Regiochemistry and mechanism of oxidation of N-benzyl-N-alkylhydroxylamines to nitrones

Article abstract of DOI:10.1002/1099-1395(200008)13:8<443::AID-POC253>3.0.CO;2-9

The oxidation of various N-(o-, m-, p-substituted benzyl)-N-alkylhydroxylamines and their dideuteriobenzyl (PhCD₂) counterparts was carried out using mercury(II) oxide and p-benzoquinone (p-BQ) as oxidants. An overwhelming preference for the formation of conjugated nitrones is observed in the oxidation of N-benzyl-N-isopropylhydroxylamines. Considerable intra- and intermolecular kinetic isotope effects and negative ρ values in the Hammet plots point towards a mechanistic pathway that involves electron transfer from nitrogen to the oxidant followed by hydrogen abstraction. The conformation of unstable (E)-nitrones, which readily isomerize to the more stable (Z)-nitrones, is deduced from ¹H NMR data. The E ? Z isomerization was found to be a bimolecular process. Copyright

Full text of DOI:10.1002/1099-1395(200008)13:8<443::AID-POC253>3.0.CO;2-9

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY
J. Phys. Org. Chem. 2000; 13: 443–451
Regiochemistry and mechanism of oxidation of N-benzyl-N-
alkylhydroxylamines to nitrones
Azfar Hassan, Mohammed I. M. Wazeer, Mohammed T. Saeed, Mohammad N. Siddiqui
and Sk. Asrof Ali*
Chemistry Department, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia
Received 21 September 1999; revised 15 December 1999; accepted 9 February 2000
ABSTRACT: The oxidation of various N-(o-, m-, p-substituted benzyl)-N-alkylhydroxylamines and their
dideuteriobenzyl (PhCD2) counterparts was carried out using mercury(II) oxide and p-benzoquinone (p-BQ) as
oxidants. An overwhelming preference for the formation of conjugated nitrones is observed in the oxidation of N-
benzyl-N-isopropylhydroxylamines. Considerable intra- and intermolecular kinetic isotope effects and negative r
values in the Hammet plots point towards a mechanistic pathway that involves electron transfer from nitrogen to the
oxidant followed by hydrogen abstraction. The conformation of unstable (E)-nitrones, which readily isomerize to the
1
more stable (Z)-nitrones, is deduced from H NMR data. The E „ Z isomerization was found to be a bimolecular
process. Copyright 2000 John Wiley & Sons, Ltd.
KEYWORDS: hydroxylamines; oxidation; mercury(II) oxide; p-benzoquinone; isotope effect; nitrones; isomeriza-
tion; kinetics
INTRODUCTION
of the E isomer (which is expected to be much more
reactive12 than the Z form), on the other hand, would lead
to cycloadducts with different stereochemistry. Oxidation
of secondary hydroxylamines leads to the more stable
(Z)-nitrones. In few cases, some unstable (E)-nitrones
have been generated by irradiation of the Z isomers.14
The mechanistic investigation of this widely used
oxidation process has been studied to some extent.10
In our continuing studies9,10 to investigate the
regiochemistry and mechanism of oxidation of unsym-
metrical secondary hydroxylamines to nitrones, we report
here a systematic study of the oxidation of various N-
benzy1-N-alkylhydroxylamines 1–4 and their deuterated
counterparts [2H2]1–4 using mercury(II) oxide and p-
Nitrone functionality has become an important chemical
tool in organic synthesis1 and in spin trapping experi-
ments to trap and identify reactive free radicals especially
in biomedical fields.2 Nitrones have been prepared by a
variety of routes.1,3–7 Whereas there are numerous
reports on the preparation of nitrones by oxidation of
symmetrical amines and hydroxylamines, studies of their
unsymmetrical counterparts remain scarce,1,7–10 appar-
ently owing to the anticipation of regiochemical
complications. While the widely used cyclic aldonitrones
must remain in E geometry owing to structural
constraints, their acyclic counterparts are involved in
E„Z isomerization at higher temperature with equili-
brium constant overwhelmingly favouring the more
stable Z form11 (Scheme 1). With rare exceptions,12,13
it is the Z form which undergoes cycloaddition reactions,
thus dictating the stereochemical outcome. The addition
Scheme 1
*Correspondence to: Sk. Asrof Ali, Chemistry Department, King Fahd
University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia.
E-mail: shaikh@kfupm.edu.sa
Scheme 2
Copyright 2000 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2000; 13: 443–451

444
A. HASSAN ET AL.
Table 1. Composition of nitrones in the oxidation of hydroxylamines 1±3 with HgO at 10 to 20°C and p-BQ at 20°C
Hydroxylamine
R
Compositiona of nitrones
No.
X
Oxidant
R1
R2
1
Me
Et
Hb
HgO
p-BQ
HgO
p-BQ
HgO
p-BQ
HgO
HgO
HgO
HgO
HgO
5
7
(60)
(65)
(48)
(49)
6
8
(40)
(35)
(52)
(51)
H
H
2
H
H
Me
Me
3a
iPr,
H
9a (95)
(95)
9b (98.5)
9d (96)
9b (98.5)
9j (96)
9d (96)
10a (05)
(05)
10b (1.5)
10d (04)
10b (1.5)
10j (04)
10d (04)
Me
3b
3d
3g
3j
iPr,
iPr,
iPr,
iPr,
iPr,
p-NO2
p-OMe
m-NO2
2,4,5-(OMe)3
o-OMe
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
3k
a
Percentage compositions are given in parentheses.
b Taken from Ref. 10.
benzoquinone (p-BQ) as oxidants (Scheme 2). Efforts are
being made to generate and study the unstable (E)-
nitrones and subsequent E „ Z isomerization process.
amines 3 (X ≠ H) and 3a (X = H), using HgO and p-BQ.
As is evident from the Hammett plots (Figs. 1 and 2), the
rate of oxidation increases with the electron donating
ability of the substituents X. A good linear free energy
relationship is obtained with r values of 0.404, 0.436
using HgO and p-BQ, respectively. The negative r values
indicate the development of positive charge on the
nitrogen in the transition states.
RESULTS AND DISCUSSION
The regiochemistry of the oxidation of the N-benzyl-N-
alkylhydroxylamines 1–3 with various substituents in the
benzene ring of the hydroxylamine 3 is shown in Table 1.
As is evident, the composition of the nitrones depends on
the nature of the N-alkyl group but is somewhat
independent of the nature of the oxidant, mercury(II)
oxide or p-BQ. In the oxidation of the hydroxylamines 1
and 3, both the oxidants afforded the conjugated nitrones
as the major products. Allowing for the statistical
correction for the number of equivalent abstractable a-
protons, the benzyl C—H in 1 and 3a is found to be 2.25
and 9.5 times, respectively, more reactive than the alkyl
a-C—H. Surprisingly, the conjugated nitrone 7 is even
formed as a minor isomer in the oxidation of N-benzyl-N-
ethylhydroxylamines 2. It is assumed that the conjugated
nitrones do not equilibrate with their non-conjugated
counterparts. A CDCl3 solution of a pure sample of
several nitrones (prepared independently) remained un-
changed for weeks without equilibration to the regioiso-
meric nitrones. The formation of the non-conjuated
nitrones 6 and 8 and conjugated nitrones 9 in consider-
able amounts implicates the involvement of the kinetic
factor in a significant way in the abstraction of the
hydrogen from sterically favoured positions.
In order to shed more light on the oxidation process,
hydroxylamines deuterated at the benzyl position were
prepared (Scheme 3). As is evident from Table 2, with
either oxidant the regiochemistry of the oxidation is
either reversed or changed in favour of the non-
conjugated nitrones. When a 1:1:1 mixture of a hydro-
xylamine (1–4), its corresponding dideuterated hydro-
xylamine ([2H2]1–4) and HgO was allowed to react, the
hydroxylamines 1–4 were found to react 1.34, 1.40, 3.35
and 7.00 times faster, respectively, than their deuterated
counterparts [2H2]1–4. Similar rate ratios are found in the
Next we focussed our attention on determining the
relative rate10,15 (kX/kH) of oxidation of the hydroxyl-
Scheme 3
Copyright 2000 John Wiley & Sons, Ltd.
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OXIDATION OF N-BENZYL-N-ALKYLHYDROXYLAMINES TO NITRONES
445
Table 2. Regiochemistry and reactivity of hydroxylamines in oxidation using HgO (0°C) and p-benzoquinone (p-BQ) (20°C) in
CDCl3
Rate ratio k(1–4)/k2H2(1–4)
Hydroxylaminea
Oxidant
Composition of nitronesb
HgO
p-BQ
PhCH2N(OH)Me
1
HgO
p-BQ
HgO
p-BQ
HgO
p-BQ
HgO
p-BQ
HgO
p-BQ
HgO
p-BQ
HgO
p-BQ
HgO
p-BQ
5
5
(57)
(65)
6
(43)
6 (35)
1.34
1.15
PhCD2N(OH)Me
[2H]5 (17)
[2H2]6 (83)
[2H2]6 (67)
8 (52)
[2H2]1
[2H]5 (33)
PhCH2N(OH)Et
2
7
7
(48)
(49)
8 (51)
1.40
3.35
7.0
1.43
4.39
7.50
PhCD2N(OH)Et
[2H]7 (10)
[2H]7 (09)
9a (95)
[2H2]8 (90)
2H2]8 (91)
10a (05)
10a (05)
[2H2]10 (32)
[2H2]10 (37)
—
[2H2]2
PhCD2N(OH)iPr
3a
9a (95)
PhCD2N(OH)iPr
[2H2]3a
[2H]9a (68)
[2H]9a (63)
11 (100)
PhCH2N(OH)tBu
4
11 (100)
—
—
—
PhCD2N(OH)tBu
[2H2]4
[2H]11 (100)
[2H]11 (100)
a
Results for the oxidation of hydroxylamine 1 and [2H2]1 were taken from Ref. 10 and that of 4 and [2H2]4 from Ref. 9.
b Percentage compositions are given in parentheses.
oxidation using p-BQ. The values of the intra- and
intermolecular kinetic isotope effects16 are given in Table
3. The intramolecular kinetic isotope effects were
calculated from the relative yields of the conjugated
nitrone and its [2H]-analogue obtained from the separate
oxidation of the protio- (1–4) and deuterohydroxylamines
([2H2]1–4) (see Table 2). In the calculation it was
assumed that the benzyl deuterons would only influence
the rate of formation of the conjugated nitrones, have the
rate of formation of the nonconjugated nitrones becomes
an internal standard common to the oxidation of both
hydroxylamines. The intermolecular kinetic isotope
effects were determined using the relative yields of the
products conjugated nitrone and its [2H]-analogue
obtained from the reaction involving direct competition
of the protio- and deuterohydroxylamines for the
oxidants (see Tables 2 and 3).
The oxidation using HgO at lower temperatures ( 10
to 20°C) afforded a mixture of (E)- and (Z)-nitrones in
all cases except in the oxidation of the test-butyl
derivative (4) (Table 4). In the oxidation of hydroxyl-
amines 3 having electron-donating substituents, it is the E
isomers which predominate. The E isomer equilibrates
completely to the Z isomer. Proton NMR signals, given in
Table 5, support the perpendicular and planar conforma-
tion for the E and Z isomers, respectively. The ortho
proton in the planar Z isomer is shifted downfield (ca
1 ppm) owing to the proximity of the negatively charged
oxygen atom of the nitrone group.17–19 The downfield
shift is more pronounced in the nitrones having an ortho
substituent in which the C(6) H is located near the oxygen
atom (e.g. in 9j by 1.42 ppm and 9k by 2.13 ppm). The
two ortho protons in the other (Z)-nitrones appear at an
Table 3. Intramoleculara and intermolecularb kinetic isotpe
effects from the separate and competitive oxidation,
respectively, of PhCH2N(OH)R (1±4) and PhCD2N(OH)R
[2H2](1±4)
Hydroxylamine
Oxidant
(kH/kD)intraa (kH/kD)interb
1 and [2H2]1
(R = Me)
HgO
p-BQ
6.47
3.77
4.49
2.27
2 and [2H2]2
(R = Et)
HgO
8.31
9.72
6.72
7.78
p-BQ
3a and [2H2]3a
(R = iPr)
HgO
p-BQ
8.94
11.2
4.68
6.62
4 and [2H2]4
(R = tBu)
HgO
p-BQ
—
—
7.00
7.50
a Calculated from the ratio of conjugated and non-conjugated nitrones
in the separate oxidation of PhCH2N(OH)R and PhCD2N(OH)R (Table
3, e.g. kH/kD = [5]/[6] Ä [2H]5/[2H2]6).
b
Calculated from the ratio of conjugated nitrones in the competitive
oxidation of PhCH2N(OH)R and PhCD2N(OH)R (e.g. kH/kD = [5]/
[2H]5).
Copyright 2000 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2000; 13: 443–451

446
A. HASSAN ET AL.
Table 4. Compositiona of the nitrones in the oxidation of N-
alkylhydroxylamines (1±4) with HgO in CDCl3 at-10 to
20°C
bond is known to deshield the proton.17–20 However, in
case of the nitrones 9j and 9k, the opposite trend is
observed; the methine hydrogen (CH=N) of the (Z)-
nitrones appears downfield owing to its proximity to the
oxygen of the o-methoxy substituent. In order to avoid
steric congestion between the aromatic ortho protons and
the isopropyl group, the E isomer adopts the perpendi-
cular conformation having the aromatic plane perpendi-
cular to the plane of the nitrone functionality, whereas
they are coplanar in the Z nitrones. The difference of
ꢀ0.4 ppm between the chemical shifts of the methine
proton of the N-CH(CH3)2 group was observed in the (E)-
and (Z)-nitrones. While the shielding effect of the
aromatic p-cloud in the non-coplanar (E)-nitrone is
supposed to induce an upfield shift of the methine signal,
conjugative electron withdrawal by the nitrone function-
ality from the aromatic ring in the planar Z form makes
the nitrogen less electronegative, thereby resulting in an
even greater upfield shift. Semi-empirical molecular
orbital calculations21 on the nitrone 5 predicted that the Z
isomer with a coplanar arrangement is more stable than
the E isomer with orthogonal geometry by 13–
17 kJ mol 1. Our experimental findings of an undetect-
able amount of E isomer after equilibration supports the
calculation. It was calculated that the planar arrangement
Hydroxylamine
No.
R
X
Nitrone
Z:Ea
1
2
Me
Et,
iPr
iPr
iPr
iPr
iPr
iPr,
tBu
H
H
H
5
7
9a
9b
9d
9g
9j
(55:45)
(62:38)
(45:55)
(86:14)
(45:55)
(90:10)
(39:61)
(26:74)
(100:ꢀ0)
3a
3b
3d
3g
3j
3k
4
p-NO2
p-OMe
m-NO2
2,4,5-(OMe)3
o-OMe
H
9k
11
a
Percentage compositions are given in parentheses.
1
in the E isomer is destabilized by ca 126 kJ mol in
comparison with the orthogonal geometry.
average position owing to the rotation of the phenyl
group, thus resulting in a smaller difference (ca 1 ppm) in
the chemical shift values of the (Z) and (E)-nitrones. The
The ease of oxidation of hydroxylamines 1–4 to the
nitrones should reflect the ease of nitrogen inversion
provided that the oxidation process, like nitrogen
inversion,22,23 involves a planar transition state in the
rate-determining step with sp2 character of nitrogen
orbitals. Any crowding in the pyramidal ground state
would be relieved in the transition state with an extended
CNC bond angle (120°). The relative rates of oxidation of
methine hydrogen (CH=N) in the E isomers, in most
cases, is shifted downfield by 0.5–0.6 ppm (in compari-
son with the Z nitrones), indicating the cis relationship
between the methine H and the negatively charged O,
since an anisotropic effect of the neighbouring N—O
Table 5. 1H chemical shifts of (E)-and (Z)-nitrones 9 in CDCl3 at 10°C
Nitrone
X
E (ppm)
Z (ppm)
9
Aromatic protons
HE
H'E
Aromatic protons
HZ
H'Z
a
b
d
g
H
7.34 (a, e)
7.51 (a, e)
7.24 (a, e)
—
8.19 (e)
7.73 (a)
7.19 (a)
7.87
7.90
7.84
7.90
4.73
4.75
4.74
4.70
8.26 (a', e')
8.44 (a', e')
8.24 (a', e')
8.64 (a')
7.40
7.67
7.36
7.65
4.22
4.35
4.17
4.34
p-NO2
p-OMe
m-NO2
9.15 (e')
j
k
2,4,5-(OMe)3
o-OMe
7.73
7.83
4.52
4.57
9.15 (a')
9.32 (a')
7.83
7.92
4.20
4.24
Copyright 2000 John Wiley & Sons, Ltd.
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OXIDATION OF N-BENZYL-N-ALKYLHYDROXYLAMINES TO NITRONES
447
Table 6. Relative rates of oxidation of various hydroxyla-
mines using p-BQ and HgO in CDCl3
Relative rate (kR/kMe) of
oxidation using
Compound
DG‡
273 K
1
No.
R
(kJ/mol
)
p-BQa
HgOb
1
Me
Et
55.8
55.3
51.6
49.2
1.00
1.35
2.32
1.20
1.00
0.902
1.40
2
3a
4
iPr
tBu
0.528
a
At 20°C.
b At 0°C.
the hydroxylamines 1–4 by HgO and p-BQ along with the
energy barrier for the nitrogen inversion process are
listed in Table 6. It is evident that the rate of oxidation of
1 or 2 or 3a using p-BQ (or HgO to a certain extent)
parallels the rate of nitrogen inversion. In the oxidation
using HgO, the tert-butylhydroxylamine 4 undergoes
oxidation at slower rate in comparison with both the
methyl 1 and isopropyl derivative 3a, reflecting the
complex interplay of the steric encounter in the approach
of the oxidant toward 4 and its desire to relieve steric
compression in the planar transition state.
The oxidation process can follow a pathway of single
electron transfer (SET)24,25 or a polar (SN2) mechanism.
Our experimental findings corroborate the mechanistic
pathway as proposed earlier.10 Approach to the con-
former A by the oxidant will be energetically preferrable
because of lesser steric hindrance (Scheme 4). SET
followed by abstraction of hydrogen from the hydro-
xylaminium radical C would lead to the (E)-nitrone,
whereas the conformer B would lead to the (Z)-nitrone.
This isopropyl group can be accommodated into a gauche
relationship with the phenyl group; steric congestion is
relieved owing to the methine hydrogen pointing towards
the phenyl ring. However, in case of the tert-butyl
derivative which lacks an a-C—H, both the conformer, A
and the intermediate C are energetically unfavourable,
Scheme 4
thus inhibiting the formation of the (E)-nitrone. The
negative r values suggest that the initial step in the
oxidation is an one-electron transfer from the hydro-
xylamine to the oxidant followed by a product-determin-
ing deprotonation of the resulting hydroxylaminium
radical. The deprotonation of a planar hydroxylamine
cation radical requires overlap between the half-vacant
nitrogen p-orbital and the incipient carbon radical p-
orbital, thus giving rise to a stereoelectronic effect on the
deprotonation step.26 While the steric congestion makes
the overlap of aminium p-orbital and the a-C—H bond of
the isopropyl group difficult, the corresponding energe-
tically favourable overlap involving the benzyl C—H
dictates the overwhelming preference for the formation
of the conjugated nitrones 9. The large intra- and inter-
molecular primary kinetic isotope effects suggest that a-
C—H bond breakage is both rate-limiting and product-
determining in these oxidations. Had the electron-transfer
step been irreversible and rate-determining, there would
be a small secondary intermolecular isotope effect (ꢀ1.3)
for the electron-transfer step and a larger intramolecular
Table 7. Rate constants and thermodynamic parameters obtained for isomerization of (E)- to (Z)-nitrones
1
1
1
1
1
E
Temperature (°C)
k/10 5 (s
)
Ea (kJ/mol
)
DH‡ (kJ/mol
)
DG‡273 K (kJ/mol
)
DS‡ (J/mol 1K
)
9aa
10
0
10
10
0
10
0
0
1.28
4.23
13.3
0.788
2.55
7.83
4.13
7.30
23.0
28.2
72.5
70.2
89.5
70.6
9ka
71.1
68.9
90.9
79.9
9ab
5b
9ac
9dc
10
10
a
The mixture of the nitrones obtained from oxidation of a mixture of 3a and 3k was taken in the NMR tube for the kinetic study.
b The mixture of the nitrones obtained from oxidation of a mixture of 3a and 1 was taken in the NMR tube for the kinetic study.
c
The mixture of the nitrones obtained from oxidation of a mixture of 3a and 3d was taken in the NMR tube for the kinetic study.
Copyright 2000 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2000; 13: 443–451

448
A. HASSAN ET AL.
for slower isomerization of the isopropyl nitrone 9a than
its methyl counterpart 5. As regards the nature of the
nucleophilic species, it could be the unreacted hydro-
xylamine, the nitrone itself or any basic entity present
during the oxidation with HgO.
A systematic study of the oxidation of N-benzyl-N-
alkylhydroxylamines has been made. Efforts are cur-
rently under way to find ways to stabilize the (E)-nitrones
and to study its cycloaddition reactions.
Scheme 5
one for the proton transfer. In order to account for the
negative r values (and hence positive charge on nitrogen)
and large kinetic isotope effect, the most likely mechan-
ism includes a rate-determining step that involves the
concerted transfer of one electron from the hydroxyl-
amine to the oxidant and concomitant cleavage of the
a-C—H bond. While changing the R group in hydro-
EXPERIMENTAL
1H NMR spectra were recorded on a JEOL Lambda-500
and a Varian XL 200 NMR spectrometer, in CDCl3
solutions using TMS as internal standard. Elemental
analyses were performed on a Fisons Instruments
Elemental Analyser 1108. All melting points are
uncorrected. IR spectra were recorded a Nicolet 5 DXB
FTIR instrument. Silica gel chromatographic separations
were performed with flash silica gel (Baker Chemicals).
The preparation of the hydroxylamine derivatives has
been described in our previous papers.22,23 The hydro-
xylamines deuterated at the benzyl position were
prepared by using the same general procedure.9,10
Condensation reactions always provided the (Z)-nitrones
and using the known positions of the proton signals of the
Z isomers, the non-overlapping chemical shifts of the (E)-
and the non-conjugated nitrones were deduced from the
spectra of their mixture. The condensation of the
hydroxylamines RNHOH with PhCDO gave the nitrone
[2H](7 and 9a), which on reduction with NaBD4 formed
the required dideuriated hydroxylamines [2H2](2 and 3a).
The kinetics of E „ Z isomerization were studied as
described previously.10
t
xylamines from Me to Bu should decrease the energy
requirement of the electron-transfer process (see above),
the stereoelectronic effect dictates the a-C—H bond
cleavage to follow the opposite trend. Combined energy
requirements for the two steps determine the overall
energy of activation, and hence no definite trend is
observed in the kinetics of oxidation of the hydroxyl-
amines 1–4 (Table 6).
The formation of a considerable amount of E isomer in
the oxidation of hydroxylamines provided us with the
opportunity to study the kinetics of E „ Z isomerization
using NMR technique.10,27 In a series of experiments a
mixture of two hydroxylamines, 3a–3k, 3a–1 and 3a–3d,
was oxidized with HgO in CDCl3 (at 15 to 20°C, 2 h)
and the rate constant for each first-order E „ Z
isomerization process was determined by linear regres-
sion analysis with excellent correlation coefficients. The
presence of two (E)-nitrones in the same NMR tube
would enable them to experience almost similar effects
(whatever those effects may be). Low values of Ea and
DG≠ and very large negative values of entropy of
activation (Table 7) cast doubt on the validity of the
assumption that the isomerization is an unimolecular
process. In any unimolecular process the entropy of
activation should be close to zero,17,21 while second-
order isomerization is expected to have high negative
values of entropy of activation.28 As is evident from
Table 7, the rate constants are not reproducible; rate
constants for the isomerization of the nitrone (E)-9a at -
N-[a,a 2H2]Benzyl-N-ethylhydroxylamine, [2H2]2.
Purified by chromatography using 4:1 hexane–diethyl
ether as eluent. Colourless liquid. Found: C, 70.4; H, 9.8;
N, 9.2. C9H11D2NO requires C, 70.56; H, 9.85; N, 9.15%.
ꢀmax (neat) (cm 1), 3205, 3021, 2963, 2868, 2837, 2221,
2121, 2058, 1486, 1442, 1374, 1286, 1239, 1166, 1096,
1078, 1045, 1026, 985, 943, 884, 730, 691; H (CDCl3,
20°C), 1.12 (3 H, t, J 7.0 Hz), 2.70 (2 H, q, J 7.0 Hz), 6.70
(1 H, br, OH), 7.35 (5 H,m).
ꢁ
5
10°C in two different runs were found to be 1.28 Â 10
N-[a,a 2H2]Benzyl-N-isopropylhydroxylamine,
[2H2]3a. Purified by chromatography using 4:1 hexane–
diethyl ether as eluent. Colourless needles, m.p. 78–80°C
(diethyl ether–hexane). Found: C, 71.7; H, 10.1; N, 9.4.
C10H13D2NO requires C, 71.83; H, 10.23; N, 8.38%. ꢀmax
(KBr) (cm 1), 3190, 3042, 2961, 2940, 2218, 2098, 1496,
1475, 1449, 1383, 1362, 1186, 1130, 1067, 1010, 960,
730, 703; ꢁH (CDCl3, 20°C), 1.16 (6 H, d, J 6.4 Hz), 2.98
(1 H, hept, J 6.4 Hz), 7.35 (5 H, s, 1 H, hydroxyl proton
underneath).
5
and 23.0 Â 10
s
1. The isomerization process was
repeated many times and different values of rate
constants were obtained.
Evidence presented so far indicates the isomerization
to be a bimolecular process as previously reported10
(Scheme 5). The slower isomerization of the nitrone (E)-
9k could be attributed to the presence of ortho substituent
which destabilizes the tetrahedral complex owing to
steric crowding. Steric crowding could also be the reason
Copyright 2000 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2000; 13: 443–451

OXIDATION OF N-BENZYL-N-ALKYLHYDROXYLAMINES TO NITRONES
449
General procedure for the preparation of the
nitrones. To a solution of N-isopropylhydroxylamine
(5.0 mmol) in ethanol (10 cm3) was added the aldehyde
(5.5 mmol). (Whereas the N-isopropylhydroxylamine
was used as its free base, N-ethylhydroxylamine was
introduced as its hydrochloride and the free base was
liberated from its salt by adding 1.1 equiv. of sodium
acetate in the reaction mixture.) The reaction mixture was
stirred at 50–60°C for 5 h and TLC (silica, diethyl ether)
revealed the complete formation of the N-oxides (Z)-9.
After removal of the ethanol the nitrones were recrys-
tallized by using suitable solvents. In case of liquid
nitrones chromatography purification (using hexane–
diethyl ether as the eluent) was carried out in order to
obtain analytical samples. For isolation of the N-oxide
(Z)-7, the solvent ethanol was removed and the residual
mixture was taken in dichloromethane (20 cm3), and the
organic layer was washed with saturated NaHCO3
solution. The organic layer was dried and concentrated
to give the nitrone as a liquid.
( 10°C) 1.45 (6 H, d, J 6.4 Hz), 4.73 (1 H, hept, J
6.4 Hz) 7.34 (5 H, m), 7.87 (1 H, s).
(Z)-N-Isopropyl[a-2H]benzylideneamine
N-oxide,
[2H](9a). Found: C, 72.9, H, 8.4; N, 8.35. C10H12DNO
requires C, 73.14; H, 8.59; N, 8.53%. ꢀmax (neat) (cm 1),
3063, 2984, 2921, 2842, 2279, 1553, 1442, 1369, 1278,
1195, 1073, 1037, 948, 917, 769, 699; ꢁH ( 10°C), 1.51
(6 H, d, J 6.6 Hz), 4.22 (1 H, hept, J 6.6 Hz), 7.34 (3 H,
m), 8.26 (2 H, d, J 7.9 Hz).
ꢁ
N-Benzyl-1-methylethylideneamine N-oxide (10a). H
( 10°C) 2.14 (3 H, s), 2.19 (3 H, s), 5.09 (2 H, s).
(Z)-N-Isopropyl-4-nitrobenzylideneamine N-oxide (9b).
Yellow needles, m.p. 99–101°C (diethyl ether–dichloro-
methane). Found: C, 57.6; H, 5.8; N, 13.5. C10H12N2O3
requires C, 57.68; H, 5.81; N, 13.46%. ꢀmax (KBr)
(cm 1), 2978, 1614, 1352, 1150, 1094, 858; ꢁH ( 10°C),
1.55 (6 H, d, J 6.6 Hz), 4.35 (1 H, hept, J 6.6 Hz), 7.67 (1
H, s), 8.30 (2 H, d, J 8.4 Hz), 8.44 (2 H, d, J 8.6 Hz).
The 1H NMR signals of the unstable (E)-nitrones were
deduced from the spectra of the mixture of (E)-and (Z)-
nitrones which were obtained from the oxidation of the
corresponding hydroxylamines at low temperature (see
below). The 1H NMR signals of the minor regioisomeric
nitrones were also deduced from the 1H NMR spectra of
the oxidized mixture.
(E)-N-Isopropyl-4-nitrobenzylideneamine N-oxide (9b).
ꢁH ( 10°C), 1.50 (6 H, d, J 6.4 Hz), 4.75 (1 H, hept, J
6.4 Hz), 7.51 (2 H, d, J 8.6 Hz), 7.90 (1 H, s), 8.35 (2 H, d,
J 8.6 Hz).
(Z)-N-Ethylbenzylideneamine N-oxide (7). Found: C,
72.3, H, 7.4; N, 9.4. C9H11NO requires C, 72.45; H, 7.43;
N, 9.39% ꢀmax (neat) (cm 1), 2980, 1582, 1446, 1164,
692; ꢁH ( 10°C), 1.58 (3 H, t, J 7.3 Hz), 4.00 (2 H, q, J
7.3 Hz), 7.40 (3 H, m, and 1 H, s at 7.42), 8.24 (2 H, d, J
7.7 Hz).
N-4-Nitrobenzyl 1-methylethylideneamine N-oxide
(10b). H ( 10°C), 2.21 (3 H, s), 2.25 (3 H, s), 5.20 (2
H, s).
ꢁ
(Z)-N-Isopropyl-4-chlorobenzylideneamine
N-oxide
(9c). White plates, m.p. 56–57.5°C (diethyl ether–
hexane). Found: C, 60.8; H, 6.0; N, 7.1. C10H12NOCl
requires C, 60.76; H, 6.12; N, 7.09%. ꢀmax (KBr) (cm 1),
ꢁ
(E)-N-Ethylbenzylideneamine N-oxide (7). H ( 10°C),
ꢁ
1.56 (3 H, t, J 7.0 Hz), 4.05 (2 H, q, J 7.0 Hz), 7.26–7.58
(5 H, m), 7.97 (1 H, s).
2978, 1578, 1454, 1308, 1150, 1086, 842; H (19°C),
1.55 (6 H, d, J 7.0 Hz), 4.27 (1 H, hept), 7.45 (2 H, d, J
8.0 Hz), 7.49 (1 H, s), 8.30 (2 H, d, J 8.0 Hz).
ꢁ
(Z)-N-Benzylethylideneamine N-oxide (8). H ( 10°C),
2.01 (3 H, d, J 5.9 Hz), 4.90 (2 H, s), 6.72 (1 H, q, J
5.9 Hz), 7.42 (5 H, m).
(Z)-N-Isopropyl-4-methoxybenzylideneamine N-oxide
(9d). Found: C, 68.3, H, 7.8; N, 7.2. C11H15NO2 requires
C, 68.37; H, 7.82; N, 7.25%. ꢀmax (neat) (cm 1), 2990,
1604, 1506, 1452, 1302, 1264, 1170, 1148, 1086, 1030,
842; H ( 10°C), 1.50 (6 H, d, J 6.6 Hz), 3.83 (3 H, s),
4.17 (1 H, hept, J 6.6 Hz), 6.93 (2 H, d, J 8.8 Hz), 7.36 (1
H, s), 8.24 (2 H, d, J 8.8 Hz).
(Z)-N-Ethyl[a 2H]benzylideneamine N-oxide, [2H](7).
Found: C, 71.8, H, 7.9; N, 9.4. C9H10DNO requires C,
71.97; H, 8.04; N, 9.33%. ꢀmax. (neat) (cm 1), 3053,
2968, 2932, 2842, 2263, 1569, 1494, 1444, 1377, 1335,
ꢁ
ꢁ
1250, 1195, 1115. 1073, 1029, 951, 897, 756, 689; H
( 10°C), 1.58 (3 H, t, J 7.3 Hz), 4.00 (2 H, q, J 7.3 Hz),
7.40 (3 H, m, and 1 H, s at 7.42), 8.24 (2 H, d, J 7.7 Hz).
(E)-N-Isopropyl-4-methoxybenzylideneamine N-oxide
(9d). H ( 10°C), 1.46 (6 H, d, J 6.2 Hz), 3.83 (3 H,
ꢁ
(Z)-N-Isopropylbenzylideneamine N-oxide (9a). ꢁH
( 10°C) 1.51 (6 H, d, J 6.6 Hz), 4.22 (1 H, hept, J
6.6 Hz), 7.34 (3 H, m), 7.40 (1 H, s), 8.26 (2 H, d, J
7.9 Hz).
s), 4.74 (1 H, hept, J 6.2 Hz), 6.97 (2 H, d, J 8.6 Hz), 7.24
(2 H, d, J 8.6 Hz), 7.84 (1 H, s).
N-4-Methoxybenzyl 1-methylethylideneamine N-oxide
(10d). ꢁH ( 10°C), 2.14 (3 H, s), 2.17 (3 H, s), 4.96 (2 H,
s).
(E)-N-Isopropylbenzylideneamine N-oxide (9a). ꢁH
Copyright 2000 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2000; 13: 443–451

450
A. HASSAN ET AL.
Figure 2. Hammett plot for the p-BQ oxidation of N-benzyl-
N-isopropylhydroxylamins (3)
Figure 1. Hammett plot for the HgO oxidation of N-benzyl-
N-isopropylhydroxylamins (3)
ꢁ
2988, 1570, 1462, 1326, 1152, 1092, 826, 766, 678; H
(19°C), 1.54 (6 H, d, J 7.0 Hz), 4.27 (1 H, hept), 7.34 (1
H, t, J 8.0 Hz), 7.48 (1 H, s), 7.70 (1 H, d, J 8.0 Hz), 8.11
(1 H, d, J 8.0 Hz), 8.68 (1 H, s).
(Z)-N-Isopropyl-4-methylbenzylideneamine
N-oxide
(9e). White plates, m.p. 43–45°C (diethyl ether–hexane).
Found: C, 74.6; H, 8.5; N, 7.9. C11H15NO requires C,
74.54; H, 8.53; N, 7.90%. ꢀmax (KBr) (cm 1), 2977,
1570, 1446, 1308, 1150, 1084, 836; ꢁH (19°C), 1.55 (6 H,
d, J 7.0 Hz), 2.42 (3 H, s), 4.26 (1 H, hept), 7.30 (2 H, d, J
8.0 Hz), 7.48 (1 H, s), 8.24 (2 H, d, J 8.0 Hz).
(Z)-N-Isopropyl-4-bromobenzylideneamine
N-oxide
(9i). White crystals, m.p. 53–55°C (diethyl ether–
hexane). Found: C, 49.6; H, 5.1; N, 5.8. C10H12NOBr
1
requires C, 49.61; H, 5.00; N, 5.79%. ꢀmax (KBr) (cm
)
(Z)-N-Isopropyl-4-dimethyaminobenzylideneamine N-
oxide (9f). White crystals, m.p. 120–121.5°C (diethyl
ether). Found: C, 69.7; H, 8.8; N, 13.6. C12H18NO2
requires C, 69.65; H, 8.80; N, 13.58%. ꢀmax (KBr)
(cm 1), 2978, 1060, 1522, 1366, 1304, 1166, 1084, 948,
840; ꢁH (19°C), 1.54 (6 H, d, J 7.0 Hz), 3.16 (6 H, s), 4.19
(1 H, hept), 6.76 (2 H, d, J 9.0 Hz), 7.35 (1 H, s), 8.26 (2
H, d, J 9.0 Hz).
2958, 1578, 1458, 1320, 1154, 1092, 832; ꢁH (19°C) 1.55
(6 H, d, J 7.0 Hz), 4.28 (1 H, hept), 7.50 (1 H, s), 7.62 (2
H, d, J 8.0 Hz), 8.23 (2 H, d, J 8.0 Hz).
(Z)-N-Isopropyl-2,4,5-trimethoxybenzylideneamine N-
oxide (9j). Light brown crystals, m.p. 114–116°C
(diethyl ether–ethanol). Found: C, 61.7; H, 7.6; N, 5.5.
C13H19NO4 requires C, 61.64; H, 7.56; N, 5.53%. ꢀmax
(KBr) (cm 1) 2958, 1578, 1458, 1320, 1154, 1092, 832;
ꢁH ( 10°C), 1.50 (6 H, d, J 6.6 Hz), 3.86 (3 H, s), 3.90 (6
H, s), 4.20 (1 H, hept, J 6.6 Hz), 6.49 (1 H, s), 7.83 (1 H,
s), 9.15 (1 H, s).
(Z)-N-Isopropyl-3-nitrobenzylideneamine N-oxide (9g).
Yellow needles, m.p. 134–136°C (diethyl ether–ethanol).
Found: C, 57.7; H, 5.8; N, 13.5. C10H12N2O3 requires C,
57.68; H, 5.81; N, 13.46%. ꢀmax (KBr) (cm 1), 2978,
ꢁ
1524, 1322, 1070, 678; H ( 10°C), 1.55 (6 H, d, J
(E)-N-Isopropyl-2,4,5-trimethoxybenzylideneamine N-
ꢁ
6.6 Hz), 4.34 (1 H, hept, J 6.6 Hz), 7.63 (1 H, t, J 8.0 Hz),
7.65 (1 H, s) 8.27 (1 H, d, J 7.9 Hz), 8.65 (1 H, d, J
7.9 Hz), 9.15 (1 H, s).
oxide (9j). H ( 10°C), 1.42 (6 H, d, J 6.4 Hz), 3.82 (6
H, s), 3.84 (3 H, s), 4.52 (1 H, hept, J 6.4 Hz), 6.54 (1 H,
s), 7.68 (1 H, s), 7.73 (1 H, s).
(E)-N-Isopropyl-3-nitrobenzylideneamine N-oxide (9g).
ꢁH ( 10°C), 1.51 (6 H, d, J 6.4 Hz), 4.70 (1 H, hept, J
6.4 Hz), 7.90 (1 H, s), 8.19 (1 H, s).
N-2,4,5-Trimethoxybenzyl 1-methylethylideneamine
N-oxide (10j). H ( 10°C), 2.15 (3 H, s), 2.17 (3 H, s),
5.00 (2 H, s).
ꢁ
N-3-Nitrobenzyl 1-methylethylideneamine N-oxide
(10g). H ( 10°C), 2.17 (3 H, s), 2.22 (3 H, s), 5.15 (2
H, s).
(Z)-N-Isopropyl-2-methoxybenzylideneamine N-oxide
(9k). Found: C, 68.3, H, 7.8; N, 7.2. C11H15NO2 requires
C, 68.37; H, 7.82; N, 7.25%. ꢀmax (neat) (cm 1), 2980,
2943, 1594, 1560, 1466, 1436, 1308, 1284, 1246, 1150,
1026, 766; ꢁH ( 10°C), 1.51 (6 H, d, J 6.6 Hz), 3.87 (3 H,
s), 4.24 (1 H, hept, J 6.6 Hz), 6.87 (1 H, d, J 8.4 Hz), 7.02
(1 H, t, J 7.7 Hz), 7.35 (1 H, t, J 7.7 Hz), 7.92 (1 H, s),
9.32 (1 H, d, J 8.1 Hz).
ꢁ
(Z)-N-Isopropyl-3-bromobenzylideneamine
N-oxide
(9h). White needles, m.p. 82–83°C (diethyl ether–
hexane). Found: C, 49.6; H, 5.1; N, 5.8. C10H12NOBr
requires C, 49.61; H, 5.00; N, 5.79%. ꢀmax (KBr) (cm 1),
Copyright 2000 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2000; 13: 443–451

OXIDATION OF N-BENZYL-N-ALKYLHYDROXYLAMINES TO NITRONES
451
(E)-N-Isopropyl-2-methoxybenzylideneamine N-oxide
(9k). H ( 10°C), 1.43 (6 H, d, J 6.4 Hz), 3.85 (3 H,
Petroleum and Minerals, Dhahran, are gratefully ac-
knowledged.
ꢁ
s), 4.57 (1 H, hept, J 6.4 Hz), 6.96 (1 H, d, J 8.5 Hz), 7.03
(1 H, t, J 7.7 Hz), 7.19 (1 H, d, J 7.5 Hz), 7.41 (1 H, t, J
7.7 Hz), 7.83 (1 H, s).
N-2-Methoxybenzyl 1-methylethylideneamine N-oxide
(10k). ꢁH ( 10°C), 2.14 (3 H, s), 2.19 (3 H, s), 5.07 (2 H,
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1
to remove the mercury salts. Careful analysis of the H
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1
hydroquinone, the reaction mixture was analysed by H
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(0.3 mmol) in CDCl3 (0.2 cm3) at 20°C was added
yellow HgO (1.0 mmol) and the mixture was stirred for
2 h. The solution was then passed through tightly packed
glass-wool with a bed of MgSO4 in a precooled pipette
(to prevent rapid isomerization) to remove the mercury
salts. The solution was collected into a base-washed
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Facilities provided by the King Fahd University of
Copyright 2000 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2000; 13: 443–451