions involve the formation
of a CꢀN bond, while the reaction products are hydrox-
amic acids. The acids are of considerable importance
due to their numerous industrial and pharmaceutical
applications.10–14
CꢀN bond formation, where the corresponding N-p-
chlorophenylhydroxamic acids are the products of the
reaction (Scheme 1). This previously unknown reac-
tion seems to be quite unexpected. Namely, the above
mentioned formation of hydroxamic acids via the
nucleophilic interaction of the C-nitroso group with
the carbonyl group of aldehydes4–6 and a-oxo
acids3,4,6 involves heterolytic CꢀH or CꢀC bond cleav-
age (proton transfer from the carbon5,7 or
decarboxylation3,4,6) at the carbonyl group to give the
electron pair needed for the final formation of the
hydroxamic group. The possibility of such a heterolytic
bond cleavage, however, does not exist in the case of
acyl chlorides.
We report here the surprising observation that acyl
chlorides can interact with nitrosobenzene leading to
Our observations are as follows:
Scheme 1.
Keywords: C-nitroso group; acyl chlorides; hydroxamates; kinetics; mechanism.
* Corresponding author. Tel.: +385-1-481-8306; fax: +385-1-485-6201; e-mail: stu@nana.pharma.hr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01812-3

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V. Pilepic´ et al. / Tetrahedron Letters 42 (2001) 8519–8522
1. Acyl chlorides react with nitrosobenzene in 99.9%
acetonitrile and in the presence of catalytic amounts
of HCl giving the corresponding N-p-chlorophenyl-
hydroxamic acids (Scheme 1). Under the conditions
employed in the kinetic investigation the reaction
goes to completion, as shown spectroscopically (Fig.
1). The evidence is corroborated by the product
analysis.† The spectroscopic evidence does not sug-
gest the accumulation of any intermediate in the
reaction. In the absence of HCl, the reaction is
negligibly slow.‡
2. The observed kinetics for the hydroxamic acid for-
mation were of the first order with respect to the
Figure 2. The dependence of the kobs versus acetyl chloride
concentration for the reaction of acetyl chloride with nitro-
sobenzene in 99.9% acetonitrile at 25.0°C. ꢀ: at 0.031 mol
dm−3 of HCl. ꢁ: at 0.150 mol dm−3 of HCl. Nitrosobenzene:
10−4 mol dm−3 (see also Fig. 3 for the remaining details).
Figure 1. Change in the UV spectrum of the reaction mixture
containing 0.007 mol dm−3 CH3COCl, 10−4 mol dm−3
C6H5NO and 0.03 mol dm−3 HCl in 99.9% acetonitrile, at
25.0°C. Scans (from A downward): 0, 5, 10, 15, 20, 25, 30, 35,
40, 45 and 160 min. The spectra of acetyl chloride were
subtracted for clarity.
† All the quoted hydroxamic acids were isolated and characterised
using CHN analysis, NMR, IR and UV–vis spectroscopy. The
evidence obtained was in accordance with published data (see Ref.
4). Thus, for example, for N-p-chlorophenylcyclopropylhydroxamic
acid we obtained: mp 114–117°C; elemental analysis calcd for
C
10H10ClNO2: C, 56.75; H, 4.76; N, 6.62; R, 31.87; found: C, 57.76;
Figure 3. The dependence of the kobs/[HCl] versus HCl con-
centration for the reaction of acetyl chloride with nitrosoben-
zene in 99.9% acetonitrile at 25.0°C. The observed rate
constants were determined spectrophotometrically by follow-
ing the disappearance of the absorbance of nitrosobenzene at
305 nm (or by following the increase in the absorbance at 256
nm) using a HP 8452 or HP 8453 UV–vis spectrophotometer.
Very good first-order kinetics within at least three half-lives of
H, 4.90; N, 6.68; R, 30.66%; 1H NMR (DMSO, 300 MHz): l 0.87
(4H, d, J=8 Hz), 2.50 (1H, s), 7.41 (2H, d, J=9), 7.66 (2H, d,
J=9), 10.84 (1H, s); 13C NMR (DMSO, 300 MHz): l 172.8, 140.9,
128.4, 128.3, 121.9, 11.3, 8.4; IR (KBr, cm−1): 3100.6, 2893.9,
1617.9, 1487.2, 1430.4, 1338.1, 1315.6, 1292.6, 1095.5, 1068.2, 936.6,
828.2, 752.8, 481.3; For N-p-chlorophenylacetohydroxamic acid we
obtained: mp 72–73°C; elemental analysis calcd for C8H8ClNO2: C,
51.77; H, 4.34; N, 7.55; R, 36.34; found: C, 51.63; H, 4.42; N, 7.68;
R, 36.27%; 1H NMR (DMSO, 300 MHz): l 2.20 (3H, s), 7.39 (2H,
d, J=9), 7.66 (2H, d, J=9), 10.69 (1H, s); 13C NMR (DMSO, 300
MHz): l 170.3, 140.6, 131.7, 128.4, 121.4, 23.4; IR (KBr, cm−1):
3135.9, 2894.4, 1623.6, 1485.9, 1381.4, 1095.8, 1013.6, 829.1, 741.3,
497.7; UV–vis (MeCN): umax=256 nm, m256 nm=9984 mol−1 dm3
the reaction were obtained. CH3COCl: 0.007 mol dm−3
;
C6H5NO: 10−4 mol dm−3; and 0.03 mol dm−3. In order to
avoid the use of aqueous HCl, a solution of dry gaseous HCl
in 99.9% acetonitrile was used throughout. Inset: The depen-
dence of the the kobs versus HCl concentration for the reac-
tion of acetyl chloride with nitrosobenzene in 99.9%
acetonitrile at 25.0°C. The reaction conditions were the same
as described above.
cm−1
.
‡ Traces of water (0.03%) were present in acetonitrile which could
lead to the very small amounts of HCl due to slow hydrolysis of
acetyl chloride.

V. Pilepic´ et al. / Tetrahedron Letters 42 (2001) 8519–8522
8521
nitroso compound but did not depend on the con-
centration of the acyl chloride (Fig. 2) (in the exper-
iments, acyl chloride was always in great excess over
the nitrosobenzene concentration). The result is the
same regardless of the starting HCl concentration
(see Fig. 2) and is consistent with the relatively fast
interaction of acetyl chloride or acetyl cation–chlo-
ride ion pair with a nucleophilic intermediate (see
below) arising from nitrosobenzene and HCl in the
preceding slow step of the reaction.
the nitrosobenzene concentration) for the acyl chlo-
ride. Hydrolysis of acyl chloride was the only reac-
tion observed when the water content in the reaction
mixture exceeded a few percent, obviously because
the formation of the intermediate arising from nitro-
sobenzene is much slower than the reaction of acetyl
chloride with water. Therefore, it seems reasonable
to conclude that a species much more nucleophilic
than nitrosobenzene should be involved in the pro-
cess of formation of hydroxamic acid.
3. The dependence of the observed pseudo first-order
rate constants on hydrochloride concentration (Fig.
3) is complex and is consistent with the rate law
(Ph=phenyl):
Rate=k1[HCl][PhNO]+k2[HCl]2[PhNO]
(1)
4. The values of the parameters k1 and k2 are 0.0167
s−1 mol−1 dm3 and 0.140 s−1 mol−2 dm6, respectively.
The observed linear term of Eq. (1) requires that the
interaction of nitrosobenzene with a single H+Cl−
ion pair§ can lead to the reactive intermediate which
we describe as N-chlorohydroxylamine (2). There
are a large number of addition reactions of the
C-nitroso group where the nitroso group acts as an
electrophile and the addition of anionic nucleophiles
to the nitroso group to give transient intermediates
is not unknown.15 In addition, chloride is in a polar,
aprotic solvent such as acetonitrile is strongly desol-
vated which makes it more basic¶ and more capable
of addition to a nitroso group. The same intermedi-
ate can, of course, arise from the interaction of two
hydrochloride ion pairs with the nitroso group
which corresponds to the quadratic term of Eq. (1).
This term could also be consistent with the forma-
tion of an alternative, 4-chlorohexadienone oxime
intermediate 2a.
5. An inverse isotope effect kH/kD of 0.80 (0.19)
between DCl and HCl in the reaction was observed.
The effect is relatively small in comparison to the
ordinary solvent isotope effects arising from the
H
D
difference between the pKa and pKa values of a
protonated/deuterated species involved in the pro-
cess.18 However, the observation probably suggests
the involvement of the proton transfer in the forma-
tion of the intermediate (2) from HCl and
nitrosobenzene.
6. Addition of chloride ion (benzyltrimethylammo-
nium chloride)¶ enhances the observed rate con-
stants of the reaction. This fact cannot be ascribed
unequivocally in favour of the proposal that N-p-
chlorophenylhydroxylamine is the reactive interme-
diate arising from nitrosobenzene and HCl. The
observation is not inconsistent with nucleophilic
attack of the chloride at the para position of the
phenyl moiety of the addition intermediate (3). At
present, there is not enough evidence to decide
which process predominates in the reaction. With
regard to the established rate law (Eq. (1)), the
observation could also mean that (in the absence of
the added quaternary salt) the chloride ion was
principally transferred within the same encounter
pair of the intermediate (3). The observed rate con-
stants decrease when the concentrations of the
added quaternary chloride approaches that of HCl,
However, only a minor contribution of that inter-
mediate to the overall process is expected, due to its
greater basicity (and subsequent protonation) in
comparison to N-chlorohydroxylamine.ꢀꢀ On the
other hand, the change in the spectra of the reac-
tants and products during the course of the reaction
remained the same when 0.15 M of water was added
to the reaction mixture. Taking into account that
nitrosobenzene is a relatively weak nucleophile, it
seems highly unlikely that, under the conditions
employed in the kinetic experiments (10−4 M of
nitroso compound), nitrosobenzene alone could
compete with water (being in 1500-fold excess over
−
probably because of the formation of HCl2 homo-
conjugate complex.**
7. A substrate KIE between nitrosobenzene and nitro-
sobenzene-d5, kH/kD of 1.25 (0.21) in the reaction
was observed. The effect is quite small and could be
consistent with a fine balance between the rates of
the initial and the final step (proton transfer from
the carbon) of the reaction.
8. The Arrhenius plot of log kobs versus 1/T is slightly
curved which is what is expected if more than one
process takes place in the reaction system.
9. Addition of the less polar solvent diminishes the
rate of the reaction in accordance with the expecta-
tion that the dissociation of the HCl ion pair in the
transition state for the formation of the intermediate
(2) is of importance for the reaction. The rate is
§ Our conductimetric measurements indicate that HCl should be
present in 99.9% acetonitrile (used in all the experiments), exclu-
sively, in the form of an ion pair (or possibly hydrogen-bonded ion
pair) whilst the measurements suggest that benzyltrimethylammo-
nium chloride is (in the same solvent) substantially dissociated.
¶ For example, the pKa of HCl in another polar aprotic solvent,
dimethyl sulfoxide, is 1.8 (see Ref. 16).
ꢀꢀ Phenylhydroxylamine, for instance, did not react with acetyl chlo-
ride when added to the reaction mixture, obviously because of only
a minute fraction of unprotonated amine can exist under the acidic
conditions. On the other hand, N-chlorophenylhydroxylamine
should be much less basic, but nevertheless, strongly nucleophilic
(cf. the case of the ‘a-effect’ nucleophiles17).
** See for example Ref. 19.

8522
V. Pilepic´ et al. / Tetrahedron Letters 42 (2001) 8519–8522
halved by the addition of 80% of dioxane and is
retarded to a somewhat lesser extent by the addition of
dichloromethane.
3. Ursˇic´, S.; Vrcˇek, V.; Gabricˇevic´, M.; Zorc, B. J. Chem.
Soc., Chem. Commun. 1992, 14, 296–298.
4. Ursˇic´, S.; Pilepic´, V.; Vrcˇek, V.; Gabricˇevic´, M.; Zorc, B.
J. Chem. Soc., Perkin Trans. 2 1993, 509–514.
5. Ursˇic´, S. Helv. Chim. Acta 1993, 76, 131–138.
6. Pilepic´, V.; Ursˇic´, S. Tetrahedron Lett. 1994, 35, 7425–
7428.
7. Ursˇic´, S.; Lovrek, M.; Vinkovic´ Vrcˇek, I.; Pilepic´, V. J.
Chem. Soc., Perkin Trans. 2 1999, 1295–1297.
8. Lovrek, M.; Pilepic´, V.; Ursˇic´, S. Croat. Chem. Acta
2000, 73, 715–731.
9. Pilepic´, V.; Ursˇic´, S. J. Mol. Struct. (THEOCHEM) 2001,
538, 43–49.
The evidence obtained is summarised in Scheme 1. The
reaction presents a new route for obtaining various
hydroxamic acids using acyl chlorides, especially in the
cases where acidic conditions are desired or cannot be
avoided. An example is the derivatisation of N-(benzo-
triazolylcarbonyl) amino acid chlorides into the corre-
sponding aminohydroxamic acid derivatives which is
not possible under the basic conditions (where the
benzotriazolyl group would be eliminated) usually used
in order to introduce the desired hydroxamic
functionality.††
10. Muller, K.; Reindl, H.; Breu, K. J. Med. Chem. 2001, 44,
814–821.
11. Fray, M. J.; Dickinson, R. P. Bioorg. Med. Chem. Lett.
2001, 11, 571–574.
12. Clare, B. W.; Scozzafava, A.; Supuran, C. T. J. Enzyme
Acknowledgements
Inhib. 2001, 16, 1–13.
13. Natchus, M. G.; Bookland, R. G.; De, B.; Almstead, N.
G.; Pikul, S.; Janusz, M. J.; Heitmeyer, S. A.; Hookfin,
E. B.; Hsieh, L. C.; Dowty, M. E.; Dietsch, C. R.; Patel,
V. S.; Garver, S. M.; Gu, F.; Pokross, M. E.; Mieling, G.
E.; Baker, T. R.; Foltz, D. J.; Peng, S. X.; Bornes, D. M.;
Strojnowski, M. J.; Taiwo, Y. O. J. Med. Chem. 2000, 43,
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14. Roush, W. R.; Hernandez, A. A.; McKerrow, J. H.;
Selzer, P. M.; Hansell, E.; Engel, J. C. Tetrahedron 2000,
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We gratefully acknowledge the collaboration of Ms
Jelena Buzˇancˇic´. We thank the Ministry of Science and
Technology of the Republic of Croatia for the support
(Project 006-142).
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†† In a separate study, one of us (M.L.) had used such a procedure in
the successful attempt to synthesise new 1,2,5-oxadiazine derivatives
starting from N-(1-benzotriazolylcarbonyl)aminohydroxamic acids.