Metal-assisted reactions. Part 29. Structure and hydrogenolysis of C-N bonds in derivatives of aromatic amines. Bond length and electronegativity changes from X-ray crystallographic data

Article abstract of DOI:10.1039/b102571f

Pseudosaccharyl and phenyltetrazolyl derivatives 1-6 were prepared with the aim of weakening the originally strong C-N bond in aromatic amines and facilitating its hydrogenolysis. Structural analyses of the amines 1-6 by ¹H and ¹³C NMR spectroscopy and X-ray diffraction methods have revealed major changes in C-N bond lengths on derivatization as a result of changes in conjugation. These changes are discussed in relation to the observed reactivity of compounds 1-6 towards catalytic and non-catalytic C-N bond hydrogenolysis.

Full text of DOI:10.1039/b102571f

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Metal-assisted reactions. Part 29.1 Structure and hydrogenolysis of
C–N bonds in derivatives of aromatic amines. Bond length and
electronegativity changes from X-ray crystallographic data
2
Amadeu F. Brigas,a William Clegg,b Christopher J. Dillon,c Custodia F. C. Fonsecaa,c
and Robert A. W. Johnstone*c
a UCEH, Campus de Gambelas, Universidade do Algarve, Faro, 8000, Portugal
b Department of Chemistry, University of Newcastle, Newcastle-upon-Tyne, UK NE1 7RU
c Department of Chemistry, University of Liverpool, Liverpool, UK L69 3BX
Received (in Cambridge, UK) 20th March 2001, Accepted 12th June 2001
First published as an Advance Article on the web 9th July 2001
Pseudosaccharyl and phenyltetrazolyl derivatives 1–6 were prepared with the aim of weakening the originally strong
C–N bond in aromatic amines and facilitating its hydrogenolysis. Structural analyses of the amines 1–6 by 1H and
13C NMR spectroscopy and X-ray diffraction methods have revealed major changes in C–N bond lengths on
derivatization as a result of changes in conjugation. These changes are discussed in relation to the observed
reactivity of compounds 1–6 towards catalytic and non-catalytic C–N bond hydrogenolysis.
bond a in ethers 7, 8 undergoes catalytic hydrogenolysis,7 solvo-
Introduction
lytic reactions8 and cross-coupling.9 However, the bond length
The use of X-ray structure determination to aid understand-
changes appear to be only part of the explanation for the
ing of reaction mechanism by considering bond lengths and
observed ease of the catalytic reactions and the nature of the
angles in relation to chemical reactivity has been used in both
heterocycles themselves plays an important role.7
theoretical and experimental contexts.2 For example, a simple
aliphatic C–C single bond length of ca. 1.53 Å is considered
Although C–O bonds have been widely investigated by X-ray
analysis, there does not appear to have been a similar interest in
normal with bond order, n = 1, as is a C᎐C double bond of 1.34
C–N bonds,3 possibly because it is known that hydrogenolytic
or nucleophilic displacement of a C–N bond in an aromatic
amine is difficult.10 Compared with SN2 reactions of ethers and
alcohols or their derivatives, similar reactions at an aromatic
C–N bond are difficult because of the smaller electronegativity
of nitrogen compared with oxygen and therefore its greater
delocalisation of electron density into an aryl ring.11 Generally,
extreme conditions are needed to effect hydrogenolytic or solvo-
lytic removal of the amino group in aromatic amines. For
example, even conversion of a primary amine into its N,N-
bis-sulfonamide does not make C–N bond cleavage easy and
reaction with NaBH4 at 175 ЊC in HMPA is required for
hydrogenolysis.11 Simple direct ipso displacement of the amino
group from the C–N bond of an aromatic amine, as in Scheme 1
᎐
Å with bond order, n = 2;3 any formal single bond length lying
between 1.53 and 1.34 Å suggests a degree of double bond
character, with a partial bond order between 1 and 2.4a,b
Changes in bond lengths and angles for a series of compounds
have been used successfully to explain chemical reactivity by
relating ground-state structure, as observed by X-ray analysis,
to supposed transition state structures.2,5
For 3-aryloxy-1,1-dioxo-1,2-benzisothiazoles (3-aryloxy-
pseudosaccharins) 7 and 5-aryloxy-1-phenyl-1H-tetrazoles 8,
the central ether C–O–C bond has been shown to be quite
exceptional amongst aromatic ethers in having one very long
C–O bond (a in structures 7, 8) and one very short C–O bond
(b in structures 7, 8).6 In effect, the heterocyclic groups in 7, 8
siphon off electron density from the original phenolic bond a so
that its bond order becomes, n = 1 and the ether bond b to the
heterocycle becomes a partial double bond with n = 1.4. It was
found that the combined bond lengths a ϩ b for a wide variety
of diaryl ethers were always close to 2.78 Å, so that the available
electron density from oxygen must be limited and the total bond
energy, D(a) ϩ D(b), is constant.
The withdrawal of electron density from the original phen-
olic C–OH partial double bond on conversion into a hetero-
cyclic ether weakens it so that it becomes more like a C–O single
bond in aliphatic alcohols or ethers. The effect at the original
aryl ring of the phenol is as if the electronegativity of the oxy-
gen has been increased to such an extent that it becomes similar
to that of fluorine. Apart from the X-ray results, evidence for
Scheme 1
1
this effective change in electronegativity can be found in H
and 13C NMR spectra of ethers 7, 8, which show that the
original electron-donating effect of oxygen in phenols or simple
phenolic ethers has been changed into a strongly electron-
withdrawing effect in the heterocyclic ethers.6 The chemical
effects of these changes can be seen in the ease with which the
(path a), remains an elusive goal. The result of attempted cat-
alytic hydrogenolysis of the C–N bond of aromatic amines with
molecular hydrogen is normally the formation of a cyclic
alkylamine in high yield.12 Indeed, the easiest way to cleave a
C–N bond in primary aromatic amines lies indirectly through
DOI: 10.1039/b102571f
J. Chem. Soc., Perkin Trans. 2, 2001, 1315–1324
This journal is © The Royal Society of Chemistry 2001
1315

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Table 1 Selected bond lengths, bond orders and bond bond energies for amines 1–6
Amine
Bonda
Bond lengthb/Å
Bond orderc (n)
Bond energyd Dn/kJ molϪ1
1
a
b
c
a
b
bЈ
c
cЈ
a
b
c
a
b
bЈ
c
cЈ
a
b
c
a
b
c
1.460(5)
1.320(4)
1.323(4)
1.501(2)
1.385(2)
1.394(3)
1.287(3)
1.295(3)
1.430(2)
1.329(2)
1.311(2)
1.448(2)
1.393(2)
1.397(2)
1.288(2)
1.288(2)
1.421(2)
1.338(2)
1.315(2)
1.403(2)
1.3559(19)
1.3280(19)
1.343(2)
1.4357(19)
1.04
1.71
1.69
0.89
1.35
1.31
1.92
1.87
1.15
1.65
1.76
1.08
1.32
1.30
1.92
1.92
1.19
1.60
1.74
1.27
1.50
1.66
1.57
1.13
365
574
567
317
463
450
637
622
400
555
589
378
453
447
637
637
412
540
583
438
509
558
531
393
2
3
4
5
6
d
e
a These are the CN bonds indicated in structures 1–6. b Obtained by X-ray crystallographic analysis (esd’s in brackets). c Obtained from
ln(n) = (1.47 Ϫ bond length)/0.28; see text. d Estimated from ln(Dn/352) = 0.91ln(n); see text.
diazotisation.13a Because of this marked contrast between
aromatic ethers and amines in resistance to hydrogenolysis, the
present study was undertaken to examine the structures and
chemistry of several heterocyclic derivatives of aliphatic and
aromatic amines.
CH, N and HCN.15 From these values, the linear relationship
(2) was derived.2,4,6
ln(Dn/D1) = pln(n)
(2)
For any C–N bond of order n its strength may be estimated
reasonably accurately through eqn. (2), in which p = 0.91. For
example, using an aniline C–N bond length of 1.386 Å,18
a
Results and discussion
bond order of 1.35 may be calculated from eqn. (1), suggesting
that its C–N bond strength should be 462 kJ molϪ1. A com-
monly suggested average C–N bond strength for anilines is 427
Carbon–nitrogen bond lengths in amines, imines and nitriles
By addition of covalent radii, the average length of an aliphatic
C–N single bond is expected to be 1.47 Å, for a C–N double
bond 1.28 Å and for a C–N triple bond 1.15 Å.4 Reference to
compilations of measured bond lengths indicates that these
values are reasonably accurate and that the C–N bond length in
an aromatic amine (an aniline) is usually about 1.38–1.39 Å.3 A
survey of the Cambridge Crystallographic Database14 revealed
that the mean Ph–N bond length for a range of over 500 substi-
tuted anilines was 1.418 Å (sd 0.026) and for saturated N–C
bonds in the same molecules was 1.465 Å (sd 0.020). These
values for bond length permit the derivation of the simple bond
order (n)/bond length (r) relationship shown in eqn. (1).4
kJ mol .
Ϫ1 15 The bond strength relationship (2) was used to cal-
culate C–N bond strengths in the compounds described here
(Table 1; bond a in structures 1–6). These bond strengths are
important for consideration of reactivity towards hydrogenoly-
sis (see later).
r = 1.47 Ϫ 0.28 ln(n)
(1)
From this equation, an aromatic C–N bond in an aniline has
a partial bond order of about 1.35. Eqn. (1) was used to calcu-
late bond orders for the compounds reported here from bond
lengths determined by X-ray crystallography (Table 1) to show
how bond order changes markedly with structure in the present
heterocyclic derivatives of amines.
Carbon–nitrogen bond energies in amines, imines and nitriles
Compilations of bond strengths15 indicate that an average
value for the C–N bond of an aliphatic amine is about 352 kJ
molϪ1. Data for C–N bonds in aliphatic imines are sparse but
some heats of hydrogenation are known.16 From these values
and known heats of formation of amines,17 a C–N double bond
strength of 657 kJ molϪ1 may be estimated.18 For a C–N triple
bond, a value of 955 kJ molϪ1 can be estimated from the geo-
metric mean of C–C and N–N triple bonds,4 a figure which is
close to the 960 kJ molϪ1 calculated from heats of formation of
1316
J. Chem. Soc., Perkin Trans. 2, 2001, 1315–1324

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Table 2 1H NMR signals (δ) for 4-methoxyaniline and amines 1–4, 12a
4-Methoxyanilineb
1
2
3
4
12
3.62 (CH3O)
1.26 (t, J = 6 Hz, CH3) 1.45 (t, J = 7 Hz, CH3) 3.81 (CH3O)
3.87 (CH3O)
1.29 (t, J = 5.9 Hz,
CH3)
6.53 (d, J = 8.7 Hz, 3.51 (q, J = 6 Hz, CH2) 4.45 (q, J = 7 Hz, CH2) 7.07 (d, J = 7 Hz) (H3Ј,5Ј) 7.17 (d, J = 9 Hz, H3Ј,5Ј) 3.55 (q, J = 5.9 Hz,
H3,5)
CH2)
4.2 (br s, NH)
6.61 (d, J = 8.7 Hz, 7.82 (m, H5,6)
H2,6)
7.71 (d, J = 8 Hz, H4)
7.76 (d, J = 7 Hz (H2Ј,6Ј) 7.23 (d, J = 7.5 Hz, H4)
7.98 (m, H4)
8.17 (m, H7)
7.85 (t, J = 8 Hz, H5)
7.96 (t, J = 8 Hz, H6)
8.28 (d, J = 8 Hz, H7)
7.88 (m, H5,6)
8.05 (d, J = 6 Hz, H4)
8.45 (d, J = 6 Hz, H7)
7.63 (d, J = 9 Hz, H2Ј,6Ј) 7.52 (m, 5H)
7.77 (t, J = 7.5 Hz, H5)
7.92 (t, J = 7.5 Hz, H6)
8.26 (d, J = 7.5 Hz, H7)
a The δ values (TMS = 0) are given first in each column, followed in parentheses by the carbon number to which the hydrogens are attached. For
numbering used (non-conventional) see structures. The CH3 and CH2 groups are shown as such. Assignments in the benzisothiazole ring system
followed from cross-coupling experiments. b The carbon atom numbering is conventional and is shown in structures 12, 13.
Measurement of electronegativity by 1H and 13C NMR
spectroscopy
1
Although use of H NMR spectroscopy to estimate electro-
negativities may be questioned because of variations in chemical
shifts due to anisotropic terms, nevertheless such shifts have
been used successfully to give an indication of effective elec-
tronegativity of any grouping X through use of eqn. (3),
Electronegativity = 0.564 δinternal ϩ 2.00
(3)
itself. In the latter, the amino and methoxy groups are both
electron-donating. This is reflected in the upfield shifts of the
protons ortho to the two substituent groups (Table 2). In the
mono-N-pseudosaccharyl-substituted 4-methoxyaniline 3, the
protons ortho to the nitrogen have been shifted downfield
strongly by 1.26 ppm compared with the corresponding protons
in 4-methoxyaniline itself; the protons meta to the amino group
are shifted by 0.42 ppm and even the methyl protons on the
methoxy group have been moved downfield by about 0.18 ppm.
applied to substituted ethanes, C2H5X.19 The same technique
was used to estimate the effective electronegativity of oxygen in
aryloxy ethers of pseudosaccharins and phenyltetrazoles.6 In
eqn. (3), δinternal is the difference in chemical shifts of the methyl
and methylene groups in the substituted ethanes. From 1H NMR
spectra of N-(1,1-dioxo-1,2-benzisothiazol-3-yl)ethylamine 1
and N,N-bis(1,1-dioxo-1,2-benzisothiazol-3-yl)ethylamine 2,
the chemical shift differences δinternal were 2.26 and 2.94 ppm
respectively, giving effective electronegativities of 3.27 and 3.66
for the substituted amino nitrogen. For the corresponding phe-
nyltetrazolyl ethylamine 12, the effective electronegativity of
the amino nitrogen is calculated similarly to be 3.27 [Table 2
and eqn. (3)]. These estimates may be compared with a typical
value for the electronegativity of nitrogen of 3.0.13b Thus, one
pseudosaccharyl or one phenyltetrazolyl group causes a shift of
0.27 units of electronegativity at nitrogen but two pseudosac-
charyl groups cause a shift of 0.66 units. These movements in
electronegativity are not so impressive as the effect of just one
pseudosaccharyl group or one phenyltetrazolyl group on the
electronegativity of oxygen in their ethers of phenols, for which
the shift in electronegativity is about 0.5 units.6 Whereas the
oxygen shift in pseudosaccharyl 7 or phenyltetrazolyl ethers 8
gives the oxygen an effective electronegativity about equivalent
to that of fluorine, in the case of similar substitution into
amines even two pseudosaccharyl groups leave the effective
electronegativity of nitrogen only about the same as that of the
normal value for oxygen (3.5).13b These considerations of elec-
tronegativity changes become important when considering ipso
replacements of the amine group in anilines.
These are the effects expected of
a strongly electron-
withdrawing amino group rather than one having its usual
electron-donating properties. The shifts indicate an abrupt
change in effective electronegativity of the amino nitrogen in
4-methoxyaniline on substitution into the amino group of a
pseudosaccharyl unit and is in keeping with the estimated
change in electronegativity derived from eqn. (3). For com-
pound 4 containing two pseudosaccharyl substituents on the
amino nitrogen, these proton shifts are similar to those in the
mono-substituted amine 3. There is no large increase in effect-
ive electronegativity as might have been expected for substitu-
tion of two strongly electron-withdrawing pseudosaccharyl sys-
tems onto the amino nitrogen. This unexpected result is echoed
by the 13C shifts and is explained by significant structural
changes (see later).
Long-range paramagnetic or diamagnetic shielding by
neighbouring groups is important for protons and it could be
argued that the apparent electronegativity effects are simply due
to long-range shielding and/or deshielding. However, these long
range effects are much less important for nuclei other than
hydrogen (or deuterium) and measurement of 13C shifts has
been suggested as a better guide to electronegativity in aromatic
systems.20 Accordingly, the 13C NMR spectra of compounds 3,
4 were examined and compared with those of 4-methoxyaniline
itself (Table 3). The 13C shifts of all the carbons in compounds
1–4 were assigned (Table 4).21,22 These 13C signals reveal a very
large downfield change for the aromatic carbon attached to
nitrogen (C8 in structure 3 and C15 in 4) with δ-values of 156.8
and 160.8 ppm respectively, compared with the carbon attached
to nitrogen in 4-methoxyaniline (δ = 145.0 ppm). The shift of
this carbon is about 8 ppm for the addition of one pseudosac-
charyl group and a further 4 ppm on addition of a second
pseudosaccharyl group. These results are in keeping with the
amine of the original 4-methoxyaniline becoming electron-
withdrawing in marked contrast to its usual electron-donating
The changes in effective electronegativity are revealed even
more so on comparing the 1H and 13C NMR spectra of the two
4-methoxyaniline derivatives 3, 4 with that of 4-methoxyaniline
J. Chem. Soc., Perkin Trans. 2, 2001, 1315–1324
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Table 3 13C NMR signals (δ) for 4-methoxyaniline and amines 1–4, 12a,b
4-Methoxyaniline
1
2
3
4
12
57.9 (CH3)
13.9 (CH3)
37.8 (CH2)
13.4 (CH3)
47.9 (CH2)
55.5 (CH3O)
114.4 (3Ј,CH)
121.6 (7,CH)
123.6 (4,CH)
123.9 (2Ј,CH)
128.5 (3a,C)
130.6 (1Ј,C)
133.5 (6,CH)
133.8 (5,CH)
141.2 (7a,C)
156.8 (4Ј,C)
157.3 (3,C)
55.9 (CH3O)
116.0 (3Ј,CH)
122.9 (7,CH)
127.0 (3a,C)
127.3 (4,CH)
129.9 (2Ј,CH)
130.9 (1Ј,C)
134.2 (5,CH)
135.0 (6,CH)
141.8 (7a,C)
160.8 (4Ј,C)
163.8 (3,C)
15.0 (CH3)
39.5 (CH2)
124.1 (CH)
129.9 (CH)
130.4 (CH)
133.5 (8,C)
155.0 (1, C)
117.2 (3,5,CH)
117.7 (2,6,CH)
145.0 (1,C)
121.4 (7,CH)
123.1 (4,CH)
128.0 (3a,C)
133.3 (6,CH)
133.6 (5,CH)
142.5 (7a,C)
159.2 (3,C)
123.1 (4,CH)
126.6 (7,CH)
126.9 (3a,C)
134.5 (5,CH)
135.2 (6,CH)
141.7 (7a,C)
164.3 (3,C)
153.5 (4,C)
a The δ values (TMS = 0) are given first in each column, followed in parentheses by the carbon number in each formula and the number of hydrogen
1
atoms attached to that carbon. The CH3 and CH2 groups are shown as such. The numbers of attached hydrogens were determined by H–13C
coupling and by DEPT experiments. Assignments in the benzisothiazole ring system were as given in ref. 22, except for positions 6, 7 which were
deduced as shown in the note presented as ref. 21. b The carbon atom numbering is conventional and is illustrated in structures 12, 13.
Table 4 13C shift values (ppm) assigned to the SO2 and C᎐N groups
is virtually a single bond (n = 1.08). Thus, to obtain similar
bond length (bond order) changes for C–N in aromatic amines
to those observed for the C–O bonds in the corresponding
᎐
of the 1,1-dioxo-1,2-isothiazole section of 1,1-dioxo-1,2-benziso-
thiazoles.a,b
phenyl ethers, two pseudosaccharyl substituents are needed,
Group
α-Position
ortho
meta
para
compared with only one for the phenols. This result from X-ray
crystallographic analysis in the solid state is in agreement with
the changes observed in effective electronegativity in solution
from NMR shifts in that one pseudosaccharyl group changes
the effective electronegativity of the amino nitrogen from 3.00
to 3.26 (a shift of 0.26 units) but two pseudosaccharyl groups
produce a shift of ϩ0.66 units in electronegativity. It seems that
the inherently smaller electronegativity of nitrogen compared
with oxygen leads to it being more difficult to stop the nitrogen
continuing to conjugate with the aryl ring to which it is
attached. This effect of two pseudosaccharyl groups on a C–N
bond are sufficient to cause even the C–N single bond in the
ethylamine derivative 2 to stretch until it has a bond order n of
only 0.89 rather than 1.0. The mono-tetrazolyl substituted
compound 6 exhibits similar but smaller changes, with the
C–N bond of the aniline (C2–N5) having a bond order of 1.27,
indicating significant residual conjugation from nitrogen into
the aryl ring.
The combined bond lengths, a ϩ b, in the four amines 1, 3, 5,
6 average 2.76 Å, very close to the 2.78 Å found in the aryl
ethers of phenyltetrazoles and pseudosaccharins.6 The com-
bined length in the disubstituted compounds 2, 4 is significantly
different at about 2.85 Å. The bond lengths shown in Table 1
reveal that, in the mono-pseudosaccharyl and phenyltetrazolyl
derivatives 3, 5, 6, the C–N bond to the heterocyclic system is
considerably shorter by some 0.03–0.04 Å than is a typical C–N
bond in an aniline. The similarity in the combined bond lengths
a ϩ b in monosubstituted ethers and amines appears to be due
to the better conjugation of nitrogen compared with oxygen to
a pseudosaccharyl or tetrazolyl ring system in addition to its
concomitant continued conjugation to another aryl ring.
The other C–N bonds in the pseudosaccharyl compounds
2, 4 show even more remarkable changes. In the mono-pseudo-
saccharyl substituted aniline 3, the C–N bond b to the pseudo-
saccharyl ring shows strong partial double bond character
(bond order 1.65) but, with two pseudosaccharyl substituents
on nitrogen, as in compound 4, the C–N bond b lengthens again
to give a bond order of about 1.31. In this bis-substituted com-
pound, there are cross-conjugated π-orbital systems, viz., one
through nitrogen between the aniline ring and either one of the
two pseudosaccharyl groups (path a–b–c or a–bЈ–cЈ in structure
4) and the other between the two pseudosaccharyl groups
themselves (path c–b–bЈ–cЈ in structure 4). The second conjug-
ation path is equivalent to that of a triazapentadienyl anion
system of 6 π-electrons, in which the phenyl ring is simply pen-
dant as a non-conjugating susbstituent on the central nitrogen
–SO2–
ϩ11.9
ϩ6.9
Ϫ7.1
Ϫ0.5
0.0
0.0
ϩ5.2
ϩ4.8
–C᎐N–
᎐
a These values were determined as in ref. 21. The α-position is that
carbon in the benzene ring of 1,1-dioxo-1,2-benzisothiazoles to which
the group SO2 or C᎐N is attached; the ortho, meta and para shifts then
᎐
refer to such positions in the benzene ring relative to the chosen α-
position. The shift at the meta positions was constrained to be zero.20
b All shifts are relative to the 13C atoms in benzene, for which δ = 128.5
in DMSO c These shifts resemble those for –NMe3ϩ (SO2) and –CH᎐O
᎐
(–C᎐N), both of which are electron-withdrawing.20
᎐
properties. The total shift in electronegativity does not give the
nitrogen in the original aromatic amine an electronegativity
near to that of fluorine but it does become more like the normal
value for oxygen.
Bond lengths, bond angles and bond orders from X-ray
crystallographic analysis
With the bond order/bond energy relationships outlined above
[eqns. (1), (2)], bond lengths derived from X-ray crystallo-
graphic analysis can be used to estimate bond strengths. In
pseudosaccharyl ethers of phenols, the original phenolic C–OH
bond strength was found to be considerably reduced in its
ethers 7, 8.6 The relevant bond length data for the amines con-
sidered here are shown in Table 1, together with those for an
analogue 5, which does not have a conjugating group in the
4-position of the substituted aniline and also for an analogous
phenyltetrazole derivative 6. Generally, corresponding bond
lengths in the monosubstituted amines are very similar (bonds
a, b, c in structures 3,5) and suggest that the methoxy group has
little effect on the conjugation of nitrogen (N2) to the benz-
enoid ring. Therefore, bond length changes around the central
nitrogen of the amino group can be considered in isolation
from other potential conjugation effects of substituents in the
aniline ring.
On introducing one pseudosaccharyl substitutent into
4-methoxyaniline to give 3, the original arylamino C–N bond
of the aniline is stretched from being a partial double bond
of order 1.35 to one of order 1.15. Although the electron-
withdrawing effects of the pseudosaccharyl group in these
amines is similar to its effect in pseudosaccharyl aryl ethers,6 the
C7–N2 bond of compound 3 still appears to be partly conjug-
ated to the aniline ring. In the bis-pseudosaccharylamine 4 the
corresponding C15–N3 bond of the aniline is stretched until it
1318
J. Chem. Soc., Perkin Trans. 2, 2001, 1315–1324

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Table 5 Crystallographic data
Compound
1
2
3
4
5
6
Formula
M
C9H10N2O2S
210.3
C16H13N3O4S2
375.4
C14H12N2O3S
288.3
C21H15N3O5S2
453.5
C14H12N2O2S
272.3
C14H13N5O
267.3
Crystal system
Space group
Monoclinic
P21/c
Triclinic
P1
Monoclinic
P21
Triclinic
P1
Monoclinic
P21/n
Monoclinic
P21/c
¯
¯
a/Å
b/Å
c/Å
α/Њ
7.141(5)
6.946(2)
18.886(5)
90
95.12(4)
90
932.9(7)
4
1.497
8.165(2)
8.224(3)
12.933(4)
98.513(16)
107.370(18)
100.413(17)
796.1(4)
2
7.111(1)
6.863(1)
13.231(3)
90
90.00(3)
90
645.7(2)
2
1.483
8.1028(8)
8.3652(8)
15.7507(16)
96.111(3)
90.830(3)
93.793(3)
1058.97(18)
2
7.2916(16)
21.129(5)
8.0546(18)
90
97.246(5)
90
1231.0(5)
4
1.469
17.689(3)
6.6556(13)
11.735(2)
90
105.61(2)
90
1330.6(4)
4
1.334
β/Њ
γ/Њ
U/Å3
Z
Dc/g cmϪ3
1.566
3.30
1.422
0.29
µ/mmϪ1
0.31
0.21
0.26
0.73
T /K
153
0.037
0.043
1063, 127
160
0.037
0.101
2803, 228
213
0.028
0.062
2011, 184
160
0.039
0.111
4706, 281
160
0.040
0.110
2654, 173
160
0.042
0.103
2290, 183
R(F, F 2 > 2σ)
Rw (F 2, all data)
Data, parameters
15. This feature is enhanced by the torsional angles (22 and
135Њ; Table 5; structure 2, 4) of the planes of the pseudo-
saccharyl rings about the central nitrogen (N3) and the near sp2
geometry of this nitrogen, which precludes effective conjugation
between the aniline ring and either of the two pseudosaccharyl
groups. In the bis-pseudosaccharyl ethylamine 2, for which the
central nitrogen (N3) is not even formally π-conjugated to the
ethyl group, the conjugation path c–b–bЈ–cЈ has similar bond
orders to those in compound 4. Since this is the only conjugated
pathway involving N3 in compound 2 and it is almost identical
in bond ordering as the corresponding pathway in compound 4,
it must be presumed that both pathways are essentially of the
triazapentadienyl type 15 and that all formal conjugation from
the central nitrogen to the aryl ring has been lost. Thus, the
introduction of a second electron-withdrawing group into a
mono-substituted aromatic amine simply leads to strong con-
jugation between the two substituting heterocyclic groups
through the central nitrogen and leads also to the original aryl
group becoming a non-conjugating appendage.
arylamines 3, 5 are broadly similar (conjugation from the aryl
ring through the oxygen or nitrogen to the pseudosaccharyl
group), the effect of adding a second pseudosaccharyl ring
system to the arylamine is to change the conjugation pattern
entirely so as to by-pass the aryl ring. This explains the anom-
alies discussed above for the NMR shifts. With the new con-
jugation path, the central amino nitrogen has only an inductive
effect on the aryl ring. It would be expected that two alkyl- or
aryl-sulfonyl groups attached to an arylamine might behave
similarly because the double substitution opens up a new more
favourable conjugation system. This deduction suggests that a
search for X-ray structures, in which there is a similar “penta-
dienyl” system, might prove informative. The Cambridge Crys-
tallographic Database provided relevant comparisons, some of
which are shown in structures 16–21.25 In five examplar com-
pounds (16–20) having an aniline-like nitrogen doubly substi-
tuted by methylsulfonyl or 4-methylphenylsulfonyl groups, the
aryl C–N bond has a bond order of about1 1.07, rather than the
value of 1.35 expected for an aniline exhibiting partial conjug-
ation of nitrogen to the aryl ring (Table 6). This stretching and
decrease in bond order exactly parallels the behaviour of the
bis-saccharyl compound 4 and is in keeping with the stretching
of the C–N single bond a in the bis-saccharyl compound 2.
Similarly, the phthalimido compound 21 has an aryl C–N bond
a that is also single rather than conjugated. In this last com-
pound, there are two other aryl C–N anilino bonds in the same
molecule but these other C–N bonds have bond orders of about
1.35, typical of partly conjugated anilino C–N bonds. Thus,
when an anilino nitrogen is doubly substituted by potentially
conjugating groups, the central nitrogen loses all delocalisation
along the C–N bond into the original aryl ring and becomes
instead a simple single bond. At the same time, the two new
substituents conjugate through the nitrogen and attain a “penta-
dienyl” anion-like conjugated pathway. In all of the compounds
2, 4, 16–21, the four bonds making up the “linear” system 15
are partial double bonds having lengths significantly different
In this second triazapentadienyl conjugation pathway 15 for
compounds 2, 4, the N–C–N–C–N system is not completely
coplanar and cannot itself fully conjugate. The inability of this
system to conjugate completely is due to steric interferences
between the pseudosaccharyl and aryl rings. Structural mini-
mization based on calculation at the B3LYP level23 using the
basis set 6–311G*, produced molecular geometries similar to
those found experimentally by X-ray diffraction methods. For
bis-N-pseudosaccharyl substituted aniline, it was confirmed
that the two pseudosaccharyl groups could not be co-planar
because of steric hindrance and therefore that they cannot be
fully conjugated through the path c–b–bЈ–cЈ. The triazapenta-
dienyl system 15 may be compared formally with the all-carbon
pentadienyl anion. 24
from simpler compounds. For example, the C᎐O bonds in com-
᎐
pound 21 have bond lengths that are shorter than those of a
simple amide, while the C–N bonds are considerably longer
than those found in simple amides. Similar arguments apply to
the N–S and S–O bonds in the sulfonamides 16–20.
Theaboveevidencesuggeststhat,whencomparedwithpseudo-
saccharyl or phenyltetrazolyl ethers of phenols, substitution of
these heterocyclic systems into the amino group of arylamines
might not be expected to have the same profound effect on ease
of ipso substitution. The effective electronegativity of oxygen
in the pseudosaccharyl aryl ethers 7 is near to that of fluorine
but, for nitrogen in amines 3, 4, the introduction of one
pseudosaccharyl group does not produce a shift to carry the
Whereas general structural features for pseudosaccharyl
ethers 7 of phenols and N-mono-pseudosaccharyl substituted
J. Chem. Soc., Perkin Trans. 2, 2001, 1315–1324
1319

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Table 6 Bond lengths/Å for some “pentadienyl” systems, 16–21
Bond
16
17
18
19
20
21
aa
b
bЈ
cb
cЈb
1.450 (1.07)
1.689
1.678
1.382, 1.416
1.421, 1.430
1.458 (1.04)
1.671
1.672
1.431, 1.408
1.414, 1.414
1.453 (1.06)
1.687
1.670
1.427, 1.421
1.421,1.420
1.446 (1.09)
1.680
1.678
1.425, 1.423
1.425, 1.425
1.455 (1.06)
1.679
1.679
1.429, 1.421
1.426, 1.439
1.451 (1.07)
1.416
1.392
1.171
1.214
a Calculated bond order is shown in parentheses. b Both S᎐O bonds are given.
᎐
hydrogen donors had no effect but, for catalytic reduction with
hydrogen gas at a temperature of 150 ЊC and a moderately high
pressure, a hydrogenolytic reaction was observed. This was not
the desired hydrogenolysis of the C–N bond (a in structures 3,
4; Scheme 1, path a) but, instead, a different C–N bond (b in
structure 4) was cleaved to give the mono-pseudosaccharyl
amine 3 and the reduced product 11 (Scheme 1, path b). When
attempts were made to effect hydrogenolysis with hydride
reagents, reduction was observed exclusively via reaction path b
(Scheme 1) and not by path a. The result is not surprising in
view of the structural evidence presented here for a change in
conjugation pattern on substituting two heterocyclic groups
onto the nitrogen of an aromatic amine (see below).
ipso Cleavage of aryl–X bonds
The removal of a substituent from an aryl ring by ipso replace-
ment is generally not easy. Aromatic amines are inert except
under a few reported extreme conditions. Phenols are largely
inert and fluorine amongst other groups is resistant to ipso
displacement unless the aromatic ring is extensively activated by
strongly electron-withdrawing groups. Easy hydrogenolysis is
found for heteroaromatic ethers of phenols 7 under hetero-
geneous catalytic conditions,6 for homogeneously catalysed
cross-coupling,9 for displacement of fluorine by hydroxy under
catalysed conditions26 and most notably for diazonium com-
pounds, which may be reduced to arene with phosphinic acid
under non-catalytic conditions.13a Simple effects of bond ener-
gies cannot account for these differences. An energy balance
of bond-forming and bond-breaking reactions at the heart
of aryl–X bond displacement suggests that it should be exo-
thermic and, specifically for C–O and C–N cleavage, that it
should be about equally exothermic in the two cases, with small
activation energies.27,28 This inference is clearly incorrect for
amines and, since the bond energy terms are well-established, it
indicates that there must be an energy of activation barrier that
is small in some reactions but sufficiently large in others as to
make bond-breaking difficult. A consideration of the bonding
and non-bonding orbitals in aryl–X compounds suggests a
reason for such changes in activation energy.
It has been shown that, for substituents providing p-orbital
overlap with the π-system in a benzene ring, the resultant π-
orbitals are arranged as 4 bonding (π1–π4) and 3 antibonding
(π5–π7).29 Most ipso displacements are nucleophilic reactions, in
which the incoming nucleophile may be HϪ or OHϪ for example
and require attack at the aromatic carbon. Frontier orbital
theory indicates that such reactions are governed mostly by two
factors, one of which concerns the Coulombic attraction or
repulsion between an incoming nucleophile and the ipso carbon
(the first term of eqn. (4)) and the other concerns bonding
between LUMO and HOMO orbitals of electrophile and
nucleophile (the second term of eqn. (4), in which ∆E is the
interaction energy, q represents the net charge of nuclei and
electrons, R is the distance apart of incoming nucleophile and
electrophilic centre, β is a resonance integral, c is the orbital
coefficient and EHOMO and ELUMO are the energies of the
HOMO and LUMO orbitals).30 The second term on the right-
hand side becomes zero if the outermost π-electron density in
the nucleophile or at the ipso carbon in the π5 orbital of the
electronegativity of nitrogen even to that of oxygen let alone to
fluorine. Further, the introduction of a second pseudosaccharyl
group onto nitrogen leads to development of a new conjugation
pattern and the effective electronegativity at nitrogen is still not
close to that of fluorine. In such circumstances, easy hydro-
genolysis of amino C–N bonds in amines 3, 4 analogous to the
easy hydrogenolysis of C–O bonds in pseudosaccharyl 7 or
phenyltetrazolyl ethers 8 of phenols might not be expected. The
experimental attempts described below to effect cleavage of
such C–N bonds were designed to test their reactivity under
typical hydrogenolytic conditions.
Hydrogenation of amines 3, 4
Based on the extremely easy catalytic transfer hydrogenolysis
of pseudosaccharyl aryl ethers 7 to give arenes and saccharin,
it was hoped that similar reduction of the anilino compounds
3, 4 would give anisole (9; Scheme 1, path a) and a bis-
pseudosaccharyl amine 10. For all of the mono-pseudo-
saccharyl or mono-phenyltetrazolyl derivatives of aromatic
amines, no hydrogenolysis of the C–N bond a to give the
desired products (Scheme1, path a) could be effected. However,
hydrogenolysis of bis-pseudosaccharyl amine 4 did occur
elsewhere. In this last case, catalytic transfer reduction using
1320
J. Chem. Soc., Perkin Trans. 2, 2001, 1315–1324

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aromatic system is zero. The latter is exactly the case29 for π5
and so the LUMO–HOMO interaction can be ignored in this
ipso series. In contrast to this negligible effect, it can be seen
that the overall (orbitals π1 to π4) density at the ipso carbon does
vary significantly, depending on the electronegativity of the
group X in aryl–X.24b,31 As the electronegativity of the sub-
stituent X increases, there is an increasing inductive effect on
the ipso carbon, making it more and more positive. Thus, easy
nucleophilic displacement at the ipso carbon should be char-
acteristic of groups having high effective electronegativities,
so that the first term in eqn. (4) becomes significant. This
Synthesis of N-substituted amines
N-(1,1-Dioxo-1,2-benzisothiazol-3-yl)ethylamine 1. A solu-
tion of ethylamine in THF (2 mL; 4.0 mmol of amine; Aldrich)
was added to 3-chloro-1,1-dioxo-1,2-benzisothiazole (pseudo-
saccharyl chloride; 1.08 g, 5.32 mmol) in THF (10 mL) and the
mixture was stirred at room temperature for 1.5 h, after which it
was made alkaline with aqueous sodium hydroxide (5% w/w)
and then an excess of cold water was added. The resulting
precipitate was filtered off and recrystallised to give the
required compound 1, mp 280–281 ЊC (from methanol–water;
0.65 g; 78% yield). Found: C, 51.3; H, 4.8; N, 13.4. Calculated
for C9H10N2O2S: C, 51.4; H, 4.8; N, 13.3%); νmax. 1153, 3332,
1525 cmϪ1; ms: [Mϩ], m/z 210.
(4)
N-(1,1-Dioxo-1,2-benzisothiazol-3-yl)-4-methoxyaniline 3. A
solution of 4-methoxyaniline (0.32 g; 2.60 mmol) and 3-chloro-
1,1-dioxo-1,2-benzisothiazole (pseudosaccharyl chloride; 0.53
g, 2.56 mmol) in THF (10 mL) was heated under reflux for 2.5
h, after which the solvent was evaporated off under pressure.
The residual solid was washed with water, dried in vacuo
at room temperature and recrystallised to give the required
product, mp > 330 ЊC (from acetone–ethanol; 0.57 g; 72%
yield). Found: C, 58.5; H, 4.2; N, 9.7. Calculated for
C14H12N2O3S: C, 58.3; H, 4.2; N, 9.7%; νmax. 1350, 1154 (SO2),
3328 (NH), 1617, 1571, 1513 (Ar) cmϪ1; ms: [Mϩ], m/z 288.
deduction runs parallel to the observed trend towards increas-
ing susceptibility to nucleophilic displacement at the ipso carbon
as the effective electronegativity of the group X in Aryl–X
increases. This indicates that a major reason for the failure of
aromatic amines to undergo hydrogenolysis when substituted
by pseudosaccharyl or phenyltetrazolyl groups, in complete
contrast to the very easy analogous hydrogenolysis of these
heteroaromatic ethers of phenols, lies in the large initial
inherent difference in electronegativities between nitrogen and
oxygen and the failure of the heterocyclic derivatives to push
the electronegativity of the amine nitrogen to a sufficiently high
value. The theoretical considerations covered here are being
investigated in greater detail through estimations of activation
energies by semi-empirical and ab initio methods.32 The new
conjugation pathway 15 provides an easier but still diffi-
cult route to hydrogenolysis than does hydrogenolysis of the
original anilino C–N bond but then leads to reversal of the
original substitution to return to the original aniline.
N-(1,1-Dioxo-1,2-benzisothiazol-3-yl)-3-methylaniline 5. This
was prepared as for compound 3. Colourless crystals (from
THF–water; 51% yield), mp 311–312 ЊC (lit.33 296–297 ЊC).
Found: C, 61.7; H, 4.4; N, 10.3. C14H12N2O2S requires: C, 61.8;
H, 4.4; N, 10.3 %; 1H NMR: δ 8.49 (1H, m), 8.08 (1H, m), 7.91
(2H, m), 7.67 (2H, d, J = 8 Hz), 7.38 (1H, t, J = 8 Hz), 7.10 1H,
d, J = 8 Hz), 2.38 (3H, s); 13C NMR (H-decoupled): δ 157.0,
141.0, 138.7, 137.6, 134.0, 133.6, 129.1, 128.5, 126.7, 123.7,
122.7, 121.7, 119.6, 21.3; νmax. 1345, 1157, 3330, 1624, 1485,
1572 cmϪ1; ms: [Mϩ], m/z 272.
Experimental
Melting points were recorded on a Gallenkamp melting point
apparatus and are uncorrected. Mass spectra were recorded on
a Trio 1000 Quadrupole Mass Spectrometer using electron
ionisation at 70 eV or on a VG Analytical 7070E double focus-
ing high resolution mass spectrometer. Infrared spectra were
recorded on a Perkin Elmer 883 instrument as Nujol mulls. 1H
NMR spectra were obtained on either a Bruker ACE200 (200
MHz) or on a Varian Gemini (300 MHz) instrument, using
tetramethylsilane as internal standard and CDCl3 as solvent,
except for the series shown in Tables 2, 3 for which d6-dimethyl
sulfoxide was the solvent. Gas–liquid chromatograms were
obtained with a Dani 3800 gas chromatograph or with a
Phillips PU 4600 gas chromatograph, both equipped with flame
ionisation detector and using Carbowax capillary columns.
Microanalyses were performed on a Carlo Erba 1106 elemental
analyser, equipped with an electrical detector. Thin layer
chromatography was performed on silica gel 60F250 plates
(Merck).
N,N-Bis-(1,1-dioxo-1,2-benzisothiazol-3-yl)-4-methoxyaniline
4. Method A. Neat 4-methoxyaniline (2.4 g; 19 mmol) and tri-
fluoroacetic anhydride (11.4 g; 54 mmol) were stirred at room
temperature for 1 h, after which the whole reaction mixture was
evaporated in vacuo to gave a solid, which was recrystallised to
give N-(4-methoxyphenyl)-1,1,1-trifluoroacetamide, mp 110–
1
112 ЊC (small needles from methanol; 4.1 g; 98.3% yield). H
NMR: δ 7.63 (2H, d, J = 9 Hz), 6.98 (2H, d, J = 9 Hz), 3.77 (3H,
s); νmax. 3300 (N–H), 1690 (CO–NH–) 822 (C–H, Ar) cmϪ1; ms:
[Mϩ], m/z: 219. To a stirred solution of this trifluoroacetamide
(0.24 g; 1.11 mmol) in dry THF (10 mL) was added portionwise
sodium hydride (60% w/w; 0.4 g; 10 mmol). After a further 20
min, pseudosaccharyl chloride (0.44 g; 2.2 mmol) was added
and the mixture was left to stir for 24 h at room temperature.
The resulting sodium chloride was filtered off and the solution
was evaporated to dryness to leave a residue, which was dis-
solved in ethyl acetate (10 mL) and washed with aqueous
sodium hydroxide (5%; 3 × 10 mL), water and finally dried
(Na2SO4); the final solution was evaporated under reduced
pressure and the residual crude solid was crystallised from
acetone to give the required amine 4 in 27% yield. Analytical
details for 4 appear in the following method.
Method B. To a stirred solution of N-(1,1-dioxo-1,2-
benzisothiazol-3-yl)-4-methoxyaniline 3 (1.6 g; 5.5 mmol) in
dry THF (10 mL) was added portionwise sodium hydride (60 %
w/w; 0.32 g; 8.0 mmol). After a further 20 min, pseudosaccharyl
chloride (1.3 g; 6.3 mmol) was added. After 1 h the mixture was
examined by TLC (ethyl acetate), which showed complete con-
version of the amine 3 (Rf = 0.46) to give a single new product
(Rf = 0.5). The reaction mixture was added to cold water and
extracted with ethyl acetate (3 × 10 mL). The combined organic
layers were washed with water, dried (Na2SO4) and evaporated
Crystals were examined at reduced temperature on a variety
of diffractometers: Stoe IPDS image-plate system at Liverpool
University for compounds
1 and 3 (Mo-Kα radiation,
λ = 0.71073 Å), Stoe-Siemens AED at Newcastle University for
compounds 2 and 6 (Cu-Kα radiation, λ = 1.54184 Å), Bruker
AXS SMART at Newcastle for compound 4 (Mo-Kα radiation,
λ = 0.71073 Å), and Bruker AXS SMART at Daresbury
Laboratory for compound 2 (synchrotron radiation, λ = 0.6879
Å, for a very small crystal). The structures were solved by direct
methods and were refined on F 2 values for all unique reflections
(except for compound 1, for which refinement on F was used).
Hydrogen atoms were constrained to idealised positions.†
† CCDC reference numbers 161957–161962 for compounds 1–6,
respectively. See http://www.rsc.org/suppdata/p2/b1/b102571f/ for crys-
tallographic files in .cif format.
J. Chem. Soc., Perkin Trans. 2, 2001, 1315–1324
1321

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to give a residual solid (2.1 g; 4.6 mmol), which was recrystal-
lised to give the required product 4, mp >330 ЊC (square yellow
transparent plates from ethanol–acetone; 1.7 g; 68% yield).
Found: C, 55.7; H, 3.3; N, 9.3. Calculated for C21H15N3O5S2: C,
stirred vigorously and heated under reflux. The reaction was
monitored by TLC (diethyl ether) but no reduction of the
amine 6 had occurred after five hours, despite addition of more
catalyst and hydrogen donor.
55.7; H, 3.3; N, 9.3 %; νmax. 1601, 1587, 1511, 1313, 1128 cmϪ1
ms: [Mϩ], m/z 453.
;
Attempted hydrogenolysis of N,N-bis(1,1-dioxo-1,2-
benzisothiazol-3-yl)-4-methoxyaniline 4
N,N-Bis-(1,1-dioxo-1,2-benzisothiazol-3-yl)ethylamine 2. To
a stirred solution of N-(1,1-dioxo-1,2-benzisothiazol-3-yl)-
ethylamine 1 (0.23 g; 1.1 mmol) in dry THF (10 mL) as added
portionwise sodium hydride (60% w/w; 0.14 g; 3.6 mmol). After
a further 20 min, pseudosaccharyl chloride (0.24 g, 1.3 mmol)
was added and the mixture was stirred at room temperature.
After 5 h, cold water (10 mL) was added to quench the reaction
and the mixture was extracted with ethyl acetate (3 × 15 mL).
The combined organic extracts were washed with water (3 × 10
mL) and dried (Na2SO4). After evaporation under reduced
pressure, the residual oily solid was recrystallised to give the
required bis-amine 2, mp >250 ЊC (small colourless needles
from ethanol–acetone; 0.22 g, 53.3%). Found: C, 51.4; H, 3.6;
N, 11.0. Calculated for C16H13N3O4S2: C, 51.2; H, 3.5; N, 11.2%;
νmax. 1326, 1132, 1601, 1531, 3441 cmϪ1; ms: [Mϩ], m/z 375.
(i) By catalytic transfer reduction. (a) To a stirred solution of
the bis-pseudosaccharylamine 4 (0.058 g; 0.127 mmol) and
dodecane (internal standard; 0.020 g) in THF (8 mL) contain-
ing Pd-on-charcoal catalyst (Pd/C; 10%, 0.077 g) at 60 ЊC was
added a solution of sodium phosphinate (0.1952 g; 2.22 mmol)
in water (2 mL). The reaction was monitored by TLC and GC
but, after 12 h, no reaction had occurred and starting material
was recovered.
(b) To a solution of the bis-pseudosaccharylamine 4 (71.4
mg; 0.157 mmol) in propan-2-ol (5 mL) was added Raney nickel
(W2; 0.083 mL) and the mixture was heated under reflux for 12
h. As in (a), no reaction was observed.
(ii) By catalytic reduction with hydrogen gas. The bis-
pseudosaccharylamine 4 (0.062 g, 0.136 mmol) and Pd/C
catalyst (10% w/w; 0.08 g) in THF (10 mL) were stirred with
hydrogen at 150 ЊC at a pressure of 125 psi (9 atm). After 7 days,
the reaction was stopped and cooled to room temperature
and the catalyst was filtered off. GC analysis of the filtrate
revealed no volatile components other than solvent. However,
on TLC, one new component appeared, the Rf of which
(Rf = 0.46) was consistent with the presence of N-(1,1-dioxo-
1,2-benzisothiazol-3-yl)-4-methoxyaniline 3. The solvent was
evaporated under reduced pressure and the residual solid
N-[1-(4-Methoxyphenyl)-1H-tetrazol-5-yl)aniline 6. 5-Chloro-
1-phenyl-1H-tetrazole (0.99 g; 5.5 mmol) and 4-methoxyaniline
(1.51 g; 12.3 mmol) were melted together and stirred under a
nitrogen atmosphere at 140 ЊC for five hours. The reaction
mixture was cooled and the resulting purple solid was shaken
with dichloromethane (100 mL) and filtered from 4-methoxy-
anilinium chloride. The filtrate was evaporated under reduced
pressure and the resulting solid was recrystallized to give the
amine 6 (pale pink plates from ethanol; 0.7582 g, 52% yield),
mp 146–150 ЊC. Found: C, 62.8; H, 4.9; N, 26.5%. Calculated
for C14H13N5O: C, 62.9; H, 4.9; N, 26.2%; νmax (Nujol mull),
3162–3310, 1590, 1532 and 1235 cmϪ1; δH 3.88 (s, 3H), 6.20
(br s, 1H), 7.09 (d, 2H, J = 8.8 Hz), 7.41 (d, 2H, J = 8.8 Hz),
7.26–7.57 (m, 5H); ms [Mϩ] m/z 267; accurate mass 267.11198
Da, C14H13N5O requires 267.11200. A further sample of this
material was recrystallized by slow diffusion of petroleum ether
(bp 60–80 ЊC) into a solution of the amine 6 in ethanol in a
closed vessel. X-Ray crystallographic diffraction analysis
showed that, as a result of a Dimroth rearrangement,34 struc-
ture 6 is correct and is not that expected of simple substitution
of chlorine in 5-chloro-1-phenyl-1H-tetrazole by aniline.
1
(37.44 mg; 95.6% recovered material) was analysed. H NMR
spectroscopy confirmed that the isolated product was the
amine 3.
(iii) Using hydride reagents. (a) Sodium tetrahydroborate
(38.0 mg, 1.00 mmol) was added gradually in small amounts to
a stirred solution of N,N-bis(1,1-dioxo-1,2-benzisothiazol-3-
yl)-4-methoxyaniline 4 (54.2 mg, 0.12 mmol) in methanol (5
mL) at room temperature. The whole was heated to 60 ЊC and,
after two days, TLC (ethyl acetate) showed one new component
had been formed. Water was added to stop the reaction and the
organic product was extracted with ethyl acetate (3 × 10 mL).
The combined organic phases were washed with water, dried
(Na2SO4) and the solvent was evaporated under reduce pressure
to give a residual solid (0.032 g; 93% recovered material).
1H NMR spectroscopy showed that N-(1,1-dioxo-1,2-
benzisothiazol-3-yl)-4-methoxyaniline 3 had been formed. A
small amount of this residue was dissolved in THF and the
resulting solution was examined by GC for the presence of 4-
methoxyaniline but only solvent was found, a result which was
confirmed by GC/MS.
N-(1-Phenyl-1H-tetrazol-5-yl)ethylamine 12. To a solution of
5-chloro-1-phenyl-1H-tetrazole (1.00 g; 5.5 mmol) in THF (1.8
mL) at room temperature was added a 2.0 M solution of ethyl-
amine in THF (6 mL; 12 mmol; 2 M, Aldrich) via a syringe
under dry nitrogen. The reaction mixture was stirred at room
temperature for 4 h before being poured into ice–water (200
mL). The mixture was allowed to warm to room temperature
and extracted with diethyl ether (3 × 40 mL). The combined
ethereal extracts were washed with saturated aqueous NaHCO3
(30 mL) and dried (MgSO4). Removal of the solvent in vacuo
yielded a pale yellow solid, which was recrystallised to give the
required amine 12, mp 162–164 ЊC (colourless plates from
toluene, 0.333 g; 32% yield). Found: C, 57.1; H, 5.8; N, 37.3%.
Calculated for C9H11N5: C, 57.1; H, 5.8; N, 37.0%; ms, m/z 189
[Mϩ], m/z 160 (41%).
(b) The above reaction (a) was repeated with the bis-
pseudosaccharylamine 4 (50.1 mg, 0.11 mmol) and sodium
tetrahydroborate (35.9 mg, 0.95 mmol) but with THF (5 mL) as
solvent. After 12 h, TLC showed a new component had formed
(Rf = 0.46), in addition to a small amount of starting material
(Rf = 0.5). Reaction was stopped by addition of cold water and
then hydrochloric acid (2 M) to destroy excess of reducing
agent. The aqueous layer was made alkaline with aqueous
NaHCO3 and extracted with diethyl ether (2 × 10 mL). The
combined extracts were dried (Na2SO4), filtered and the
solvent removed under reduced pressure to give a residual
solid (12.2 mg, 90%), which was shown to be almost entirely 4-
Attempted reduction of N-[1-(4-methoxyphenyl)-1H-tetrazol-5-
yl]aniline 6 using palladium-on-charcoal as catalyst and sodium
phosphinate as hydrogen donor
1
Pd/C catalyst (10% w/w; 120 mg) in absolute ethanol (3 mL)
was added to a vigorously stirred solution of N-[1-(4-
methoxyphenyl)-1H-tetrazol-5-yl]aniline 6 (150 mg; 0.56 mmol)
in toluene (8 mL). A solution of sodium phosphinate (150 mg)
in distilled water (2.5 mL) was added and the mixture was
methoxyaniline by GC/MS and H NMR, δ 3.75 (s, 3H), 6.65
(d, 2H, J 9Hz), 6.75 (d, 2H, J 9 Hz).
(c) Reaction (a) above was repeated with the bis-
pseudosaccharylamine 4 (37.5 mg, 0.083 mmol), sodium
tetrahydroborate (36.6 mg, 0.97 mmol) and 1,4-dioxane (5 mL)
1322
J. Chem. Soc., Perkin Trans. 2, 2001, 1315–1324

View Article Online
11 S. W. McCombie in, Comprehensive Organic Synthesis, Vol. 8, eds.
as solvent. After 2 days at 60 ЊC, TLC showed that no reaction
had occurred.
B. M. Trost and I. Fleming, Pergamon Press, Oxford, ch. 4.2,
pp. 826–828; and references therein.
12 M. Hudlicky, Reduction in Organic Chemistry, 2nd. edn., ACS
Monograph 188, American Chemical Society, Washington DC,
1996, pp. 129–135.
13 (a) J. March, Advanced Organic Chemistry, 3rd edn., Wiley, New
York, 1985, pp. 646–647; (b) J. March, Advanced Organic Chemistry,
3rd edn., Wiley, New York, 1985, p. 14.
(d) Reaction (a) above was repeated using the amine 4 (23.6
mg, 0.052 mmol), sodium tetrahydroborate (23.6 mg, 0.623
mmol) in DMF (5 mL) as solvent. After 12 h, TLC showed only
one spot (Rf = 0.46), corresponding to N-(1,1-dioxo-1,2-
benzisothiazol-3-yl)-4-methoxyaniline 3. Water was added to
stop the reaction and the resulting mixture was extracted with
diethyl ether (3 × 10 mL). The combined diethyl ether extracts
were dried (Na2SO4), filtered and the solvent was removed
14 F. H. Allen, O. Kennard and R. Taylor, Acc. Chem. Res., 1983, 16,
146.
15 Handbook of Chemistry and Physics, 76th edn., ed., D. R. Lide, CRC
Press, Boca Raton, 1995–1996, pp. 9-51 to 9-73.
1
under reduced pressure. A H NMR spectrum of the residual
solid (15.6 mg) in d6-DMSO verified the formation of the
compound 3.
16 L. M. Jackson and D. I. Packham, Proc. Chem. Soc., 1957, 349.
17 The heat of formation of methanimine (CH2᎐᎐NH) has been
determined indirectly from hydride affinities as being 107 kJ molϪ1
(D. J. DeFrees and W.J. Hehre, J. Phys. Chem., 1978, 82, 391). A
MOPAC calculation at the PM3 level yields a value of 88.1 kJ molϪ1
(J. J. P. Stewart, MOPAC 6.00, QCPE No. 455; supplied by CAChe
WorksSystem v. 4.1, Oxford Molecular, Oxford Science Park,
Oxford, UK OX4 4GA); from the geometric mean of the heats of
formation of ethene (52.5 kJ molϪ1) and diimide (157.8 kJ molϪ1), a
methanimine becomes 91.2 kJ molϪ1. Incorporating the mean value
(e) Reaction (a) above was repeated but with lithium tetra-
hydroaluminate (8.8 mg, 0.23 mmol) in place of NaBH4 and
THF (5 mL) at room temperature. After 12 h, TLC showed two
spots with Rf = 0.46, 0.5, corresponding respectively to N-(1,1-
dioxo-1,2-benzisothiazol-3-yl)-4-methoxyaniline 3 and starting
material 4. Water was added to stop the reaction and the mix-
ture was extracted with diethyl ether. The combined extracts
were dried (Na2SO4), filtered and the solvent was evaporated
from all of these figures gives a C᎐N bond strength of 657 kJ molϪ1
.
᎐
18 The C–N bond length in aniline is given as 1.43 Å in ref. 16, as
derived by microwave spectroscopy. This length is at variance with
the suggested average C–N bond length in compilations.4c A search
of the Cambridge Crystallographic Database14 gives 1.385 and
1.399 Å for two independent molecules of aniline at 252 K35 and an
average of 1.375 Å for aniline as solvent or clathrate guest. For the
present purposes, a mean of these last three values (1.386 Å) has
been used.
1
under reduced pressure to give a solid (29.1 mg). H NMR
spectroscopy of this solid verified it to be a mixture of amines 3,
4. From the integrals for the characteristic peaks at δ = 1.1, 2.8
ppm the compounds 3, 4 were estimated to be present in a ratio
of 72 : 28.
19 J.-C. Muller, Bull. Soc. Chim. Fr., 1964, 1815; L. M. Jackman and
S. Sternhell, Applications of Nuclear Magnetic Resonance Specroscopy,
2nd edn., Pergamon Press, 1969, pp. 64–66.
Acknowledgements
The authors thank FCT Portugal (CF, RAWJ), the
Eschenmoser Trust (AFB), EPSRC and CCLRC (WC) and the
Royal Society of Chemistry (AFB) for generous financial
assistance.
20 H. Spiesecke and W. G. Schneider, J. Chem. Phys., 1961, 35, 731;
E. Breitmeier and W. Voelter, 13C NMR Spectroscopy, 2nd edn.,
in Monographs in Modern Chemistry, No. 5, ed. H. F. Ebel,
Verlag Chemie, Weinheim, 1978, pp. 183, 272.
21 Ref. 22 gives assignments of 13C shifts for most positions in 1,1-
dioxo-1,2-benzisothiazoles, except for positions 6, 7 (conventional
numbering) which are listed as uncertain. By using the extra
information in the present series of compounds, it has been possible
to confirm these existing assignments and to assign positions 6, 7
References
1 Part 28: A. F. Brigas and R. A. W. Johnstone, J. Chem. Soc., Perkin
Trans. 1, 2000, 1735.
exactly. The SO2 and C᎐N groups of the 1,1-dioxo-1,2-
᎐
2 For examples of discussion of X-ray structure determination in
relation to chemical reactivity see ref. 4 and H. Bent, Chem. Rev.,
1968, 68, 587; H. B. Bürgi, J. D. Dunitz and E. Shefter, J. Am. Chem.
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Chemistry and Physics, ed., D. R. Lide, CRC Press, Boca Raton,
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4 (a) L. Pauling, J. Am. Chem. Soc., 1947, 69, 542; (b) L. Pauling, The
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5 A. J. Kirby and P. G. Jones, J. Am. Chem. Soc., 1984, 106, 6207.
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7 R. A. W. Johnstone, A. H. Wilby and I. D. Entwistle, Chem. Rev.,
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Group Preparations, VCH, New York, 1989.
8 A. F. Brigas, P. M. Gonçalves and R. A. W. Johnstone, Acta
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9 R. A. W. Johnstone and W. N. McLean, Tetrahedron Lett., 1988, 29,
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benzisothiazole section were regarded as substituents of a benzene
ring. It was then assumed that these electron-withdrawing
substituents had no effect on their respective meta positions in the
benzene ring. For 13C shifts of similar substituents, this assumption
is sufficiently close to actuality as to make little or no difference to
the final results. Knowing the assignments for positions 4–7a in the
benzene ring of some 1,1-dioxo-1,2-benzisothiazoles,22 it was then
possible to treat the effects on the ortho and para positions to the
SO2 and C᎐N groups as unknowns in a series of simultaneous
᎐
equations. Solution of these equations gave the results shown in
Table 4, from which it was then possible to make definite
assignments for all positions in the 1,1-dioxo-1,2-benzisothiazole
system, as given in Table 3.
22 R. F. Chapman and B. J. Peart, Comprehensive Heterocyclic
Chemistry II, Vol. 3, ed. I. Shirokai, Pergamon, Elsevier Science,
1996, p. 329.
23 Gaussian 98, Revision A.7, M. J. Frisch, G. W. Trucks, H. B.
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O. Farkas, J. Tomasi, V. Barone, M. Cossi, R. Cammi, B. Mennucci,
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Al-Laham, C. Y. Peng, A. Nanayakkara, C. Gonzalez, M.
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J. A. Pople, Gaussian, Inc., Pittsburgh, PA, 1998.
24 (a) C. A. Coulson and A. Streitwieser, Dictionary of Π-Electron
Calculations, Pergamon Press, Oxford, 1965, pp. 184–185; (b) C. A.
Coulson and A. Streitwieser, Dictionary of Π-Electron Calculations,
Pergamon Press, Oxford, 1965, pp. 37 et seq.
10 H. Freytag, F. Möller, G. Pieper and H. Söll in, Methoden der
Organischen Chemie, Vol. XI/2, ed. E. Müller, Georg Thieme Verlag,
Stuttgart, 1958, pp. 205–221; Methoden der Organischen Chemie,
Vol. 4/1c, 4/1d, eds. E. Müller and O. Bayer, Georg Thieme Verlag,
Stuttgart, 1980.
25 (a) Structure 16: Z. H. L. Abraham, S. D. Cutbush, R. Kuroda,
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1323

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considerations do not specifically include H–H bond-breaking
because the effect of the catalyst is to do this before hydrogenolysis
occurs.
28 J. E. Leffler, Science, 1953, 117, 340; G. S. Hammond, J. Am. Chem.
Soc., 1955, 77, 334; M. Sola and A. ToroLabbe, J. Phys. Chem., A,
1999, 103, 8847.
29 (a) H. H. Jaffé and M. Orchin, Theory and Applications of
Ultraviolet Spectroscopy, Wiley, New York, 1964, pp. 242–259;
(b) C. A. Coulson and A. Streitwieser, Dictionary of Π-Electron
Calculations, Pergamon Press, Oxford, 1965, pp. 263–272.
30 G. Klopman, J. Am. Chem. Soc, 1968, 90, 223; I. Fleming, Frontier
Orbitals and Organic Chemical Reactions, Wiley, London, 1976,
pp. 37 et seq.
31 R. L. Flurry, Molecular Orbital Theories of Bonding in Organic
Molecules, Marcel Dekker, New York, 1968, pp. 131–135.
32 A. F. Brigas and R. A. W. Johnstone, unpublished work.
33 A. Mannessier-Mameli, Gazz. Chim. Ital., 1935, 65, 51.
34 D. J. Brown, in Mechanisms of Molecular Migrations, Vol. 1, ed.
B. S. Thyagarajan, Wiley Interscience, 1968, pp. 209–245.
35 M. Fukuyo, K. Hirotsu and T. Higuchi, Acta Crystallogr., Sect. B,
1982, 38, 640.
26 R. P. Telford, PhD Thesis, University of Liverpool, Faculty of
Science, 1978.
27 In a C–H bond forming reaction at the ipso carbon of aryl–X
molecules, the energy gain is about 460 kJ molϪ1. The energy
requirement for breaking an aryl C–O bond is about 435 kJ molϪ1
and for C–N is almost the same. This suggest a net energy gain of
about 25 kJ molϪ1 for each. Any bond-forming reaction of H–X
simply adds to the exothermicity of the reaction. Thus, overall
catalytic hydrogenolysis of C–O or C–N bonds to form C–H and
O–H or N–H bonds should be very similar in exothermicity and
the latter should be sufficiently large that Hammond’s postulate28
would imply an equally small activation energy in each case. These
1324
J. Chem. Soc., Perkin Trans. 2, 2001, 1315–1324