Crystal structures and properties of mutagenic N-acyloxy-N- alkoxyamides - "most pyramidal" acyclic amides

Article abstract of DOI:10.1039/b306098p

X-Ray data for two N-acyloxy-N-alkoxyamides, a class of direct-acting mutagens, indicate extreme pyramidalisation at the amide nitrogen in keeping with spectroscopic and theoretically determined properties of amides with bisoxo-substitution at nitrogen. T

Full text of DOI:10.1039/b306098p

View Article Online / Journal Homepage / Table of Contents for this issue
Crystal structures and properties of mutagenic N-acyloxy-N-
alkoxyamides — “most pyramidal” acyclic amides
Ashley-Mae E. Gillson,a Stephen A. Glover,*a David J. Tuckera and Peter Turnerb
a Division of Chemistry, School of Biological, Biomedical and Molecular Sciences,
University of New England, Armidale 2351, New South Wales, Australia
b School of Chemistry, University of Sydney, Sydney 2006, New South Wales, Australia
Received 29th May 2003, Accepted 31st July 2003
First published as an Advance Article on the web 27th August 2003
X-Ray data for two N-acyloxy-N-alkoxyamides, a class of direct-acting mutagens, indicate extreme pyramidalisation
at the amide nitrogen in keeping with spectroscopic and theoretically determined properties of amides with bisoxo-
substitution at nitrogen. The combined electronegativity of two oxygens leads to average angles at nitrogen of 107.8
and 108.1Њ and |χN| of 66Њ and 65Њ. The sp3 nature of nitrogen results in negligible amide resonance as evidenced
by long N–C(O) bonds, high IR carbonyl stretch frequencies, carbonyl 13C NMR data and very low amide
isomerisation barriers. In addition, conformations in the solid state support a strong nO–σ*NOAc anomeric interaction
as predicted by molecular orbital theory. HF/6-31G* calculations on formamide, N-methoxyformamide and
N-formyloxy-N-methoxyformamide support these findings.
synthesis, reactions and biological properties of mutagenic
Introduction
N-acetoxy-N-alkoxybenzamides,25–33 we have discovered that
The nitrogen atom of normal amides is almost always planar or
close to planar and has a p-type lone pair of electrons that is
amides, geminally substituted at nitrogen with two electro-
negative heteroatoms (Fig. 1a) display vastly different proper-
ties when compared to normal amides. To maximize electron
loosely bound and therefore interacts strongly with the carb-
onyl, principally through pi overlap with the carbonyl carbon.1
density distribution near the electronegative atoms, such
This process creates a partial double bond (typically around
amides possess tetrahedral nitrogens without their incor-
132–137 pm long) between the amide nitrogen and the carbon
which is strengthened, additionally, by sigma donation from
carbon to the nitrogen. Both effects result in severely restricted
rotation about this bond since this process removes pi over-
poration into a restraining configuration and the lone pair
gains s character and is in an sp3 hybrid orbital. As a con-
sequence, these too have very little lone pair delocalisation
onto the carbonyl. They have reduced N–CO double bond
character and low barriers to rotation about the amide
lap and reduces the electronegativity of the nitrogen, which
becomes sp3 hybridised and less electron-withdrawing in the
linkage. Collectively, N,N-bisheteroatom-substituted amides
orthogonal form. Thus normal amide linkages are both planar,
exhibit high carbonyl stretch frequencies (1730–1750 cmϪ1
)
or nearly so, and undergo E–Z isomerisation relatively slowly
and time-averaging of E–Z conformations in their NMR
with a ∆G‡ of between 70 and 90 kJ molϪ1 2–4 To a large degree,
.
spectra.34,35
lone pair resonance accounts for the chemistry of amides which
are far less readily hydrolysed or reduced when compared to say
esters.4 In addition, although there is often a small distortion
from coplanarity, many of the properties of polypeptides, sim-
ple and complex proteins relate to their tertiary structure, which
is a function of the amide connecting units. The idea that amide
linkages might be without these properties is a relatively new
one.
Recently there has been a good deal of interest in “twisted
amides”, amides in which the carbonyl orientation is signifi-
cantly rotated about the R2N–C(O) bond and in which reson-
ance delocalisation of the nitrogen lone pair is partially or
completely lost.4–14 Such amides can act as acylating agents, are
more basic than planar amides and behave as both amines and
ketones or aldehydes.6,8,10,15–18 Twisted amides form in situations
where the amide nitrogen is incorporated into a rigid or semi-
rigid ring structure best accommodated by sp3 hybridised nitro-
gen.6,8–10,14,19 Such hybridisation is not conducive to both lone
pair orbital overlap with the carbonyl carbon and sigma
acceptance from that carbon and, as a consequence, these
amides have long N–C(O) bonds and high IR stretch frequen-
cies more appropriate to ketones or aldehydes. In certain sub-
stances, twisting about N–C(O) bonds is brought about by
steric constraints.6,7,11,12,15,20,21 Such amides exhibit similar carb-
onyl characteristics to those above, although pyramidalisation
at nitrogen is not a prerequisite.
Fig.
1
(a) Pyramidal structure, (b) anomeric interaction and
(c) conformation about the N–Y bond in anomeric amides.
Theoretical calculations have supported our spectroscopic
findings.36–38 Calculations on the ONO system N,N-dimethoxy-
formamide (1), the ONCl system N-chloro-N-methoxyform-
amide (2) and NNCl system N-chloro-N-dimethylaminoform-
amide (3) all predict a strong degree of pyramidalisation at
nitrogen (average angles between 112Њ and 115Њ), together with
longer than normal N–C(O) bonds (139.6–141.8 pm). Calcu-
lated barriers to E–Z isomerisation are reduced to between 25
and 42 kJ molϪ1 36
. The NNO system, N-methoxy-N-dimethyl-
aminoformamide (4) exhibited properties somewhere between
1–3 and normal amides (E–Z isomerisation barrier of 53 kJ
molϪ1; N–C(O) bond length 138.5 pm; average angle at nitro-
gen of 116Њ) as a consequence of the net reduced electro-
negativity of the nitrogen/oxygen substituents.37 Nitrogen
inversion barriers are low in all four configurations (10.5 kJ
As a spin-off from our extensive research on formation and
reactions of N-alkoxynitrenium ions22–24 and subsequently on
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 4 3 0 – 3 4 3 7
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
3430

View Article Online
molϪ1) on account of resonance delocalisation in the planar
transition state for this isomerisation process.
activity of this class of direct-acting mutagens.27,29,30,32,33 In line
with the protocol for the formation of a wide range of
substrates (9), 17 and 18 were made by benzoyloxylation of the
N-chlorinated hydroxamic esters, N-(4-tert-butylbenzyloxy)-
benzamide (15) and N-(4-tert-butylbenzyloxy)-4-tert-butyl-
benzamide (16) with either sodium benzoate or sodium 4-tert-
butylbenzoate in anhydrous acetone (Scheme 1).27,30 Upon
purification by centrifugal chromatography, this class of muta-
gens normally gives oils but, in these cases, solids were obtained
which crystallised from ethyl acetate–petroleum spirit Single crys-
tals of 17 and 18 suitable for X-ray diffraction analysis were
accordingly obtained, and resultant ORTEP52 depictions are pre-
sented in Figs. 2 and 3. Pertinent structural and spectroscopic
features are provided in Table 1 together with corresponding data
for the theoretical model, N-formyloxy-N-methoxyformamide
(5), hydrazine 13 and Kirby’s “most twisted” amide 14.
In addition, calculations predict strong nY–σ*NX anomeric
effects between nitrogen substituents (Fig. 1b).36,37 In the case
of NNCl and NNO systems 3 and 4, this negative hyper-
conjugation gives rise to very significant N–N rotation barriers
of 81 and 60 kJ molϪ1 respectively. Where oxygen lone pairs are
involved (ONO and ONCl systems 1 and 2), the analogous N–O
rotation barrier is reduced to about 45 kJ molϪ1. In all cases,
ground-state conformations in which there is optimum overlap
between the p-type lone pair on the donor heteroatom, nY, and
the σ*NX orbital (Fig. 1c) are preferred. For these reasons, we
have called bisheteroatom-substituted amides “anomeric
amides”.34
While some such amides have been made before by other
groups (hydrazines (7),39–42 N-alkoxy-N-chloroamides (8)43–45),
they have not emphasised or exploited their unusual properties.
However, we have verified, spectroscopically, many of these
theoretical properties and have discovered new chemistry of
NNO (7 and 10),28,31,35,46,47 ONO (9 and 11),27–31,48,49 ONCl
(8)25,38,49 and ONS (12)48,50 systems. Recently we published the
crystal structure of the symmetrically substituted hydrazine 13,
which exhibits strong pyramidalisation at both nitrogens and
other properties in confirmation of the theoretical predictions
for NNO systems.35 In this paper, we report the structures of
two N-acyloxy-N-alkoxyamides 17 and 18, both of which are
ONO systems in which the effective electronegativity of one
oxygen atom attached to nitrogen is enhanced by acylation and
these confirm structural features outlined above. Recently
Kirby reported the “most twisted” amide 14 in which the
nitrogen is incorporated into the bridgehead position of
2-adamantanone.8–10,51 Compounds 17 and 18 represent the
“most pyramidal” acyclic amides synthesised to date.
Twist and pyramidal indices τ, χC and χN are in accordance
with the Winkler–Dunitz system19,53 for which defining
geometrical parameters are illustrated in Fig. 4.
Results and discussion
N-acyloxy-N-alkoxyamides 17 and 18 were synthesised as a
part of our investigations into steric factors affecting the
Fig. 2 ORTEP52 depiction of N-benzoyloxy-N-(4-tert-butylbenzyl-
oxy)benzamide (17) with displacement ellipsoids shown at the 20%
level.
Scheme 1
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 4 3 0 – 3 4 3 7
3431

View Article Online
Table 1 Selected structural and spectroscopic properties of N-acyloxy-N-alkoxyamides 17 and 18, hydrazine 13, 1-aza-2-adamantanone 14 and
theoretical model 5
13
Parametera
17
120.70
18
120.52
5e
117.70
N1
N2
120.70
14
rCO/pm
121.30
121.00
145.50
—
rCN/pm
rNOR/pm
rNOAcyl/pm
144.14
140.17
143.96
143.94
140.14
144.14
141.10
136.10
137.50
141.20
140.30
138.90f
141.00
141.10
—
β1/Њ
β2/Њ
β3/Њ
110.60
109.00
104.52
324.14
35.86
109.40
108.59
105.48
323.51
36.49
109.9
111.3
108.60
329.8
30.2
117.32
116.57
109.47
343.36
16.64
116.71
111.23
113.25
341.19
18.81
109.00
109.00
110.00
328.00
32.00
Σβ/Њ
δ/Њb
<β>/Њc
108.05
107.84
109.9
114.45
113.73
109.33
ω1/Њ
ω2/Њ
ω3/Њ
ω4/Њ
49.25
Ϫ21.39
Ϫ135.77
163.63
50.36
Ϫ19.34
Ϫ134.01
165.03
Ϫ31.6
32.6
152.9
Ϫ36.00
19.03
151.70
Ϫ38.80
16.10
147.20
Ϫ60.00
Ϫ120.00
120.00
Ϫ151.9
Ϫ168.70
Ϫ169.88
60.00
τ/Њd
13.93
5.02
Ϫ65.62
15.51
4.37
Ϫ65.33
0.50
Ϫ4.50
59.70
Ϫ8.49
Ϫ7.70
47.33
Ϫ11.35
Ϫ6.00
48.90
Ϫ90.00
0.00
Ϫ60.00
χC/Њd
χN/Њd
νmax/cmϪ1
δ13C
1730
174.2
1726
174.2
1711g
168.7
1732
200
a See Fig. 4 for definition of angles. b δ = 360 Ϫ Σβ c <β> = Σ(β)/3 d Amide distortion parameters defined in accordance with Winkler–Dunitz.19,53
e Geometry calculated at HF/6-31G* level of theory. f N–N bond distance. g Degenerate carbonyl absorptions.
pyramidal at nitrogen (average angle of 116Њ) and the extreme
pyramidality at nitrogen must be attributed to the presence on
nitrogen of two electronegative oxygen atoms. Furthermore,
from the X-ray structural data for 17 and 18, as well as the
theoretical comparisons for N,N-dimethoxyformamide (1)36
Fig.3 ORTEP52diagramofN-(4-tert-butylbenzoyloxy-N-(4-tert-butyl-
and N-formyloxy-N-methoxyformamide (6),50 O-acylation
benzyloxy)-4-tert-butylbenzamide (18) with displacement ellipsoids
clearly results in even greater pyramidalisation at nitrogen. In
shown at the 20% level.
addition, the degree of pyramidality (Table 1) is greater in 17
and 18 than at either nitrogen of the symmetrical hydrazine
1335 which reflects the lower net combined electronegativity of
substituents at nitrogen in this system.
Analysis of the Cambridge Structural Database54 showed
that there are no acyclic tertiary amides (nitrogen not incorpor-
ated into a ring structure) with average angles at nitrogen less
than 112Њ. Fig. 5(a) indicates that of the 1552 entries, average
angles at nitrogen in all cases fall above 112Њ and 17 and 18
represent the “most pyramidal” acyclic tertiary amides dis-
covered to date. In addition, the role of electronegative substi-
tuents in pyramidalisation of amides is reinforced by the fact
that all but one of seven tertiary amide entries below 116Њ are
either hydroxamic esters or hydroxamic acids.† Of 5382 primary,
secondary and tertiary acyclic amide entries in the database,
only 17 have angles smaller than 109Њ and all of these have N–H
bonds. The apparent pyramidality in these few cases appears to
be a consequence of errors in the placement of the hydrogen
atoms in the structure model.
Fig. 4 Winkler–Dunitz parameters for defining twist and pyramidality
in amides.
Pyramidality at nitrogen
N-Acyloxy-N-alkoxyamides 17 and 18 are strongly pyramidal
at nitrogen with |χN| values of well over 60Њ and average angles
at nitrogen below that required by pure tetrahedral geometry as
exemplified by the tetrahedral nitrogen in 1-aza-2-adaman-
tanone (14) (Table 1). The geometrical distortion at nitrogen is
consistent with trends in theoretical predictions of B3LYP/
6-31G* which show average angles decreasing in the order
NNO > ONO ∼ ONCl > NNCl systems.36,37 Recent calculations
on N-formyloxy-N-methoxyformamide (5) at the HF/6-31G*
level predicted an average angle at nitrogen of 109.9Њ.50 In the
same study, N-formyloxy-N-methylformamide (6) was far less
Twist angle
Both 17 and 18 also exhibit a significant degree of twisting
around the N–C(O) bond (τ = 13.9 and 15.5Њ respectively). The
† One entry is an N,N-dimethyl urea. Pyramidalisation at one urea
nitrogen is likely a result of reduced demand for amide delocalisation.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 4 3 0 – 3 4 3 7
3432

View Article Online
Table 2 Characteristic carbonyl vibrational frequencies for various
anomeric amides34
Class
νC᎐O/cmϪ1 (CHCl3)
᎐
7
8
9
1700–1722
1717–1727
1720–1730
1718–1735
1705–1715
RЉ = Me
RЉ = Aryl
11
The carbonyl bond length is similar in 17, 18, 1-aza-2-adam-
antanone 14 and the hydrazine 13 despite the different degrees
of lone pair resonance (Table 1). Density functional calcu-
lations on 1–5 support this.36,37,50 This is consistent with the
carbonyl bond lengths in twisted amides, which are relatively
insensitive to the degree of lone pair resonance. Kirby has attri-
buted this to a negative hyperconjugative effect involving an
nO–σ*CN interaction impacting in an opposite sense upon the
C᎐O bond length9 but, based on Frontier Molecular Orbital
᎐
concepts, Wiberg has suggested that transfer of pi density to the
carbonyl carbon is the main process and oxygen gains relatively
little electron density.1 Similar arguments can account for the
relative insensitivity of C᎐O bonds to loss of pi overlap in
᎐
anomeric amides.
Spectroscopic properties
In contrast to C᎐O bond lengths, C᎐O vibrational frequencies
᎐
᎐
are very sensitive to the extent of lone pair resonance in amides.
In particular, increasing combined electronegativity of substi-
tuents at nitrogen results in a marked increase in the νC᎐O
values.34 Typical ranges for C᎐O stretch frequencies of ano-
᎐
meric amides are presented in Table 2. In accord with the
increased electron-withdrawing effect of the ester carbonyl,
N-acyloxy-N-alkoxyamides (9) absorb at a significantly greater
νC᎐O than the N,N-dialkoxyamides (11). In general, we have
found that electron-withdrawing substituents on both nitrogen
substituents result in a νC᎐O at the higher ends of the ranges. In
the case of N-aroyloxy-N-alkoxyamides (9, RЉ = aryl) the amide
carbonyl absorption is strongly sensitive to para substituents on
the ester group.30,34 The carbonyls of 17 and 18 are typical of
N-aroyloxy-N-alkoxyamides (9, RЉ = aryl) and the difference,
albeit small, can be accounted for on the basis of the strong ϩI
effect of the tert-butyl group on the ester group of 18.
The vibrational frequencies of N-acyloxy-N-alkoxyamides, 9,
including 17 and 18, correspond to that observed for the twisted
1-aza-2-adamantanone 14.8,9 In all cases where the nitrogen
lone pair, either through twisting/pyramidalisation or pyramid-
alisation alone (anomeric amides), loses conjugation with the
carbonyl, the configuration is analogous to an ester rather than
a ketone. As with esters and acid halides,55,56 the carbonyl
stretch frequency is higher than ketones and aldehydes on
account of destabilisation of the polar form of the carbonyl by
the ϪI effect of the nitrogen (Fig. 6).
Fig. 5 (a) Average angles at nitrogen and (b) N–C(O) bond lengths
from 1552 acyclic, tertiary amides in the Cambridge Structural
Database, CSD 5.24.
barrier to E–Z isomerisation in N-acyloxy-N-alkoxyamides has
been estimated to be below 30 kJ molϪ1 34 in line with the theor-
etical barrier for 5 (23.5 and 28.6 kJ molϪ1 50). Since the lone
pair on nitrogen resides in an sp3 hybrid orbital, twisting angles
in 17 and 18 are likely to arise from steric interactions or crystal
packing rather than pi-orbital overlap considerations.
Amide bond lengths
The N–C(O) bonds (rC–N, Table 1) are long when compared
with normal, acyclic amides in the CSD (average bond length
of 135.9 pm, median 135.3 pm). In the database, N–C(O)
bonds show greater variability than the average bond angles but
fewer than a hundred amides out of 1552 have similar or longer
N–C(O) bonds (Fig. 5b) and in all of these, deviation from sp3
hybridisation is minimal (<β> > 117Њ). Although N–C(O)
bonds of N-acyloxy-N-alkoxyamides 17 and 18 cannot be com-
pared directly with tertiary N,N-dialkylamides, they are only
slightly shorter than the corresponding bond in the fully twisted
lactam 1-aza-2-adamantanone (14) even though the twist angle
is relatively small (Table 1). They are significantly longer than
the amide bonds in the hydrazine 13 where E–Z isomerisation
Fig. 6 Inductive destabilisation of the polar form of anomeric amide
carbonyls.
The 13C NMR amide 13C᎐O resonances for 17 and 18 are
᎐
affected in a predictable manner and support this assertion.
Both are in a similar region to ester carbonyl carbons (typically
164–176 ppm). While chemical shifts in N-acetoxy-N-alkoxy-
amides (9) [174.1 ppm benzamides, 176.5 ppm acetamides] are
uniformly shifted to higher frequency by about 8 ppm relative
to their precursor hydroxamic esters,27,31,34 they are not ketonic
and appear some 20 ppm upfield of aryl/alkyl ketones. The shift
in the “most twisted” amide 14 is at a significantly higher
barriers were of the order of 54 kJ molϪ1 35
.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 4 3 0 – 3 4 3 7
3433

View Article Online
Fig. 7 Carbonyl and C–N vibrational frequencies (cmϪ1) and bond lengths (pm; in parentheses), twist angles (τ), average angles at nitrogen <β> and
energies (hartrees) computed at HF/6-31G* level for ground state and orthogonal conformations of (a) formamide, (b) N-methoxyformamide and
(c) N-formyloxy-N-methoxyformamide (5).
frequency (200 ppm) and has been labelled as aldehydic by
Kirby and coworkers.10 However, rigid bicyclic ketones exhibit
much higher carbonyl 13C NMR shifts and 200 ppm represents
a shift to higher field of similar magnitude relative to 2-adam-
antanone which has a carbonyl 13C NMR resonance at 218
ppm.
hydrazines 7 yielded N–N rotational barriers of between 65 and
72 kJ molϪ1 which is indicative of substantial nN–σ*NOR overlap
and accordingly, the N–N bond in the crystal structure of 13
was only 138.9 pm.35 In N-acyloxy-N-alkoxyamides 17 and 18,
such negative hyperconjugation would be expected in the direc-
tion nO–σ*NOAcyl as opposed to nOAcyl–σ*NOR and pBP/DN*//
6-31G* calculations on 5 confirmed this; the p-type lone pair on
the methoxyl oxygen was collinear with the N–OCHO bond.50
X-ray data for 17 and 18 provides structural evidence for a nO–
σ*NOAcyl anomeric interaction. The dihedrals C(14)O(3)N(1)-
O(1) for 17 and C(18)O(3)N(1)O(1) for 18 were 96.7 and 96.2Њ
respectively, which is almost ideal for an nO–σ*NOAcyl overlap,
whereas dihedrals C(7)O(1)N(1)O(3) in 17 (Ϫ137.6Њ) and 18
(Ϫ141.6) would indicate a poor nOAcyl–σ*NOR interaction. As a
consequence, N–OR bonds should be shorter than normal. A
comparison between N–OR bond lengths of 17 and 18 with
those of the parent hydroxamic esters is inappropriate on
account of differences in hybridisation at nitrogen (in hydrox-
amic esters, nitrogen is largely sp2 hybridised leading naturally
to shorter N–O bonds). However, a comparison can be made
with hydroxylamines since the nitrogen is fully tetrahedral in
these, as well as in N-acyloxy-N-alkoxyamides (9). Typically, the
N–O bond in hydroxylamines is of the order of 144–146 pm.
Values in this range have also been computed for fully twisted
hydroxamic esters where the nitrogen also assumes a pyramidal
geometry.36 The rNOR distances of 140.17 pm and 140.14 pm
in 17 and 18 respectively represent very significant shorten-
ing, presumably through an effective nO–σ*NOAc anomeric
interaction.
The solid-state structure of both molecules indicates a degree
of interaction between the benzyloxy and benzoyloxy substi-
tuents, which is most probably brought about by several factors
including desolvation, an electrostatic pi–pi stacking inter-
action and CH/π interactions. The ester carbonyl C(7), with the
normal positive electrostatic potential over the carbon, is 322
and 332 pm from C(13) in 17 and C(17) in 18, respectively,
which is ideal for a pi–pi stacking interaction with the benzyl-
oxy ring which has a negative electrostatic potential.60 In addi-
tion, both benzyloxy tert-butyls have C–H bonds pointing
towards the ester aryl pi-cloud. A C(18)–H in 17 points directly
at C(4) (C(18)–C(4) = 396 pm) while in 18, a C(20)–H points
directly at C(5) (C(20)–C(5) = 420 pm). Nishio and coworkers
have shown that such interactions can affect conformation
in crystal structures although the distances are larger for the
interactions in 17 and 18 than the Dmax chosen in their study
(305 ppm).61 Recently, Tsuzuki et. al. have computed much
longer C–C distances for optimum CH/π interactions (380–400
pm).62
The mutagens 17 and 18 have small twist angles (Table 1).
However, the lone pair in these and other N-acyloxy-N-alkoxy-
amides is essentially non-conjugated even though its axis lies
close to a plane containing the carbon p-orbital. Gas-phase
vibrational frequencies can be computed with some accuracy
using molecular orbital methods,57,58 which can also provide
structural data about transition states or unstable conform-
ations. Using HF/6-31G* optimised geometries, we have calcu-
lated the gas phase carbonyl and C–N stretch frequencies for
ground-state and fully twisted conformations of formamide
(Fig. 7a), N-methoxyformamide (Fig. 7b) and N-formyloxy-N-
methoxyformamide (5) (Fig. 7c). Fully twisted formamide and
N-methoxyformamide have carbonyl stretch frequencies that
are ∼30 cmϪ1 higher than the planar or near-planar ground state
structures indicating a significant loss of resonance in the
twisted forms. The C–N stretch frequencies are reduced by 149
and 119 cmϪ1 respectively. The carbonyl vibrational frequencies
for twisted N-formyloxy-N-methoxyformamide (5) are strongly
coupled but both the symmetrical and asymmetrical stretch
frequencies are very similar to those of the ground state con-
formation (Fig. 7c). In this case, the C–N stretch frequency is
reduced by only 48 cmϪ1. Thus, when compared to formamide
or N-methoxyformamide, both the carbonyl stretch and the
C–N bond stretch frequencies are much less sensitive to the
orientation of the sp3 lone pair. Changes in the frequencies and
bond lengths upon twisting the lone pair of N-formyloxy-
N-methoxyformamide out of conjugation (Fig. 7c) would sug-
gest that, at HF/6-31G* level in the gas phase at least, some
residual pi overlap is lost. The calculated variations in C᎐O and
᎐
C–N vibrational frequencies for formamide (ϩ31 and Ϫ149
cmϪ1 respectively) upon twisting the lone pair into the OCN
plane are in accordance with changes in bond lengths (Ϫ1 and
ϩ7.6 pm respectively) and reflect the contemporary view that pi
donation to the carbonyl carbon in the planar form does not
result in an equivalent loss in C᎐O pi-bond character.1 Similar
᎐
results are found for N-methoxyformamide.
Conformation and anomeric effects
Calculations on various bisheteroatom-substituted amides pro-
vided evidence for operation of anomeric interactions through
the amide nitrogen.36,37,59 In addition, dynamic NMR studies on
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 4 3 0 – 3 4 3 7
3434

View Article Online
The conformations in the solid state are not expected in solu-
tion. Although the 1H NMR resonances of the three tert-butyl
groups in 18 are very similar (δH 1.29, 1.33 and 1.35) careful
analysis enabled assignment of the upfield singlet to the benzyl-
oxy tert-butyl group. A NOESY spectrum failed to detect any
correlations between these protons and those at C(5) or C(6) on
the benzoyloxy side chain. In addition, the chemical shifts of
the benzyloxy aryl protons in 18 (singlet at δ 7.34) and 4-tert-
butylbenzyloxy-4-tert-butylbenzamide 16 (AB system at δ 7.42
are very similar suggesting that in 18 they are not under the
influence of the anisotropy of the 4-tert-butylbenzoyloxy sub-
stituent. We conclude from this that conformations similar to
those shown in Figs. 2 and 3 are likely to be minor contributors
in the solution state. Interestingly, the AM1 optimised geom-
etry of 17 (Fig. 8) satisfactorily reproduces the unique proper-
ties of this ONO system but the benzyloxy and benzoyloxy
groups are rotated away from each other in a conformation that
is significantly lower in energy in the gas phase than the single
point energy computed for the conformation in the crystal
structure.
(CDCl3) was commercially obtained from Aldrich. All routine
samples for structural analysis were run at 300 K in CDCl3,
with tetramethylsilane (0.1%) or CHCl3 as an internal stand-
ard. Chemical shifts are reported in ppm down field of TMS.
Abbreviations used to indicate spectral multiplicity are: s (sing-
let), d (doublet), t (triplet), q (quartet), m (multiplet). Pre-
parative plate chromatography was carried out centrifugally on
a Harrison 7924T Research Chromatotron. Microanalyses were
performed at the Microanalytical Unit, Research School of
Chemistry, Australian National University. Electrospray mass
spectral data was obtained on a Varian 1200L spectrometer.
Computational methods
Molecular orbital calculations were executed with MACSPAR-
TAN PRO and SPARTAN 5 molecular modelling software.64,65
Geometries were optimised at the HF/6-31G* level of theory.
Frequency calculations at the HF/6-31G* level were carried
out to verify stationary points as minima (all real frequencies)
and transition states (exactly one imaginary frequency) and
to determine gas phase carbonyl and C–N stretch frequencies
in ground state and twisted conformations of formamide,
N-methoxyformamide and N-formyloxy-N-methoxyform-
amide.
Syntheses
The synthesis of N-(4-tert-butylbenzyloxy)benzamide (15)
and 4-tert-butylbenzyl bromide, potassium 4-(tert-butyl)benzo-
hydroxamate27 and sodium 4-tert-butylbenzoate have been
described previously.30
General synthesis of alkyl substituted benzohydroxamates.66
The appropriate benzohydroxamic ester was synthesised in
good yield by the reaction of the potassium salt with the rele-
vant alkyl bromide and a 10% excess of sodium carbonate in a
50% aqueous solution of methanol.
Fig. 8 AM1 optimised geometry of N-benzoyloxy-N-(4-tert-butyl-
benzyloxy)benzamide (17).
N-(4-tert-Butylbenzyloxy)-4-tert-butylbenzamide 16. Potas-
sium 4-(tert-butyl)benzohydroxamate and 4-tert-butylbenzyl
bromide were reacted in the presence of a 10% excess of sodium
carbonate in a 50% aqueous solution of methanol. Crystallis-
ation from benzene–petroleum spirit, afforded 4-tert-butyl-
benzyloxy-4-tert-butylbenzamide in 57% yield. Mp 179–181 ЊC,
(Found: C, 77.84; H, 8.66; N, 4.04%. C22H29NO2 requires C,
77.84; H, 8.61, N, 4.13%); νmax (CHCl3) 3300 (N–H) and 1679
Both 17 and 18 have recently been subjected to the Ames
Salmonella assay by which we determine relative mutagenicities
for these direct-acting mutagens.63 While 17, with a single
benzyloxy tert-butyl group, exhibits mutagenic activity that is
largely in keeping with its hydrophobicity and reactivity,
moderated slightly by the steric influence of the tert-butyl
group, the tri-tert-butylated substrate, 18, was found to be
completely inactive.‡ In a future publication we will report that
N-benzoyloxy-N-benzyloxybenzamides with one para tert-butyl
group (on any of the three side chains) are appreciably muta-
genic but the same tri-arylated substrate with two or three para
tert-butyl groups are essentially non-mutagenic. We attribute
this difference to a severe impediment to binding in the major
and minor grooves of DNA with the bulkier substrates. These
differences in mutagenicity would imply that the conformation
in the crystal structures of 17 and 18 is unlikely to reflect their
behaviour in solution, or in association with DNA, since the
spatial requirements of both molecules, as depicted in Figs. 2
and 3 are very similar.
cmϪ1 (C᎐O); δ (300 MHz, CDCl ) 1.34 (9H, s, C[CH ] ), 1.35
᎐
H
3
3 3
(9H, s, C[CH3]3), 5.03 (2H, s, OCH2Ar), 7.40 (6H, m, ArH ),
and 7.63 (2H, d, o-ArH–CO). δC(75 MHz, CDCl3) 31.1 (q,
Ar–C[CH3]3), 31.3 (q, Ar–C[CH3]3) 34.7 (s, Ar–C[CH3]3), 35.0
(s, Ar–C[CH3]3), 76.6 (t, OCH2Ar), 125.3 (d, m-ArC-tBu), 125.4
(d, mЈ-ArC–tBu), 126.9 (d, oЈ-ArC), 129.2 (d, o-ArC), 130.4 (s,
ArC–CO), 137.8 (s, OCH2–ArC), 146.0 (s, ArC–C[CH3]3), 150.5
(s, ArC–C[CH3]3), and 166.3 (s, Ar–CO–NH); m/z (ESI) 362
[M ϩ Naϩ].
General synthesis of N-benzyloxy-N-chlorobenzamides. A
solution of the appropriate N-benzyloxybenzamide and a 2–3
molar excess of tert-butyl hypochlorite in CH2Cl2 was stirred in
the dark under anhydrous conditions for 3–6 hours. The pro-
gress of the reaction was monitored by thin-layer chromato-
graphy until complete, at which time the solvent and excess tert-
butyl hypochlorite were removed in the dark under reduced
pressure at 30 ЊC to afford the N-chlorohydroxamic ester in
excellent yield (90–100%). The N-chlorohydroxamic esters were
used without further purification.
Experimental
Melting points were determined on a Reichert Microscopic
Hot-Stage and are uncorrected. Infrared spectra were recorded
on a Perkin-Elmer 1725X Fourier-transform instrument. 300
1
MHz H and 75 MHz 13C NMR spectra were recorded on a
Bruker Avance 300 FT spectrometer. Deuterated chloroform
N-(4-tert-Butylbenzyloxy)-N-chlorobenzamide.
N-4-tert-
butylbenzyloxy-N-chlorobenzamide was produced quanti-
tatively as a yellow oil. νmax (CHCl ) 1709 (C᎐O) cmϪ1; δH(300
‡ For 17, Log (TA100/1 µmol plateϪ1) = 3.05; for 18, Log (TA100/1 µmol
plateϪ1) = 2.5 (background reversion rate).
᎐
3
MHz, CDCl3) 1.36 (9H, s, C[CH3]3), 5.11 (2H, s, OCH2Ar), 7.24
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 4 3 0 – 3 4 3 7
3435

View Article Online
(2H, t, m-ArH ), 7.42 (4H, m, ArH ), 7.57 (1H, t, p-ArH ), and
7.73 (2H, d, o-ArH).
supported on a thin piece of copper wire inserted in a copper
mounting pin. The crystals were quenched at at 150(2) Kelvin in
a cold nitrogen gas stream from an Oxford Cryosystems Cryo-
stream. A Bruker SMART 1000 CCD diffractometer employing
graphite monochromated MoKα radiation generated from a
sealed tube was used for the data collection, and data were
collected with ω scans to 0.75 Å. The data integration and
reduction were undertaken with SAINT and XPREP,67 and
subsequent computations were carried out with the teXsan68
WinGX,69 XSHELL70 and XTAL71 graphical user interfaces.
The structures were solved by direct methods with SIR97,72 and
extended and refined with SHELXL-97.73 The non-hydrogen
atoms were modelled with anisotropic displacement param-
eters, and a riding atom model with group displacement param-
eters was used for the hydrogen atoms. ORTEP52 depictions of
the molecules with 20% displacement ellipsoids are provided in
Figs. 2 and 3.
N-(4-tert-Butylbenzyloxy)-N-chloro-4-tert-butylbenzamide.
N-4-tert-butylbenzyloxy-N-chloro-4-tert-butylbenzamide was
prepared in 89% yield and was a yellow oil,. νmax (CHCl3) 1693
(C᎐O) cmϪ1; δH(300 MHz, CDCl3) 1.32 (9H, s, C[CH3]3), 1.36
᎐
(9H, s, C[CH3]3), 5.08 (2H, s, OCH2Ar), 7.21 (2H, d, ArH ), 7.36
(2H, d, ArH ), 7.43 (2H, d, m-ArH–CO), and 7.67(2H, d,
o-ArH–CO).
General synthesis of N-acyloxy-N-alkoxyamides. N-Benzyl-
oxy-N-chlorobenzamides were benzoyloxylated by treatment
with 1.4 molar equivalents of the appropriate sodium benzoate
in dry acetone, at room temperature, for 12–72 hours in the
dark. The reaction was monitored by thin-layer chromato-
graphy. Filtration and concentration under reduced pressure
provided the N-benzoyloxyl derivatives in good yields. Products
were either obtained in a pure state or were further purified by
centrifugal chromatography (15% ethyl acetate: 85% petroleum
spirit or 10% ethyl acetate–90% petroleum spirit). In all cases,
mutagens were characterised spectroscopically (1H and 13C
NMR chemical shift assignments for the benzyloxy and benz-
oyloxy side chains are indicated by the ЉЈЉ and Љ*Љ symbols
respectively).
Crystal data for (17). Formula C25H25NO4, M 403.46, mono-
clinic, space group P21/c(#14),
a 9.974(3), b 14.182(5),
c 16.104(5) Å, β 107.088(5)Њ, V 2177.4(12) Å3, Dc 1.231 g cmϪ3
,
Z 4, crystal size 0.445 by 0.310 by 0.244 mm, colour: colourless,
habit prismatic µ(MoKα) 0.083 cmϪ1, T(Gaussian67,68 [Bruker,
1995 #709;1997–1998 #710])min,max 0.963, 0.979, 2θmax 56.46, hkl
range Ϫ13 12, Ϫ18 18, Ϫ20 20, N 18940, Nind 5007(Rmerge
0.0274), Nobs 4069(I > 2σ(I )), Nvar 274, residuals¶ R1(F) 0.0349,
wR2(F 2) 0.0951, GoF(all) 1.465, ∆ρmin,max Ϫ0.203, 0.222 eϪ ÅϪ3
.
N-Benzoyloxy-N-(4-tert-butylbenzyloxy)benzamide
(17).
Purification by centrifugal chromatography (15% ethyl acetate–
85% petroleum spirit) provided the title compound as a colour-
less prismatic solid (86% yield). Recrystallisation from ethyl
acetate–petroleum spirit afforded prisms mp 87–89 ЊC. νmax
Crystal data for (18). Formula C33H41NO4, M 515.67, mono-
clinic, space group P21/n(#14), a 9.2910(19), b 17.063(4),
c 18.640(4) Å, β 98.007(4)Њ, V 2926.2(11) Å3, Dc 1.171 g cmϪ3
,
(CHCl3) 1758 (ester CO stretch), 1728 (amide CO stretch) cmϪ1
;
Z 4, crystal size 0.465 by 0.174 by 0.173 mm, colour: colourless,
habit prism, µ(MoKα) 0.076 mmϪ1, 2θmax 56.56, hkl range Ϫ12
12, Ϫ22 22, Ϫ24 24, N 29776, Nind 7092(Rmerge 0.0300), Nobs
5242(I > 2σ(I )), Nvar 352, residuals|| R1(F) 0.0425, wR2(F 2)
δH(300 MHz, CDCl3) 1.30 (9H, s, C[CH3]3), 5.26 (2H, s,
OCH2Ar), 7.35 (4H, s, oЈ, mЈ-ArH), 7.43 (4H, m- and m*-ArH),
7.54 (1H, t, p-ArH ), 7.61 (1H, t, p*-ArH ), 7.83 (2H, d, o-ArH ),
and 7.98 (2H, d, o*-ArH ). δC(75 MHz, CDCl3) 31.1 (q,
Ar–C[CH3]3, 34.6 (s, Ar–C[CH3]3), 77.4 (t, OCH2Ar), 125.4 (d,
mЈ-ArC-tBu), 126.9 (d, oЈ-ArC–tBu), 127.4 (d, o-ArC), 128.3
(d, m*-ArC), 128.6 (d, m-ArC), 129.2 (d, o*-ArC), 130.0 (s,
C*–C(O)ON), 131.7 (d, p-ArC), 132.7 (s, ArC–C(O)N), 133.9
(d, p*-ArC), 134.5 (s, OCH2–ArC) 151.8 (s, ArC–C[CH3]3),
164.2 (s, OC*OAr), and 174.4 (s, Ar–CO–NH); m/z (ESI) 426
[M ϩ Naϩ].
0.0909, GoF(all) 1.318, ∆ρmin,max Ϫ0.260, 0.238 eϪ ÅϪ3
.
Acknowledgements
The authors are grateful to the Australian Research Council for
financial support and to the Canadian Rotary Exchange
Fellowship scheme for a scholarship to Ashley-Mae Gillson.
2
¶ R1 = Σ|Fo| Ϫ |Fc|/Σ|Fo| for Fo > 2σ(Fo); wR2 = (Σw(Fo Ϫ Fc2) 2/Σ-
2
(wFc2) 2)1/2 all reflections; w = 1/[σ2 (Fo ) ϩ (0.0400P) 2] where P = (Fo2 ϩ
2Fc2)/3
N-(4-tert-Butylbenzoyloxy)-N-(4-tert-butylbenzyloxy)-4-tert-
butylbenzamide 18. Purification by centrifugal chromatography
(15% ethyl acetate–85% petroleum spirit) provided this com-
pound as a white solid in 79% yield. Crystallisation from ethyl
acetate–petroleum spirit afforded prisms, mp 148–150 ЊC
(Found: C, 77.18; H, 8.26; N, 2.45% C22H29NO2 requires C,
76.86; H, 8.01, N, 2.72%). νmax (CHCl3) 1754 (ester CO stretch),
1726 (amide CO stretch) cmϪ1; δH(300 MHz, CDCl3) 1.29 (9H,
s, C[CHЈ3]3), 1.33 (9H, s, C[CH3]3), 1.35 (9H, s, C [CH*3]3), 5.26
(2H, s, OCHЈ2Ar), 7.35 (4H, s, oЈ,mЈ-ArH–tBu), 7.42 (2H, d, m-
ArH ), 7.45 (2H, d, m*-ArH ), 7.79 (2H, d, o-ArH ), and 7.91
(2H, d, o*-ArH ). δC(75 MHz, CDCl3) 31.2 (2 × q, Ar–C[CH3]3,
Ar–C[C*H3]3), 31.4 (q, ArCЈ[CH3]3), 34.6 (s, Ar–CЈ[CH3]3),
35.1 (s, Ar–C[CH3]3), 35.2(s, Ar–C*[CH3]3), 76.6 (t, OCЈH2Ar),
125.0 (d, m-ArC), 125.2 (d, mЈ-ArC), 125.2 (d, m*-ArC), 125.7
(s, ArC*–C(O)ON), 128.9 (d, oЈ-ArC–CH2ON), 129.1 (d,
o-ArC–C(O)N), 129.8 (d, o*-ArC–C(O)ON), 128.7 (s, ArC–
C(O)N), 132.0 (s, ArCЈ–CH2ON), 151.7 (s, ArCЈ-tBu), 156.5 (s,
ArC–tBu), 157.7 (s, p*-ArC), 164.3 (s, OC*(O)Ar) and 174.5.
(s, Ar–C(O)N); m/z (ESI) 538 [M ϩ Naϩ].
2
|| R1 = Σ|Fo| Ϫ |Fc|/Σ|Fo| for Fo > 2σ(Fo); wR2 = (Σw(Fo Ϫ Fc2)2/
Σ(wFc2) )1/2 all reflections; w = 1/[σ2 (Fo ) ϩ (0.02P) ϩ 0.5P] where
2
2
2
P = (Fo2 ϩ 2Fc2)/3
References
1 K. B. Wiberg, in Origin of the Amide Rotational Barrier, ed.
A. Greenberg, C. M. Breneman and J. F. Liebman, John Wiley &
Sons, Inc., New York, 2000.
2 E. L. Eliel, S. H. Wilen and L. N. Mander, Stereochemistry of
Organic Compounds, John Wiley & Sons, Inc., New York, 1994.
3 J. Sandström, Dynamic NMR Spectroscopy, Academic Press,
London, 1982.
4 A. Greenberg, C. Breneman and J. F. Liebman, The Amide Linkage:
Structural Significance in Chemistry, Biochemistry and Material
Science, Wiley, New York, 2000.
5 S. Yamada, N. Nunami and K. Hori, Chem. Lett., 1998, 451.
6 S. Yamada, Rev. Heteroat. Chem., 1999, 19, 203.
7 S. Yamada and A. Homma, Chem. Commun., 2002, 2656.
8 A. J. Kirby, I. V. Komarov, P. D. Wothers and N. Feeder,
Angew. Chem., Int. Ed., 1998, 37, 785.
9 A. J. Kirby, I. V. Komarov, K. Kowski and P. Rademacher, J. Chem.
Soc., Perkin Trans. 2, 1999, 1313.
10 A. J. Kirby, I. V. Komarov and N. Feeder, J. Chem. Soc.,
Perkin Trans. 2, 2001, 522.
X-Ray crystallography.§ Colourless prismatic crystals were
attached with Exxon Paratone N, to a short length of fibre
11 C. N. Cow, J. F. Britten and P. H. M. Harrison, Chem. Commun.,
1998, 1147.
12 P. A. Duspara, C. F. Matta, S. I. Jenkins and P. H. M. Harrison,
Org. Lett., 2001, 3, 495.
§ CCDC reference numbers 212185 (17) and 212186 (18). See http://
www.rsc.org/suppdata/ob/b3/b306098p/ for crystallographic data in .cif
or other electronic format.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 4 3 0 – 3 4 3 7
3436

View Article Online
13 T. Ohwada, T. Achiwa, I. Okamoto, K. Shudo and K. Yamaguchi,
Tetrahedron Lett., 1998, 39, 865.
14 T. Ohwada, Yakugaku Zasshi, 2001, 121, 65.
15 S. Sun, L. Edwards and P. Harrison, J. Chem. Soc., Perkin Trans. 2,
1998, 437.
16 S. Yamada and H. Katsumata, J. Org. Chem., 1999, 64, 9365.
17 A. Greenberg and T. D. DuBois, J. Mol. Struct., 2001, 567,
303.
45 M. Kawase, T. Kitamura and Y. Kikugawa, J. Org. Chem., 1989, 54,
3394.
46 J. M. Buccigross, S. A. Glover and G. P. Hammond, Aust. J. Chem.,
1995, 48, 353.
47 S. A. Glover, G. Mo and A. Rauk, Tetrahedron, 1999, 55, 3413.
48 M. Adams, S. A. Glover and D. J. Tucker, 2001, unpublished results.
49 S. A. Glover and G. Mo, J. Chem. Soc., Perkin Trans. 2, 2002, 1728.
50 S. A. Glover, Arkivok, 2001. Issue in Honour of Prof. O. S. Tee, ms.
18 C. G. Bashore, I. J. Samardjiev, J. Bordner and J. W. Coe, J. Am.
Chem. Soc., 2003, 125, 3268.
19 F. K. Winkler and J. D. Dunitz, J. Mol. Biol., 1971, 59, 169.
20 G. Yamamoto, N. Tsubai, H. Murakami and Y. Mazaki, Chem.
Lett., 1997, 1295.
21 G. Yamamoto, F. Nakajo, N. Tsubai, H. Murakami and Y. Mazaki,
Bull. Chem. Soc. Jpn., 1999, 72, 2315.
22 S. A. Glover, A. Goosen, C. W. McCleland and J. L. Schoonraad,
J. Chem. Soc., Perkin Trans. 2, 1984, 2255.
OT-308C
Tee/OT-308C/OT-308.htm).
(http://www.arkat-usa.org/ark/journal/Volume2/Part3/
51 A. J. Kirby, I. V. Komarov and N. Feeder, J. Am. Chem. Soc., 1998,
120, 7101.
52 C. K. Johnson, ORTEP-II: A FORTRAN Thermal Ellipsoid Plot
Program for Crystal Structure Illustrations, Report ORNL-5138,
Oak Ridge National Laboratory, Oak Ridge, TN, USA, 1976.
53 J. D. Dunitz, X-Ray Analysis and Structure of Organic Molecules,
Cornell University Press, London, 1979.
23 S. A. Glover, A. Goosen, C. W. McCleland and J. L. Schoonraad,
Tetrahedron, 1987, 43, 2577.
24 S. A. Glover, C. A. Rowbottom, A. P. Scott and J. L. Schoonraad,
Tetrahedron, 1990, 46, 7247.
25 R. G. Gerdes, S. A. Glover, J. F. Ten Have and C. A. Rowbottom,
Tetrahedron Lett., 1989, 30, 2649.
26 J. J. Campbell, S. A. Glover and C. A. Rowbottom, Tetrahedron
Lett., 1990, 31, 5377.
54 F. H. Allen, Acta Crystallogr., Sect. B: Struct. Sci., 2002, 58, 380.
55 L. J. Bellamy, Advances in Infrared Group Frequencies, Methuan and
Co. Ltd., Bungay, 1968.
56 L. J. Bellamy, The Infra-red Spectra of Complex Molecules,
Chapman and Hall, London, 1975.
57 W. J. Hehre, L. Radom, P. v. R. Schleyer and J. A. Pople, Ab Initio
Molecular Orbital Theory, John Wiley and Sons, New York, 1986.
58 A. P. Scott and L. Radom, J. Phys. Chem., 1996, 100, 16502.
59 J. M. Buccigross and S. A. Glover, J. Chem. Soc., Perkin Trans. 2,
1995, 595.
27 J. J. Campbell, S. A. Glover, G. P. Hammond and C. A. Rowbottom,
J. Chem. Soc., Perkin Trans. 2, 1991, 2067.
28 J. J. Campbell and S. A. Glover, J. Chem. Soc., Perkin Trans. 2, 1992,
1661.
29 A. M. Bonin, S. A. Glover and G. P. Hammond, J. Chem. Soc.,
Perkin Trans. 2, 1994, 1173.
60 C. A. Hunter, K. R. Lawson, J. Perkins and C. J. Urch, J. Chem.
Soc., Perkin Trans. 2, 2001, 651.
61 Y. Umezawa, S. Tsuboyama, H. Takahashi, J. Uzawa and M. Nishio,
Tetrahedron, 1999, 55, 10047.
30 A. M. Bonin, S. A. Glover and G. P. Hammond, J. Org. Chem., 1998,
63, 9684.
31 J. J. Campbell and S. A. Glover, J. Chem. Res. (S), 1999, 8, 474;
J. J. Campbell and S. A. Glover, J. Chem. Res. (M), 1999, 2075.
32 T. M. Banks A. M. Bonin, J. J. Campbell, S. A. Glover,
G. P. Hammond, A. S. Prakash and C. A. Rowbottom, Mutat. Res.,
2001, 494/1-2, 115.
33 T. M. Banks, A. M. Bonin, S. A. Glover and A. S. Prakash,
Org. Biomol. Chem., 2003, 1, 2238.
34 S. A. Glover, Tetrahedron, 1998, 54, 7229.
62 S. Tsuzuki, K. Honda, T. Uchimaru, M. Mikami and K. Tanabe,
J. Am. Chem. Soc., 2000, 122, 3746.
63 A. M. Bonin, A.-M. E. Gillson and S. A. Glover, unpublished
results.
64 MacSpartan Pro Version 1, Wavefunction, Inc., 18401 Van Karman,
Suite 370, Irvine, California, 92612.
65 Spartan Version 5, Wavefunction, Inc., 18401 Van Karman, Suite
370, Irvine, California, 92612.
66 J. H. Cooley, W. D. Bills and J. R. Throckmorton, J. Org. Chem.,
1960, 25, 1734.
35 S. A. Glover, G. Mo, A. Rauk, D. Tucker and P. Turner, J. Chem.
Soc., Perkin Trans. 2, 1999, 2053.
36 S. A. Glover and A. Rauk, J. Org. Chem., 1996, 61, 2337.
37 S. A. Glover and A. Rauk, J. Org. Chem., 1999, 64, 2340.
38 S. A. Glover and A. Rauk, J. Chem. Soc., Perkin Trans. 2, 2002,
1740.
67 Bruker, SMART, SAINT and XPREP. Area detector control and
data integration and reduction software, Bruker Analytical X-ray
Instruments Inc., 1995, Madison, Wisconsin, USA.
68 teXsan for Windows: Single Crystal Structure Analysis Software,
Molecular Structure Corporation, 1997–1998, 3200 Research Forest
Drive, The Woodlands, TX 77381, USA.
39 R. O. C. Norman, R. Purchase and C. B. Thomas, J. Chem. Soc.,
Perkin Trans. 1, 1972, 1701.
40 R. J. Crawford and R. Raap, J. Org. Chem., 1963, 28, 2419.
41 J. H. Cooley, M. W. Mosher and M. A. Khan, J. Am. Chem. Soc.,
1968, 90, 1867.
42 J. H. Cooley, D. H. Stone and H. Oguri, J. Am. Chem. Soc., 1977, 42,
3096.
69 L. J. Farrugia, J. Appl. Crystallogr., 1999, 32, 837.
70 XSHELL. Graphical interface for crystal structure refinement,
Bruker Analytical X-ray Instruments Inc., 1995, Madison,
Wisconsin, USA.
71 S. R. Hall, D. J. du Boulay and R. Olthof-Hazekamp, Eds. Xtal3.6
System, University of Western Australia, 1999.
72 A. Altomare, M. Cascarano, C. Giacovazzo and A. Guagliardi,
J. Appl. Crystallogr., 1993, 26, 343.
73 G. M. Sheldrick, SHELXL-97, Program for refinement of crystal
structures, University of Göttingen, Germany, 1997.
43 Y. Kikugawa and M. Kawase, J. Am. Chem. Soc., 1984, 106,
5728.
44 Y. Kikugawa and M. Shimada, Chem. Lett., 1987, 1771.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 4 3 0 – 3 4 3 7
3437