SN2 substitution reactions at the amide nitrogen in the anomeric mutagens, N-acyloxy-N-alkoxyamides

Article abstract of DOI:10.1071/CH09166

N-Acyloxy-N-alkoxyamides 1a are unusual anomeric amides that are pyramidal at the nitrogen because of bis oxyl substitution. Through this configuration, they lose most of their amide character and resemble -haloketones in reactivity. They are susceptible to S_N2 reactions at nitrogen, a process that is responsible for their mutagenic behaviour. Kinetic studies have been carried out with the nucleophile N-methylaniline that show that, like S_N2 reactions at carbon centres, the rate constant for S_N2 displacement of carboxylate is lowered by branching to the nitrogen centre, or bulky groups on the alkoxyl side chain. Branching or bulky groups on the carboxylate leaving group, however, do not impact on the rate of substitution, which is mostly controlled by the pK_A of the departing carboxylate group. These results are in line with computed properties for the model reaction of ammonia with N-acetoxy-N-methoxyacetamide but are in contrast to the role of steric effects on their mutagenicity. CSIRO 2009.

Full text of DOI:10.1071/CH09166

RESEARCH FRONT
Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2009, 62, 700–710
www.publish.csiro.au/journals/ajc
SN2 Substitution Reactions at the Amide Nitrogen in the
Anomeric Mutagens, N-Acyloxy-N-alkoxyamides
Katie L. Cavanagh,A Stephen A. Glover,A,B Helen L. Price,A
and Rhiannon R. SchumacherA
ADepartment of Chemistry, School of Science and Technology, University of New England,
Armidale, NSW 2351, Australia.
BCorresponding author. Email: sglover@une.edu.au
N-Acyloxy-N-alkoxyamides 1a are unusual anomeric amides that are pyramidal at the nitrogen because of bis oxyl
substitution. Through this configuration, they lose most of their amide character and resemble α-haloketones in reactivity.
They are susceptible to SN2 reactions at nitrogen, a process that is responsible for their mutagenic behaviour. Kinetic
studies have been carried out with the nucleophile N-methylaniline that show that, like SN2 reactions at carbon centres,
the rate constant for SN2 displacement of carboxylate is lowered by branching β to the nitrogen centre, or bulky groups
on the alkoxyl side chain. Branching or bulky groups on the carboxylate leaving group, however, do not impact on the
rate of substitution, which is mostly controlled by the pKA of the departing carboxylate group. These results are in line
with computed properties for the model reaction of ammonia with N-acetoxy-N-methoxyacetamide but are in contrast to
the role of steric effects on their mutagenicity.
Manuscript received: 19 March 2009.
Final version: 14 May 2009.
O
Introduction
N
N-Acyloxy-N-alkoxyamides 1a are a class of mutagenic amides
that react as electrophiles towards DNA without the need for
metabolic activation.[1–10] Structure–activity studies and DNA
damage studies point to an SN2 displacement of carboxylate by
attack of guanine-N7 at the amide nitrogen.[7,10] Compounds 1a
are members of the wider class of anomeric amides 1 (Scheme 1)
in which the nitrogen is substituted with two electronegative
atoms that can interact anomerically.[11–15] This configuration
has been shown to radically alter the amide properties. On
account of the electron demand of these atoms, the nitrogen
becomes sp3 hybridized with loss of much of the classical
amide resonance, which in conventional amides and peptides is
responsible for restricted rotation about the N–C bond, and other
manifestations such as low carbonyl stretch frequencies in their
infrared spectra.[11,13,14,16,17] In effect, such amides behave more
as N-acylamines. The structural, spectroscopic and chemical
properties of 1a–d and 1f have recently been reviewed.[15]
Accompanying this changed configuration, some of these
amides are susceptible to both SN1[2–5] and SN2 reactions at the
amide nitrogen and, in many respects, the chemistry of 1a and
1b resembles that of α-haloketones.[9,10,15,18–22] In particular,
N-acyloxy-N-alkoxyamides 1a undergo facile SN2 replacement
of the acyloxyl group at nitrogen by a variety of nucleophiles
includingneutralaromaticaminesandthiolsaswellasnegatively
charged azide and hydroxide ions.[5,10,19,20,22]
R
Y
X
1a X ꢀ OAcyl, Y ꢀ OR
1b X ꢀ Cl, Y ꢀ OR
1c X ꢀ Y ꢀ OR
1d X ꢀ NR2, Y ꢀ OR
1e X ꢀ Y ꢀ Halogen
1f X ꢀ SR, Y ꢀ OR
Scheme 1.
have demonstrated that N-acyloxy-N-alkoxyamides 2 react
bimolecularly with aromatic amines such as N-methylaniline
3
in methanol, generating intermediate N-alkoxy-N-(Nꢀ-
methylanilino)amides 4 that themselves are anomeric but
that undergo a novel rearrangement, the HERON reaction¶
(Scheme 2).[10,15,17,22–27] In this reaction, the loosely bound lone
pair on nitrogen drives migration of the alkoxyl group from nitro-
gen to the carbonyl carbon.The N–C bond breaks in concert with
the migration, yielding esters 5 and the 1,1-diazene 6 in what
is, in effect, an SN2 reaction at the acyl carbon. Under these
conditions, the diazene 6 dimerizes to the tetrazene 7.
The SN2 reaction of anilines with a wide range of N-acyloxy-
N-alkoxyamides has been studied and relative rate constants,
Arrhenius activation energies and entropies of activation are in
In a series of studies aimed at understanding the under-
lying structural features controlling their mutagenicity, we
¶Heteroatom rearrangements on nitrogen; first presented to the 2nd Heron Island Conference on Reactive Intermediates and Unusual Molecules, Heron Island,
Australia, 1994.
© CSIRO 2009
10.1071/CH09166
0004-9425/09/070700

RESEARCH FRONT
SN2 Substitution Reactions
701
σ constants with ρ = +1.7.[10,19,20] However, to date we have not
investigated the influence of steric factors on the leaving group.
The steric effect of branching γ to the reactive nitrogen would
be expected to be less important on this side chain relative to the
amide and alkoxyl side chains because the predicted transition
state is similar to that known for classical SN2 reactions at car-
bon; the nitrogen is sp2 hybridized and the leaving the group is
anti to the incoming nucleophile.
Inthepresentpaper, wereportfurtherevidencethatbranching
at the β-position on the alkoxyl group, as well as bulky benzyloxy
substituents, have an influence on the SN2 reaction at nitrogen.
Furthermore, we show that in contrast to the amide and alkoxyl
side chains, steric effects on the leaving group are far less signif-
icant in support of the classical SN2 transition state for reaction
at nitrogen.
CH3
O
O
NH Ph
CH3
Ar
Ar
AcOH
3
N
N
Ph
N
OR
RO
AcO
2
4
Ph
N
O
CH3
N
CH3
Ar
N
N
H3C
N
N
OR
Ph
Ph
5
6
7
Scheme 2.
ꢁꢃ
RNHPh
R
RNHPh
ꢃ
O
O
N
O
R1
NHPh
O
O
N
R1
O
O
ꢂ
R2
Results and Discussion
N
ꢃ
O
R3
R3
R2
R3
O R1
O
O
Reactions of N-acyloxy-N-alkoxyamides with N-methylaniline
leading to HERON reactions can be conveniently carried
out in the probe of the NMR spectrometer and followed in
[D4]methanol by monitoring the disappearance of the methyl
signal of either an N-acetoxyl group or an oxymethylene
resonance of the substrate, together with the N-methyl reso-
nance of aniline, and their transformation to the corresponding
ester and tetrazene. They conform to classical bimolecular
kinetics, being first-order with respect to both mutagen and
N-methylaniline.[9,18–20,36]
The classical SN2 transition state (Scheme 3) has been sup-
ported by computational modelling that confirms the charge
separation in the transition state and the likely impact of steric
effects.[21] In addition to branching on the amide side chain,
which strongly impedes SN2 reaction with N-methylaniline, the
inclusion of steric bulk on the alkoxyl group should also, to a
degree, hinder the incoming amine.
Rate constants for reaction of N-methylaniline with
some N-acetoxy-N-alkyloxyamides 11 and N-acetoxy-N-
benzyloxyamides 12 (Scheme 5), at 303 K, are given in Table 1.
Earlier work from our laboratory showed that relative to an
ethoxyl group, the isopropoxyl group in 11a hindered SN2
reactivity with N-methylaniline.[10,20] This result has been con-
firmed in a repeat study with 11a reacting with a rate constant
approximately one-fifth of the ethoxy substrate 11d (n = 1). In
addition, 2-butyloxyl behaves similarly, reducing the rate con-
stant for reaction of 11b to approximately one-tenth that of
the propoxyl, butoxyl and pentoxyl substrates 11d (n = 2–4).
The tert-butyloxyl group strongly inhibits reaction with N-
methylaniline as no rate constant could be obtained for 11c at
similar temperatures. At higher temperatures, it decomposed via
other pathways in a non-second-order fashion.
Rate constants for the benzyloxy substrates also pointed
to a steric effect. Substrates bearing the benzyl (12a), 3,5-
dimethylbenzyl (12d), and 2- and 3-methylbenzyl (12b, 12c)
groups reacted with relatively similar rate constants, but
with dual methylation on the ortho positions in the 2,6-
dimethylbenzyloxy substrate 12e, the bimolecular rate constant
was significantly reduced.
O
ꢁꢂ
R2
Scheme 3.
accord with bimolecular attack at nitrogen leading to a transition
state with significant charge separation (Scheme 3).[9,10,19,20]
Entropies of activation are more negative than found in SN2
reactions of alkyl halides owing to a greater degree of solvation
in the transition state.[28] These reactions have been modelled
computationally by the reaction of ammonia with N-formyloxy-
N-methoxyformamide and ammonium ion and carboxylate ion
character is significant at the transition state.[10,15,21]
The reactions have an analogy in the SN2 reactions of α-
haloketones such as phenacyl bromides.[29] These are facilitated
by the carbonyl substitution at the reactive centre, which has been
attributed to conjugation of the p-orbital on the α-carbon in the
SN2 transition state with the carbonyl π-bond,[29–32] and stabi-
lization of ionic character at the central carbon as outlined by
Pross,[30,33] as well as electrostatic attraction of the nucleophile
to the carbonyl carbon.[31] Although there are no comparative
rate data for reactions on amines or alkoxyamines, these argu-
ments could also apply to substitution at the amide nitrogen in
N-acyloxy-N-alkoxyamides.
SN2 in α-haloketones is also strongly impeded sterically
by branching at the αꢀ-carbon and SN2 reactions in general
are hindered by substitution β to the reactive centre.[34,35]
N-Acyloxy-N-alkoxyamides behave similarly. We have shown
from studies on series 8 (Scheme 4) that branching α to
the amide carbonyl completely prevents their reaction with
N-methylaniline.[9] Interestingly, to a degree the mutagenic
behaviour of these hindered N-acyloxy-N-alkoxyamides follows
the rates of reactivity, suggesting that the attack by DNA is also
an SN2 process.
The computed transition state also suggests that steric effects
on the alkoxyl group should be important and there is limited
evidence from relative rates of reaction of the alkoxyl series 9
that branching α to the oxygen on the alkoxyl group also slows
SN2 reactivity relative to straight-chain analogues, as to a lesser
extent does branching further along an alkyl chain.[10,19,20]
Electronic effects of para substituents in series 10 with
benzoyloxyl leaving groups support the predicted transition state
properties as rate constants at 308 K correlated with Hammett
Table 1 gives Arrhenius data for a series of mutagens for
which a range of rate constants could be measured, together
with relevant data previously published by our group. Acti-
vation energies were similar to those obtained previously
for N-methylaniline reaction with a wide selection of such
compounds and reflect the balance between bond-formation and

RESEARCH FRONT
702
K. L. Cavanagh et al.
O
N
O
N
O
N
Ph
Bn
Ph
AcO
R
R
Bu
O
O
O
X-C6H4CO2
BzO
R ꢀ Me, Et, Pri, But, CH2But,
X ꢀ H, OMe, Me, Cl, But
R ꢀ Et, Pr, Bu, pentyl, octyl,
Pri, Bui, pentyli
1-adamantyl
10
8
9
Scheme 4.
O
N
O
N
O
O
Ph
AcO
Ph
AcO
Ph
Ph
CH2 Ar
Bu
Bu
OR
O
N
O
O
O
N
O
O
O
R
Ar
11a R ꢀ Pri
12a Ar ꢀ Ph
13a R ꢀ Me
14a Ar ꢀ Ph
14b Ar ꢀ 4-MeC6H4
14c Ar ꢀ 4-MeOC6H4
12b Ar ꢀ 2-MePh
12c Ar ꢀ 3-MePh
12d Ar ꢀ 3,5-diMePh
12e Ar ꢀ 2,6-diMePh
13b R ꢀ Pr
11b R ꢀ 2-Butyl
13c R ꢀ Pri
11c R ꢀ But
13d R ꢀ (S)-2-Butyl
13e R ꢀ CH2But
13f R ꢀ But
11d R ꢀ (CH2)nCH3
13g R ꢀ 1-Adamantyl
13h R ꢀ 2,6-diMePh
13i R ꢀ 3,5-diMePh
Scheme 5.
Table 1. Arrhenius data and bimolecular rate constants at 303 K for the reaction of N-methylaniline with N-acyloxy-N-alkoxybenzamides 11 and
12, 13f and 14a in [D4]methanol
Compound (R, Ar)
lnA
ꢀS‡298
[J K−1 mol−1
EA [kJ mol−1
]
104k3203
[L mol−1 s−1
]
r2
]
11a (Pri)
18.9
2
2
1
2
2
1
1
1
2
1
−110 16
−100 13
59
62
49
50
57
53
60
44
48
55
4
4
2
4
4
2
3
7
4
2
52
66
0.984
0.986
0.997
0.988
0.984
0.998
0.990
0.983
0.986
0.997
1.000
0.999
0.999
0.993
0.970
11a (Pri)A
19.5
13.4
15.9
19.5
17.8
19.9
13.9
14.7
17.1
20 0.1
16.3 0.5
15.1
13.5
18.6
11b (2-Butyl)
11d (Et)A
−150
6
38.0
276
435
414
442
273
114
78
97
102
26
34
1844
−130 14
−100 15
−114 14
−96 11
11d (Pr)A
11d (Bu)A
11d (Pent)A
11d (Oct)A
12a (Ph)B
−145 10
−139 14
12b (2-MePh)
12c (3-MePh)
12d (3,5-diMePh)
12e (2,6-diMePh)
13f (But)
−119
−95
6
1
4
5
8
62 0.3
−126
−136
−149
53
53
48
51
1
1
2
7
1
1
3
14a (Ph)B
−105 22
AData taken from refs [10,20,21].
BData taken from refs [7,36].
bond-breaking at the transition state.[10,20] The ꢀS‡ values were
similarly large and more negative than are observed in SN2 reac-
tions involving negatively charged nucleophiles, which we have
previously attributed to a transition state that is not only subject
to the spatial demands of both the nucleophile and substituents
around the central nitrogen, but also to the degree of charge sep-
aration and resultant solvent organization. ꢀS‡ is rendered more
negative by both steric interactions, which result in the require-
ment for a more ordered transition state, and also the extent of
overlap, because a well-developed transition state results in more
charge separation and solvation than a less advanced one. Thus,
steric inhibition cannot readily be signalled by strongly negative
entropies of activation alone.
The isokinetic plot in Fig. 1 presents clear evidence for the
steric impact of branching β to the amide nitrogen. Data for
straight chain N-acetoxy-N-alkoxybenzamides (11d, open cir-
cles) fit a straight line (r = 0.991) but the averaged data for the
isopropoxy substrate and that for the 2-butyloxy system (11a and
11b, closed circles) deviate significantly and similarly from the
line of best fit. These plots are open to two interpretations; for a
similarly developed transition state (similar EAs) ꢀS‡ is much
more negative than it would be with a straight-chain alkoxyl
‡Electron density-electrostatic potential energy surface.

RESEARCH FRONT
SN2 Substitution Reactions
703
ꢂ85
3-MeBn
Pent
ꢂ95
ꢂ105
ꢂ115
ꢂ125
ꢂ135
ꢂ145
ꢂ155
ꢂ165
Pr
Pri
y ꢀ 3.6409x ꢂ 307.64
R2 ꢀ 0.991
Bu
Benzyloxyls
2,6-Dimethyl
Alkyloxyls
2-MeBn
3,5-diMeBn
2,6-diMeBn
Et
Branched
Bn
Oct
y ꢀ 3.1812x ꢂ 293.17
R2 ꢀ 0.9944
2-Bu
50
40
45
55
60
65
E
A [kJ molꢂ1
]
Fig. 1. Isokinetic plot for the reaction of N-methylaniline with N-acetoxy-N-alkoxyamides 11 and N-acetoxy-N-benzyloxyamides 12.
Table 2. Bimolecular rate constants for the reaction of N-methylaniline
with N-acyloxy-N-butoxybenzamides 13 and 14 in [D4]methanol at
303 K
group. Alternatively, a straight-chain substrate with a similar
ꢀS‡ would form with a much lower EA.
Isokinetic analysis of the benzyloxy substrates 12 differ-
entiates similarly between the unmethylated, mono- and 3,5-
dimethylated benzyloxyl side chains (in 12a–d; Fig. 1, open
squares) and the sterically more demanding 2,6-dimethylated
substrate (12e; Fig. 1, closed square). It is noteworthy that the
2-methylated benzyloxy group in 12b exerts a similar influence
to the 3-methylated ring in 12c and 3,5-dimethylated ring in 12d.
Presumably, one ortho methyl group can be turned away from
the approaching nucleophile whereas such steric avoidance is
more difficult with two ortho methyl substituents.
Steric effects of branching on the acyloxyl side chain
are insignificant. Table 2 gives relative rate constants for
the reaction of N-methylaniline with a range of N-butoxy-N-
alkanoyloxybenzamides 13a–g in [D4]methanol at 303 K, and
the corresponding data for N-butoxy-N-benzoyloxybenzamides
14a–c together with pKAs and molar refractivities of the
leaving-group carboxylic acid. Comparison of rate constants for
straight-chain (13a and 13b) and branched substrates (13c–g)
clearly indicates that steric influences are minimal. The range of
pKAs for series 13 is relatively small. However, when plotted
with the previously reported rate data for N-benzoyloxy-N-
butoxybenzamide 14a and new data for the N-butoxy-N-(4-
methyl)- and -(4-methoxybenzoyloxy) benzamides 14b and 14c,
it is clear that the logarithm of the bimolecular reaction rate con-
stant yields a good linear correlation with pKA (Eqn 1), which
supports the theoretical transition state properties in which sub-
stantial charge transfer to the carboxyl group takes place. It is
also consistent with the positive Hammett correlation for the
series of N-benzoyloxy-N-benzyloxybenzamides 10.[20]
A
A
Substrate (R, Ar)
104k303
[L mol−1 s−1
pKA
MR [cm3 mol−1
]
]
13a (CH3)
13b (Pr)
13c (Pri)
13d ((S)-2-Butyl)
13e (CH2But)
13f (But)
13g (1-Adamantyl)
14a (Ph)
175C
122
91
97
78
34
61
1844
818
469
4.76
4.82
4.85
4.80
4.79B
5.03
4.86B
4.20
4.34
4.47
11.96
21.3
21.63
26.22
30.48
26.17
47.47
32.09
37.99
39.24
14b (4-MeC6H4)
14c (4-MeOC6H4)
ApKA and MR[38] of departing carboxylic acid.
BCalculated value.[39]
CSlightly lower but within experimental error similar to Campbell’s data.[20]
For Fig. 2, an averaged rate constant of 294 × 10−4 L mol−1 s−1 was used.
pKA is poorly correlated with molar refractivity (r = 0.115).
Fig. 2 shows the predicted and observed rate constants deter-
mined by both regression analyses. Eqn 2 behaves well but the
smallnegativedependenceonMRsuggeststhatbulkycarboxylic
acid side chains impede rather than promote transition-state
formation. However, the rate retardation is negligible when com-
paredwiththeimpactofbranchingonboththeamideandalkoxyl
side chains.
ln k303 = −4.7( 0.3)pKA + 18( 1) (r = 0.986)
ln k303 = −4.9( 0.2)pKA − 0.017( 0.005)MR
(1)
Thecorrelationisimprovedmarginallybyinclusionofasteric
factor in the form of calculated molar refractivities (MR) of the
carboxylic acid corresponding to the leaving group (Eqn 2).[37]
+ 19.6( 0.9) (r = 0.995, s = 0.14, F = 367) (2)

RESEARCH FRONT
704
K. L. Cavanagh et al.
ꢂ1
ꢂ1.5
ꢂ2
Ph
ꢂ2.5
ꢂ3
C6H4Me
C6H4OMe
ꢂ3.5
ꢂ4
pKA ꢃ MR
pKA
2-Bu
Pri
Me
CH2But
Ad
ꢂ4.5
ꢂ5
Pr
ꢂ5.5
ꢂ6
But
ꢂ6
ꢂ5.5
ꢂ5
ꢂ4.5
ꢂ4
ꢂ3.5
ꢂ3
ꢂ2.5
ꢂ2
ꢂ1.5
ꢂ1
Experimental ln k 303
Fig. 2. Predicted (Eqns 1 and 2) versus experimental bimolecular rate constants for the reaction of N-methylaniline with
N-alkanoyloxy-N-butoxybenzamides 13 and N-benzoyloxy-N-butoxybenzamides 14.
the gas phase but by only 18 kJ mol−1 with solvation energies.
The stabilization of the transition state and the products in aque-
oussolutionrelativetothegasphasereflectspartialandcomplete
charge separation respectively.
δꢃ
NH3
NH3
ꢃ
O
O
O
O
N
O
CH3
CH3
O
N
ꢂO
NH3
ꢃ
O CH3
O
N
H3C
H3C
CH3
O CH3
H3C
O
O
δꢂ
The methoxy group, amide nitrogen, and acetyl group are
largely in plane in support of a conjugative interaction between
the central nitrogen 2pz orbital, partially overlapping with the
ammonia and acetate, and both the carbonyl carbon 2pz and
the 2pz methoxyl oxygen lone pair. We have previously shown
that the presence of methoxyl as opposed to methyl at the amide
nitrogen radically reduces the EA for reaction with ammonia.[21]
It is clear from the density surface (Fig. 3b) that branching α to
the alkoxyl oxygen or α to the amide carbonyl would present
significant steric interactions to a large incoming nucleophile.
However, although dependent on the nature and conformation
of the alkoxyl group, bulky groups on the acyloxyl group should
have much less of a steric effect on the reaction.
The minor and negative influence of bulk in the leaving group
in these unusual SN2 reactions at nitrogen indicates that there
is also no relief of steric compression at the transition state.
Although the transition state for these SN2 reactions in most
respects resembles that for SN2 substitution at primary and sec-
ondary carbons, the lone pair, in place of a fourth atom at the
reactive centre (Scheme 3) may negate this effect. Indeed, the
nucleophile and the leaving group are bent towards the lone pair
in the transition state.
CH3
15
16
17
18
Scheme 6.
To gauge the spatial requirements of substituents at the
amide nitrogen, the reaction has been modelled at the HF/6–
31G(d) level by the reaction of ammonia on N-acetoxy-
N-methoxyacetamide according to Scheme 6. The lowest
unoccupied molecular orbital (LUMO) of N-acetoxy-N-
methoxyacetamide 15 exhibited both C=O π* and N–OAc σ*
character. However, although approach of ammonia to the car-
bonyl carbon does not lead to a stationary point on the energy
surface, attack at the amide nitrogen leads to substitution of the
acetoxyl by ammonia and formation of 17 and 18.
The transition state 16 for the reaction is depicted in Fig. 3a
and is similar in most respects to that computed at HF/6–31G(d)
for the corresponding reaction of ammonia and N-formyloxy-N-
methoxyformamide.[21] The structure is characteristic of an SN2
process. Nitrogen is sp2 hybridized with long bonds to both the
leaving group and nucleophile, which are largely trans to one
another, subtending an angle of 158◦. Relative to the ground-
state reactants, the group charges on ammonia (ꢀq = +0.4)
and acetate (ꢀq = −0.73) are indicative of the expected charge
separation in the transition state. The rest of the charge is
on the central nitrogen (ꢀq = 0.13) and the methoxyl group
(ꢀq = 0.14), indicating partial alkoxynitrenium ion character.At
the B3LYP/6–31G(d)//HF/6–31G(d) level in the gas phase, the
reactionhasanactivationenergyof127 kJ mol−1 butthisreduces
to 57 kJ mol−1 when aqueous solvation energies are incorpo-
rated. Overall, the reaction is endothermic by 540 kJ mol−1 in
Conclusion
Bis oxygen functionalization at nitrogen in N-acyloxy-N-
alkoxyamides 1a, as with other anomeric amides, renders the
amide quite atypical in structure, properties, and reactivity.
Structural effects on the bimolecular reaction of N-methylaniline
with N-acyloxy-N-alkoxyamides are predictable based on the
known properties of SN2 reactions at saturated carbon.The com-
bination of the anomerically destabilizing alkoxyl oxygen and

RESEARCH FRONT
SN2 Substitution Reactions
705
(a)
(b)
N(1)
O(5)
N(2)
O(7)
C(6)
C(4)
N
(1)-N(2) ꢀ 1.866 Å
N(2)-O(3) ꢀ 2.333 Å
N(2)-C(4) ꢀ 1.504 Å
N(2)-O(5) ꢀ 1.281 Å
N(1)-N(2)-O(5) ꢀ 110.8°
C(4)-N(2)-O(3) ꢀ 158.0°
C(4)-N(2)-O(5) ꢀ 110.8°
C(4)-N(2)-O(3) ꢀ 72.4°
C(4)-N(2)-N(1) ꢀ 96.9°
O(5)-N(2)-O(3) ꢀ 98.0°
O(5)-N(2)-N(1) ꢀ 103.9°
O(3)-N(2)-O(5)-C(6) ꢀ ꢂ87.3°
O(7)-C(4)-N(2)-O(5) ꢀ ꢂ159.7°
O(3)
O(9)
C(8)
Fig. 3. (a) HF/6–31G(d) transition state for the reaction of ammonia with N-acetoxy-N-methoxyacetamide (i 446.7 cm−1); and (b) associated EDEP‡
surface.
the acyloxyl leaving group in this case likens the reactivity to
that of α-haloketones, which undergo accelerated SN2 displace-
ment of halogen. However, like such reactions at carbon α to a
carbonyl, SN2 reactions at amide nitrogen are also affected by
branching β to the reactive centre, either as previously demon-
strated on the amide in 8,[9] or as shown in the present study, by
branching on the alkoxyl side chain in 11a–c. This is reinforced
by the reduced rate of SN2 reactivity for 12e.
Branching and bulkiness close to nitrogen on the alkoxyl side
chain, which impedes SN2 reactivity, hinder neither binding to
DNA nor reactivity at guanine-N7. Steric demands of the leaving
group do not greatly influence SN2 reactivity at nitrogen, but the
carboxylic acids have higher pKAs than acetic or benzoic acids,
which should favour mutagenic activity.As the opposite is found,
these bulky side chains most probably hinder binding to DNA or
the attainment of the transition state for reaction with guanine.
Though with branching α to the amide carbonyl, binding to DNA
is possible, any SN2 reaction, including that at guanine-N7 in the
major groove of DNA, is impeded.[9]
Bulky groups on the carboxoyloxyl side chain in 13 appear
to influence SN2 reactivity almost exclusively on the basis of
changes to the pKA of the leaving carboxylic acid.
The mutagenic activity of some 80 N-acyloxy-N-alkoxy-
amides has been determined by the Ames test and a quan-
titative structure–activity relationship based on 50 of these
allows prediction, with some accuracy, of the activity of other
congeners.[8,10] Importantly, activity is dependent on pKA of the
leaving carboxylic acid in a positive sense, which indicates that
the better the leaving group, the more reactive is the mutagen to
adventitious SN2 reactivity that decreases the concentration of
the active material in the assay.
Branching at the α-carbon on the amide side chain in 8 has
previouslybeenshowntoimpede, strongly, bothSN2reactivityat
nitrogen as well as mutagenicity.[9] Experimental and predicted
mutagenic activity for N-acyloxy-N-alkoxyamides used in the
current kinetic study will be presented elsewhere. However, it
is interesting that although SN2 reactivity is decreased with iso-
propoxy or 2,6-dimethylbenzyloxy on the alkoxyl side chain,
these effects do not reduce mutagenic activity to a measurable
extent, both substrates being well predicted by our quantitative
structure–activity relationship.[10] In addition, like the amide
series 8, the activity of mutagens 13b–g is strongly and adversely
affected by branching and bulkiness on the leaving group. All
but the butanoyloxy substrate 13b reduced activity by nearly an
order of magnitude. A 2,6-dimethylbenzoyloxyl group in 13h,
and to some extent a 3,5-dimethylbenzoyloxyl substituent in 13i
had a similarly influence.[10]
Experimental
Materials and Methods
Infrared spectra were recorded on a Perkin–Elmer 1600 series
Fourier-transform (FT)-IR spectrophotometer as chloroform
solutions. Mass spectra were recorded on a Varian 1200L liquid
chromatograph-mass spectrometer. All samples for analysis
were carried out at a 30-V capillary voltage and 350◦C, 138 kPa
drying gas temperature and pressure, in HiPerSolv aceto-
nitrile. Nuclear magnetic resonance spectra were recorded on
a Bruker Avance 300P FT NMR spectrometer with a 5-mm
1H inverse/Broad Band probe with a z-gradient, operating at
300.13 MHz (1H), 75.46 MHz (13C), or 30.42 MHz (15N). H
1
and 13C samples studied for structural analysis were run in
CDCl3, 15N NMR shifts were measured indirectly using a gra-
dient enhanced heteronuclear multiple bond correlation pulse
3
sequence (inv4 gplplrnd) optimized for JNH = 8 Hz. Values
were referenced relative to nitromethane (0 ppm).
Kinetic Studies
Rate constants for the bimolecular reaction between N-
methylaniline and various mutagens were determined using 1H
NMR spectroscopy. Mutagen (2–10 mg weighed out accurately)
in [D4]methanol (400 µL) in an ultra-high-precision NMR tube
was equilibrated at the required temperature in the probe of an
NMR spectrometer.The sample was shimmed, removed from the
Clearly the factors controlling SN2 reactivity and biologi-
cal activity are different where these side chains are concerned.
‡Electron density-electrostatic potential energy surface.

RESEARCH FRONT
706
K. L. Cavanagh et al.
probe, and a microsyringe was used to add a minimum of twice
the molar equivalent of N-methyl aniline (2–20 µL). The exact
time of mixing and the initial concentrations of both compounds
were noted. After brief shimming, a series of acquisitions were
accumulated at a preset time interval, and the extent of reaction
was monitored by analysing the disappearance of both starting
materials according to peak integrals of characteristic signals in
the mutagen and the N-methyl resonance of the N-methylaniline,
using the integral of the methyl hydrogens of [D4]methanol as an
internal constant. Initial substrate concentrations were obtained
by back-extrapolation of concentration plots for both reagents
to the initial time of mixing, to.
2,6-Dimethylbenzylbromide
2,6-Dimethylbenzyl alcohol (0.21 g, 1.52 mmol) was added to
a mixture of conc. HBr (2 mL), conc. sulfuric acid (0.3 mL),
and diethyl ether (30 mL). Further H2SO4 (0.3 mL) was added
and the mixture then refluxed (2.5 h). Diethyl ether (25 mL)
was added before the mixture was washed with HCl, H2O,
10% aq. Na2CO3, and H2O. The solution was dried over
Na2SO4; concentration under reduced pressure to afford pure
2,6-dimethylbenzyl bromide (0.21 g, 1.06 mmol, 70%) as a
pale yellow semi-solid at room temperature (Lit. mp 37.5–
38.5◦C[44]). νmax(CHCl3)/cm−1 1588, 1472 (C=C, str). δH 2.44
(6H, s), 4.6 (2H, s), 7.04 (2H, d, J 7.4), 7.11 (1H, t, J 7.4). δC
19.3, 29.4, 128.5, 128.6, 134.1, 137.5.
Computational Methods
N-(2-Butoxy)benzamide (General Procedure)[45]
Structures were optimized at the HF/6–31G(d) level using
Spartan 04.[40] Ground state structures for reactants and
transition state for reaction of ammonia with N-acetoxy-N-
methoxyacetamide were verified by frequency calculations.
Density functional energies were determined on the stationary
pointsusingtheB3LYP/6–31G(d)//HF/6–31G(d)method.Aque-
ous solvation energies were estimated using the SM5.4 method
of Cramer and coworkers.[41]
The cartesian coordinates of the transition state, reactants and
products from reaction of N-acetoxy-N-methoxyacetamide with
ammonia, their absolute energies, solvation energies and group
electrostatic charges are provided as an Accessory Publication.
Synthesis of N-acetoxy-N-butoxybenzamide 13a and N-
acetoxy-N-isopropoxybenzamide 11a has been described
previously.[1,3]
Potassium benzohydroxamate (1.0 g, 92 mmol), 2-butylbromide
(18.8 g, 137 mmol), and sodium carbonate (10.64 g, 0.1 mol)
were stirred overnight at room temperature in 50% aqueous
methanol (250 mL) and refluxed (2 h). Excess methanol was
removed under reduced pressure and the mixture extracted with
dichloromethane, dried over anhydrous Na2SO4, and concen-
trated under reduced pressure. Flash chromatography with 10%
ethyl acetate/petroleum spirit afforded N-(2-butoxy)benzamide
(13.5 g, 69.9 mmol, 51%) as a brown oil. νmax(CHCl3)/cm−1
3221br (NH), 1686 (C=O). δH 0.96 (3H, t, J 7.3), 1.28 (3H, d, J
6.2), 1.50–1.85 (2H, split m), 4.04 (1H, sextet, J 6.4), 7.40 (2H,
t, J 7.3), 7.49 (1H, t, J 7.6), 7.74 (2H, d, J 7.1), 8.77 (1H, br s). δC
9.6, 17.9, 27.5, 83.4, 127.1, 128.6, 131.9, 132.4, 166.9 (C=O).
δN −199.9 0.7. m/z 194.1 (M + 1), 216.1 (M + 23).
N-(2-Methylbenzyloxy)benzamide
2,6-Dimethylbenzyl Alcohol[42]
Potassium benzohydroxamate (6.1 g, 34.7 mmol), (2-methyl-
benzyl)bromide (6.42 g, 34.7 mmol), and sodium carbon-
ate (4.05 g, 3.82 mmol) were combined according to the
general procedure. Centrifugal chromatography with 10%
ethyl acetate/petroleum spirit afforded N-(2-methylbenzyloxy)
benzamide (5.1 g, 21.2 mmol, 61%) as pale orange crystals. Mp
62–64◦C. νmax(CHCl3)/cm−1 3203br (NH), 1684 (C=O). δH
2.46 (3H, s), 5.07 (2H, s), 7.19–7.34 (3H, m), 7.3–7.5 (3H, m),
7.47 (1H, t, J 7.7), 7.69 (2H, d, J 7.03), 9.13 (1H, br s). δC 19.0,
76.5, 125.9, 127.1, 128.4, 128.6, 129.0, 130.5, 130.7, 132.0,
133.2, 138.2, 166.5 (C=O). m/z 264.2 (M + 23).
2,6-Dimethylbenzoic acid (0.75 g, 4.99 mmol) was added to
ethereal LiAlH4 (0.21 g, 5.49 mmol) in dry diethyl ether (30 mL)
at such a rate that the reaction mixture boiled gently. Following
addition, the reaction was refluxed (48 h). The reaction flask
was placed in an ice-bath and moist diethyl ether (20 mL) was
added dropwise before filtration and washing with 0.1 M HCl
followed by aq. Na2CO3. The solution was then dried over
Na2SO4 andsolventwasremovedunderreducedpressureafford-
ing 2,6-dimethylbenzyl alcohol (0.21 g, 1.54 mmol, 31%) as
colourless crystals. Mp 82.5–83.5◦C (Lit. mp 82.5–83.5◦C[42]).
νmax(CHCl3)/cm−1 3691.4 (free OH), 3607.0 (bonded OH). δH
2.46 (6H, s), 4.78 (2H, s), 7.06 (2H, d, J 7.4), 7.12 (1H, t, J 7.4).
δC 19.4, 59.3, 128.1, 128.4, 136.6, 137.4.
N-(3-Methylbenzyloxy)benzamide
Potassium benzohydroxamate (3.39 g, 19.3 mmol), (3-methyl-
benzyl)bromide (3.56 g, 19.3 mmol), and sodium carbon-
ate (2.24 g, 2.12 mmol) were combined according to the
general procedure. Centrifugal chromatography with 10%
ethyl acetate/petroleum spirit afforded N-(3-methylbenzyloxy)
benzamide (2.46 g, 10.3 mmol, 53%) as pale orange crystals.
Mp 62–64◦C. νmax(CHCl3)/cm−1 3403br (NH), 1684 (C=O).
δH 2.39 (3H, s), 5.03 (2H, s), 7.19 (1H, d, J 7.5), 7.22–7.34 (3H,
m), 7.41 (2H, t, J 7.9), 7.51 (1H, t, J 7.3), 7.67 (2H, d, J 7.9), 8.49
(1H, br s). δC 21.3, 77.5, 126.2, 127.1, 128.4, 128.5, 129.3, 129.9,
131.0, 133.4, 136.0, 138.3, 165.6 (C=O). δN −195.9 1.6. m/z
242.5 (M + 1), 264.0 (M + 23).
3,5-Dimethylbenzylbromide
3,5-Dimethylbenzyl alcohol (1.12 g, 8.22 mmol) was added to a
mixture of conc. HBr (4 mL), conc. H2SO4 (0.6 mL), and diethyl
ether (55 mL). Further H2SO4 (0.6 mL) was added and the mix-
ture refluxed (3 h). The mixture was extracted with CHCl3, then
washed successively with HCl, H2O, 10% aq. Na2CO3, and H2O.
The solution was dried over Na2SO4 and concentration under
reduced pressure to afford a pale yellow oil. Purification by cen-
trifugal chromatography with 10% ethyl acetate/petroleum spirit
afforded pure 3,5-dimethylbenzyl bromide (1.01 g, 5.07 mmol,
62%) as a pale yellow semi-solid at room temperature (Lit. mp
37.5–38◦C[43]). νmax(CHCl3)/cm−1 1606, 1462 (C=C, str). δH
2.34 (6H, s), 4.47 (2H, s), 6.96 (1H, s), 7.04 (2H, s). δC 21.1,
33.9, 126.8, 130.2, 137.6, 138.4.
N-(3,5-Dimethylbenzyloxy)benzamide
Potassium benzohydroxamate (0.86 g, 4.84 mmol), (3,5-
dimethylbenzyl)bromide (0.96 g, 4.84 mmol), and sodium car-
bonate (0.57 g, 5.32 mmol) were combined according to the

RESEARCH FRONT
SN2 Substitution Reactions
707
general procedure. Centrifugal chromatography with 10% ethyl
N-Chloro-N-(2-methylbenzyloxy)benzamide
acetate/petroleum spirit afforded N-(3,5-dimethylbenzyloxy)
N-(2-Methylbenzyloxy)benzamide (1.50 g, 6.22 mmol) and
tert-butyl hypochlorite (3.19 g, 29.4 mmol) were combined
according to the general procedure, to give N-chloro-N-
(2-methylbenzyloxy)benzamide (1.65 g, 56.9 mmol, 96%) as
a yellow oil, which was used without further purification.
νmax(CHCl3)/cm−1 1720 (C=O). δH 2.28 (3H, s), 5.13 (2H, s),
7.16–7.31 (4H, m), 7.39 (2H, t, J 7.67), 7.53 (1H, t, J 7.1), 7.68
(2H, d, J 7.5). δC 18.8, 74.5, 126.1, 128.3, 129.3, 129.6, 130.5,
131.2, 131.3, 132.8, 138.3, 174.1 (C=O). δN −161.7 0.3.
benzamide (0.69 g, 2.73 mmol, 56%) as
a brown oil.
νmax(CHCl3)/cm−1 3405br (NH), 1686 (C=O). δH 2.35 (6H, s),
5.00 (2H, s), 7.03 (1H, s), 7.08 (2H, s), 7.41 (2H, t, J 7.3), 7.51
(1H, t, J 7.3), 7.67 (2H, d, J 7.3), 8.44 (1H, br s). δC 21.2, 78.4,
125.7, 127.1, 128.6, 130.4, 131.9, 135.2, 137.9, 138.2, 166.0
(C=O). δN −202.0 0.3. m/z 256.2 (M + 1), 278.1 (M + 23).
N-(2,6-Dimethylbenzyloxy)benzamide
Potassium benzohydroxamate (0.19 g, 1.05 mmol), (2,6-
dimethylbenzyl)bromide (0.21 g, 1.04 mmol), sodium car-
bonate (0.12 g, 1.14 mmol) were combined according to
the general procedure. N-(2,6-Dimethylbenzyloxy)benzamide
crystallized from orange oil on standing. Recrystalliza-
tion from benzene/petroleum spirit afforded pure N-(2,6-
dimethylbenzyloxy)benzamide (0.18 g, 0.71 mmol, 68%) as
a low-melting solid. νmax(CHCl3)/cm−1 3406br (NH), 1684
(C=O). δH 2.50 (6H, s), 5.22 (2H, s), 7.07 (2H, d, J 7.9), 7.16
(1H, t, J 7.9), 7.42 (2H, t, J 7.3), 7.52 (1H, t, J 7.3), 7.69 (2H, d,
J 7.3), 8.46 (1H, br s). δC 19.7, 72.4, 127.0, 128.3, 128.5, 128.7,
129.0, 131.4, 132.0, 139.1, 166.7 (C=O). δN −202.4 0.6. m/z
255.9 (M + 1), 278.2 (M + 23).
N-Chloro-N-(3-methylbenzyloxy)benzamide
N-(3-Methylbenzyloxy)benzamide (0.66 g, 2.74 mmol) and
tert-butyl hypochlorite (1.6 g, 14.7 mmol) were combined
according to the general procedure, to give N-chloro-N-
(3-methylbenzyloxy)benzamide (0.73 g, 2.63 mmol, 96%) as
a yellow oil, which was used without further purification.
νmax(CHCl3)/cm−1 1723 (C=O). δH 2.33 (3H, s), 5.07 (2H, s),
7.07 (2H, m), 7.15–7.28 (2H, m), 7.40 (2H, t, J 8.1), 7.54 (1H,
t, J 7.1), 7.70 (2H, d, J 7.8). δN −162.2 0.5.
N-Chloro-N-(3,5-dimethylbenzyloxy)benzamide
N-(3,5-Dimethylbenzyloxy)benzamide (0.54 g, 2.13 mmol) and
tert-butyl hypochlorite (1.16 g, 10.6 mmol) were combined
according to the general procedure, to give N-chloro-N-(3,5-
dimethylbenzyloxy)benzamide (0.58 g, 3.03 mmol, 94%) as
a yellow oil, which was used without further purification.
νmax(CHCl3)/cm−1 1717 (C=O). δH 2.29 (6H, s), 5.02 (2H, s),
6.86 (2H, s), 6.98 (1H, s), 7.40 (2H, t, J 8.1), 7.54 (1H, t, J 7.3),
7.70 (2H, d, J 7.8).
N-(tert-Butoxy)benzamide
O-(tert-Butyl)hydroxylaminehydrochloride(0.26 g, 2.07 mmol)
was added to dry diethyl ether (40 mL) in a two-necked round-
bottom flask in an ice bath. While stirring, triethylamine (0.42 g,
4.14 mmol) was added. Over a period of 1 h, a mixture of ben-
zoyl chloride (0.29 g, 2.07 mmol) in dry diethyl ether (10 mL)
was added dropwise such that the temperature did not rise
above 5◦C, and the reaction mixture was left to stir overnight at
room temperature. The mixture was washed with sat. NaHCO3,
dried over Na2SO4, and concentrated under reduced pressure.
Recrystallization from benzene/petroleum spirit afforded pure
N-(tert-butoxy)benzamide (0.16 g, 0.80 mmol, 39%) as colour-
less crystals. Mp 118–120◦C. νmax(CHCl3)/cm−1 3384br (NH),
1686 (C=O). δH 1.37 (9H, s), 7.42 (2H, t, J 7.5), 7.51 (1H, t, J
7.3), 7.75 (2H, d, J 7.5), 8.25 (1H, br s). δC 26.4, 82.3, 127.0,
128.6, 131.8, 132.4, 167.9 (C=O). m/z 194.1 (M + 1), 216.1
(M + 23).
N-Chloro-N-(2,6-dimethylbenzyloxy)benzamide
N-(2,6-Dimethylbenzyloxy)benzamide (0.123 g, 0.48 mmol)
and tert-butyl hypochlorite (0.26 g, 2.4 mmol) were combined
according to the general procedure, to give N-chloro-N-(2,6-
dimethylbenzyloxy)benzamide (0.135 g, 0.47 mmol, 97%) as
pale crystals, which were used without further purification.
νmax(CHCl3)/cm−1 1720 (C=O). δH 2.30 (6H, s), 5.20 (2H, s),
7.02 (2H, d, J 7.5), 7.15 (1H, t, J 7.5), 7.41 (2H, t, J 7.5), 7.54
(1H, t, J 7.1), 7.73 (2H, d, J 7.5). δC 19.5, 70.6, 128.4, 129.3,
129.5, 129.7, 131.5, 132.7, 139.2, 174.0 (C=O).
N-(tert-Butoxy)-N-chlorobenzamide (General Procedure)
N-Butanoyloxy-N-butoxybenzamide 13b
(General Procedure)
N-(tert-Butoxy)benzamide (0.10 g, 0.52 mmol) and tert-butyl
hypochlorite (0.28 g, 2.6 mmol) were stirred in the dark at
room temperature and monitored byTLC until complete conver-
sion. Excess tert-butyl hypochlorite was removed under reduced
pressure to give N-(tert-butoxy)-N-chlorobenzamide (0.10 g,
0.44 mmol, 84%) as a yellow oil, which was used without further
purification. νmax(CHCl3)/cm−1 1729 (C=O). δH 1.39 (9H, s),
7.43 (2H, t, J 7.3), 7.54 (1H, t, J 7.3), 7.82 (2H, d, J 7.1).
N-Butoxy-N-chlorobenzamide (0.3 g, 1.29 mmol) was stirred in
the dark with sodium butyrate (0.2 g, 1.81 mmol) in dry ace-
tone and monitored by TLC until all N-chloro compound had
beenconsumed. Filtrationandconcentrationunderreducedpres-
sure yielded the crude product. Centrifugal chromatography
with10%ethylacetate/petroleumspiritafforded N-butanoyloxy-
N-butoxybenzamide as a light brown oil. νmax(CHCl3)/cm−1
1773.7 (ester C=O), 1721.4 (amide C=O). δH 0.92 (6H, 2 × t, J
7.3), 1.38 (2H, sextet, J 7.7), 1.6–1.7 (4H, m), 2.33 (2H, t, J 7.5),
4.19 (2H, t, J 6.8), 7.43 (2H, t, J 7.9), 7.54 (1H, t, J 7.5), 7.78
(2H, d, J 7.9). δC 13.4, 13.7, 18.2, 19.0, 30.1, 34.0, 75.4, 128,
128.2, 129.0, 132.6, 170.9 (ester C=O), 174.4 (amide C=O).
N-(2-Butoxy)-N-chlorobenzamide
N-(2-Butoxy)benzamide (0.62 g, 3.21 mmol) and tert-butyl
hypochlorite (1.35 g, 1.24 mmol) were combined according to
the general procedure, to give N-(2-butoxy)-N-chlorobenzamide
(0.67 g, 2.84 mmol, 91%) as a yellow oil, which was used with-
out further purification. νmax(CHCl3)/cm−1 1724 (C=O). δH
0.90 (3H, t, J 7.5), 1.29 (3H, d, J 6.4), 1.50–1.80 (2H, m), 4.24
(1H, m), 7.43 (2H, t, J 7.3), 7.54 (1H, t, J 7.5), 7.80 (2H, d, J
7.3). δN −164.5 0.3.
N-Butoxy-N-(2-methylpropanoyloxy)benzamide 13c
N-Butoxy-N-chlorobenzamide (0.74 g, 3.24 mmol) and sodium
isobutyrate (0.5 g, 4.54 mmol) were combined according to

RESEARCH FRONT
708
K. L. Cavanagh et al.
the general procedure. Purification by centrifugal chromato-
graphy with 5% ethyl acetate/petroleum spirit afforded N-
butoxy-N-(2-methylpropanoyloxy)benzamide as a light brown
oil. νmax(CHCl3)/cm−1 1775.2 (ester C=O), 1721.1 (amide
C=O). δH 0.92 (3H, t, J 7.3), 1.12 (6H, d, J 6.8), 1.39 (2H,
sextet, J 7.4), 1.67 (2H, quin, J 7.3), 2.55–2.63 (1H, septet, J
6.6), 4.19 (2H, t, J 6.6), 7.42 (2H, t, J 8.1), 7.54 (1H, t, J 7.3),
7.76 (2H, d, J 8.0). δC 13.7, 18.5, 19.0, 30.1, 32.4, 75.4, 128.1,
129.2, 132.1, 132.5, 174.3 (amide C=O), 174.5 (ester C=O).
N-Acetoxy-N-(2-butoxy)benzamide 11b
N-(2-Butoxy)-N-chlorobenzamide (0.50 g, 2.20 mmol) and
sodium acetate (0.25 g, 3.07 mmol) were combined according
to the general procedure. Purification by centrifugal chromato-
graphy with 10% ethyl acetate/petroleum spirit afforded pure
N-acetoxy-N-(2-butoxy)benzamide (0.34 g, 1.36 mmol, 62%) as
an orange-brown oil. νmax(CHCl3)/cm−1 1790 (ester C=O),
1720 (amide C=O). δH 0.91 (3H, t, J 7.5), 1.30 (3H, d, J 6.2),
1.53–1.79 (2H, split m), 2.05 (3H, s), 4.25–4.35 (1H, m), 7.40
(2H, t, J 7.7), 7.51 (1H, t, J 7.0), 7.76 (2H, d, J 7.6). δC 9.5, 18.5,
18.7, 27.7, 83.4, 128.2, 128.9, 132.0, 132.4, 168.3 (ester C=O),
174.9 (amide C=O). δN −126.9 0.6. m/z 274 (M + 23).
N-Butoxy-N-((S)-(+)-2-methylbutanoyloxy)benzamide 13d
N-Butoxy-N-chlorobenzamide (0.26 g, 1.15 mmol) and sodium
(S)-(+)-2-methylbutyrate (0.2 g, 1.61 mmol) were combined
according to the general procedure. Purification by centrifugal
chromatography with 5% ethyl acetate/petroleum spirit afforded
N-butoxy-N-(S)-(+)-2-methylbutanoyloxybenzamide as a light
brown oil. [α]D25 11.53◦ in CHCl3. νmax(CHCl3)/cm−1 1773.7
(ester C=O), 1725 (amide C=O). δH 0.86 (3H, t, J 7.3), 0.93
(3H, t, J 7.1), 1.10 (3H, d, J 6.8), 1.36–1.45 (3H, m), 1.65–1.70
(3H, m), 2.42 (1H, m), 4.18 (2H, t, J 6.8), 7.42 (2H, t, J 7.3),
7.54 (1H, t, J 7.5), 7.77 (2H, d, J 7.3). δC 13.7, 11.3, 16.3, 19.0,
26.4, 30.1, 39.4, 75.4, 128.1, 129.0, 132.1, 132.5, 173.9 (ester
C=O), 174.5 (amide C=O).
N-Acetoxy-N-(tert-butoxy)benzamide 11c
N-(tert-Butoxy)-N-chlorobenzamide (0.48 g, 2.11 mmol) and
sodium acetate (0.26 g, 3.16 mmol) were combined according
to the general procedure. Purification by centrifugal chro-
matography with 5% ethyl acetate/petroleum spirit afforded
N-acetoxy-N-(tert-butoxy)benzamide (0.31 g, 1.23 mmol, 58%)
as an orange oil. νmax(CHCl3)/cm−1 1786 (ester C=O), 1707
(amide C=O). δH 1.37 (9H, s), 1.97 (3H, s), 7.38 (2H, t, J 7.7),
7.48 (1H, t, J 7.3), 7.77 (2H, d, J 7.0). δC 18.7, 27.0, 83.8, 127.9,
129.1, 131.9, 132.4, 168.4 (ester C=O), 174.9 (amide C=O).
m/z 274.1 (M + 23).
N-Butoxy-N-(3,3-dimethylbutanoyloxy)benzamide 13e
N-Butoxy-N-chlorobenzamide (0.59 g, 2.59 mmol) and sodium
3,3-dimethylbutyrate (0.5 g, 3.62 mmol) were combined accord-
ing to the general procedure. Purification by centrifugal chro-
matography with 10% ethyl acetate/petroleum spirit afforded
N-butoxy-N-(3,3-dimethylbutanoyloxy)benzamide as a light
brown oil. νmax(CHCl3)/cm−1 1778.1 (ester C=O), 1721.4
(amide C=O). δH 0.92 (3H, t, J 7.1), 1.01 (9H, s), 1.39 (2H,
sextet, J 6.7), 1.62 (2H, quin, J 7.3), 2.24 (2H, s), 4.18 (2H, t, J
7.0), 7.42 (2H, t, J 7.8), 7.52 (1H, t, J 7.5), 7.78 (2H, d, J 7.8).
δC 13.7, 19.0, 29.4, 30.1, 31.0, 45.4, 75.3, 128.2, 129.1, 132.1,
132.5, 169.5 (ester C=O), 174.4 (amide C=O).
N-Acetoxy-N-(2-methylbenzyloxy)benzamide 12b
Sodium acetate (0.67 g, 8.17 mmol) and N-chloro-N-(2-
methylbenzyloxy)benzamide (1.61 g, 5.84 mmol) were com-
bined according to the general procedure. Purification by
centrifugal chromatography with 5% ethyl acetate/petroleum
spirit afforded N-acetoxy-N-(2-methylbenzyloxy)benzamide
(0.96 g, 3.21 mmol, 55%) as pale yellow oil. νmax(CHCl3)/cm−1
1792 (ester C=O), 1726 (amide C=O). δH 2.07 (3H, s), 2.35
(3H, s), 5.21 (2H, s), 7.17–7.34 (3H, m), 7.33 (1H, d, J 7.0),
7.39 (2H, t, J 7.7), 7.52 (1H, t, J 7.5), 7.73 (2H, d, J 7.7). δC
18.7, 18.9, 75.7, 125.9, 128.1, 128.3, 129.0, 129.1, 130.4, 130.7,
131.8, 132.7, 138.0, 168.1 (ester C=O), 174.2 (amide C=O). δN
−123.3 0.5. m/z 322 (M + 23).
N-Butoxy-N-(2,2-dimethylpropanoyloxy)benzamide 13f
N-Butoxy-N-chlorobenzamide (0.66 g, 2.88 mmol) and sodium
pivalate (0.5 g, 4.03 mmol) were combined according to the
general procedure. Purification by centrifugal chromatography
with 5% ethyl acetate/petroleum spirit afforded N-butoxy-N-
(2,2-dimethylpropanoyloxy)benzamide as a light brown oil.
νmax(CHCl3)/cm−1 1770.5 (ester C=O), 1721.8 (amide C=O).
δH 0.93 (3H, t, J 7.1), 1.15 (9H, s), 1.40 (2H, sextet, J 8.1), 1.68
(2H, quin, J 7.5), 4.18 (2H, t, J 7.5), 7.44 (2H, t, J 7.5), 7.55 (1H,
t, J 7.5), 7.73 (2H, d, J 7.5). δC 13.7, 19.0, 26.7, 30.0, 38.4, 75.4,
127.9, 128.1, 129.4, 132.8, 174.7 (amide C=O), 175.4 (ester
C=O).
N-Acetoxy-N-(3-methylbenzyloxy)benzamide 12c
Sodium acetate (0.31 g, 3.68 mmol) and N-chloro-N-(3-
methylbenzyloxy)benzamide (0.73 g, 2.63 mmol) were com-
bined according to the general procedure. Purification by
centrifugal chromatography with 10% ethyl acetate/petroleum
spirit afforded N-acetoxy-N-(3-methylbenzyloxy)benzamide
(0.55 g, 1.84 mmol, 70%) as an orange-brown oil. νmax(CHCl3)/
cm−1 1792 (ester C=O), 1729 (amide C=O). δH 2.09 (3H,
s), 2.35 (3H, s), 5.16 (2H, s), 7.1–7.25 (3H, m), 7.28 (1H, s),
7.40 (2H, t, J 7.6), 7.53 (1H, t, J 7.5), 7.74 (2H, d, J 7.6). δC
18.7, 21.3, 77.7, 126.2, 128.3, 128.4, 129.1, 129.4, 129.9, 131.7,
132.7, 134.5, 138.2, 168.1 (ester C=O), 174.2 (amide C=O). δN
−123.6 0.5. m/z 322.1 (M + 23).
N-(Adamantane-1-carboxoyloxy)-N-butoxybenzamide 13g
N-Butoxy-N-chlorobenzamide (0.44 g, 1.94 mmol) and sodium
adamantane-1-carboxylate (0.55 g, 2.72 mmol) were combined
according to the general procedure. Purification by centrifugal
chromatography with 5% ethyl acetate/petroleum spirit afforded
a light brown oil. νmax(CHCl3)/cm−1 1767.4 (ester C=O),
1722.5 (amide C=O). δH 0.93 (3H, t, J 7.3), 1.39 (2H, sextet, J
7.7), 1.63–1.87 (8H, m), 1.83 (6H, br s), 1.99 (3H, br s), 4.17
(2H, t), 7.41 (2H, t, J 7.5), 7.53 (1H, t, J 7.3), 7.74 (2H, d, J 7.5).
δC 13.7, 19.0, 27.7, 30.2, 36.2, 38.3, 40.5, 75.3, 128.1, 129.0,
132.1, 132.4, 174.4, 174.7.
N-Acetoxy-N-(3,5-dimethylbenzyloxy)benzamide 12d
Sodium acetate (0.30 g, 3.70 mmol) and N-chloro-N-(3,5-
dimethylbenzyloxy)benzamide (0.77 g, 2.64 mmol) were com-
bined according to the general procedure. Purification by
centrifugal chromatography with 5% ethyl acetate/petroleum
spiritaffordedN-acetoxy-N-(3,5-dimethylbenzyloxy)benzamide
(0.48 g, 1.56 mmol, 59%) as a yellow oil. νmax(CHCl3)/cm−1

RESEARCH FRONT
SN2 Substitution Reactions
709
1791 (ester C=O), 1728 (amide C=O). δH 2.06 (3H, s), 2.30
(6H, s), 5.07 (2H, s), 6.95 (2H, s), 6.98 (1H, s), 7.44 (2H, t, J
7.7), 7.57 (1H, t, J 7.1), 7.75 (2H, d, J 7.7). δC 18.7, 21.2, 77.7,
127.0, 128.2, 129.1, 130.3, 131.8, 132.7, 134.4, 138.0, 168.1
(ester C=O), 174.1 (amide C=O). δN −122.1 0.3. m/z 336
(M + 23).
[2] J. J. Campbell, S.A. Glover, C.A. Rowbottom,Tetrahedron Lett. 1990,
31, 5377. doi:10.1016/S0040-4039(00)98076-6
[3] J. J. Campbell, S. A. Glover, G. P. Hammond, C. A. Rowbottom,
J. Chem. Soc., Perkin Trans.
2 1991, 2067. doi:10.1039/
P29910002067
[4] A. M. Bonin, S. A. Glover, G. P. Hammond, J. Chem. Soc., Perkin
Trans. 2 1994, 1173. doi:10.1039/P29940001173
[5] A. M. Bonin, S. A. Glover, G. P. Hammond, J. Org. Chem. 1998, 63,
9684. doi:10.1021/JO980863Z
N-Acetoxy-N-(2,6-dimethylbenzyloxy)benzamide 12e
[6] A. M. Bonin,T. M. Banks, J. J. Campbell, S.A. Glover, G. P. Hammond,
A. S. Prakash, C. A. Rowbottom, Mutat. Res. 2001, 494, 115.
[7] T. M. Banks, A. M. Bonin, S. A. Glover, A. S. Prakash, Org. Biomol.
Chem. 2003, 1, 2238. doi:10.1039/B301618H
[8] L. E.Andrews,T. M. Banks,A. M. Bonin, S. F. Clay,A.-M. E. Gillson,
S. A. Glover, Aust. J. Chem. 2004, 57, 377. doi:10.1071/CH03276
[9] L. E. Andrews, A. M. Bonin, L. Fransson, A.-M. E. Gillson,
S. A. Glover, Mutat. Res. 2006, 605, 51.
[10] S. A. Glover, in Advances in Physical Organic Chemistry (Ed.
J. Richard) 2008, Vol. 42, p. 35 (Elsevier: London).
[11] A. Rauk, S. A. Glover, J. Org. Chem. 1996, 61, 2337.
doi:10.1021/JO9521817
[12] S. A. Glover, Tetrahedron 1998, 54, 7229. doi:10.1016/S0040-
4020(98)00197-5
Sodium acetate (0.052 g, 0.63 mmol) and N-chloro-N-(2,6-
dimethylbenzyloxy)benzamide (0.12 g, 0.42 mmol) were com-
bined according to the general procedure. Purification by
centrifugal chromatography with 5% ethyl acetate/petroleum
spiritaffordedN-acetoxy-N-(2,6-dimethylbenzyloxy)benzamide
(0.09 g, 0.30 mmol, 71%) as a yellow oil. νmax(CHCl3)/cm−1
1791 (ester C=O), 1729 (amide C=O). δH 2.12 (3H, s), 2.36
(6H, s), 5.28 (2H, s), 7.02 (2H, d), 7.14 (1H, t), 7.43 (2H, t, J
7.7), 7.55 (1H, t, J 7.5), 7.76 (2H, d, J 7.7). δC 18.6, 19.4, 71.3,
128.3, 128.6, 129.0, 129.1, 130.6, 131.9, 132.7, 139.0, 168.1
(ester C=O), 174.2 (amide C=O). δN −123.5 0.5. m/z 336
(M + 23).
[13] S. A. Glover, G. Mo, A. Rauk, D. Tucker, P. Turner, J. Chem. Soc.,
Perkin Trans. 2 1999, 2053. doi:10.1039/A904575I
[14] S. A. Glover, A. Rauk, J. Org. Chem. 1999, 64, 2340.
doi:10.1021/JO982048P
[15] S. A. Glover, in The Chemistry of Hydroxylamines, Oximes and
Hydroxamic Acids, Part 2 (Eds Z. Rappoport, J. F. Liebman) 2009,
p. 839 (Wiley: Chichester).
[16] A.-M. E. Gillson, S. A. Glover, D. J. Tucker, P. Turner, Org. Biomol.
Chem. 2003, 1, 3430. doi:10.1039/B306098P
[17] S. A. Glover, A. Rauk, J. Chem. Soc., Perkin Trans. 2 2002, 1740.
doi:10.1039/B204232K
[18] J. J. Campbell, S.A. Glover, J. Chem. Soc., PerkinTrans. 2 1992, 1661.
doi:10.1039/P29920001661
[19] J. J. Campbell, S. A. Glover, J. Chem. Res. (S) 1999, 8, 474.
doi:10.1039/A903555I
[20] J. J. Campbell, S. A. Glover, J. Chem. Res. (M) 1999, 8, 2075.
[21] S. A. Glover, Arkivoc 2001, xii, 143.
N-Butoxy-N-(p-methylbenzoyloxy)benzamide 14b
N-Butoxy-N-chlorobenzamide (0.5745 g, 2.523 mmol) and
sodium toluate (1.1692 g, 7.3939 mmol) were combined accord-
ing to the general procedure. Purification by centrifugal chro-
matography with 10% ethyl acetate/petroleum spirit afforded
N-butoxy-N-(p-methylbenzoyloxy)benzamide as a yellow oil.
νmax(CHCl3)/cm−1 1756 (ester C=O), 1733 (amide C=O). δH
0.88 (3H, t, J 7.6), 1.36 (2H, sextet, J 7.1), 1.65 (2H, quin, J 7.6),
2.39 (3H, s), 4.27 (2H, t, J 6.6), 7.22 (2H, d, J 8.1), 7.39 (2H, t, J
7.3), 7.5 (1H, t, J 7.6), 7.82 (2H, d, J 7.4), 7.88 (2H, d, J 8.1). δC
13.8, 19.0, 21.8, 30.1, 75.5, 124.5, 128.3, 129.0, 129.4, 130.0,
131.9, 132.66, 145.0, 164.4 (amide C=O), 174.6 (ester C=O).
m/z 350.1 (M + 23).
N-Butoxy-N-(p-methoxybenzoyloxy)benzamide 14c
[22] S. A. Glover, G. Mo, J. Chem. Soc., Perkin Trans. 2 2002, 1728.
doi:10.1039/B111250N
[23] J. M. Buccigross, S. A. Glover, J. Chem. Soc., Perkin Trans. 2 1995,
595. doi:10.1039/P29950000595
[24] J. M. Buccigross, S. A. Glover, G. P. Hammond, Aust. J. Chem. 1995,
48, 353.
[25] S. A. Glover, G. Mo, A. Rauk, Tetrahedron 1999, 55, 3413.
doi:10.1016/S0040-4020(98)01151-X
[26] S. A. Glover, A. Rauk, J. M. Buccigross, J. J. Campbell, G. P. Ham-
mond, G. Mo, L. E. Andrews, A.-M. E. Gillson, Can. J. Chem. 2005,
83, 1492. doi:10.1139/V05-150
[27] S. A. Glover, in Merck Index, Organic Name Reactions ONR-43 (Ed.
M. J. O’Neil) 2006 (Merck & Co., Inc.: Whitehouse Station, NJ).
[28] N. S. Isaacs, Physical Organic Chemistry 1995, p. 422 (Longman
Scientific and Technical: New York, NY).
N-Butoxy-N-chlorobenzamide (0.6872 g, 3.018 mmol) and
sodium anisate (1.39 g, 7.983 mmol) were combined according
to the general procedure. Purification by centrifugal chro-
matography with 10% ethyl acetate/petroleum spirit afforded
N-butoxy-N-(p-methoxybenzoyloxy)benzamide as a yellow oil.
νmax(CHCl3)/cm−1 1751 (ester C=O), 1723 (amide C=O). δH
0.88 (3H, t, J 7.3), 1.36 (2H, sextet, J 8.2), 1.66 (2H, quin, J 7.6),
3.85 (3H, s), 4.26 (2H, t, J 6.2), 6.91 (2H, d, J 7.8), 7.39 (2H, t, J
7.5), 7.5 (1H, t, J 7.3), 7.82 (2H, d, J 7.5), 7.96 (2H, d, J 7.8). δC
13.8, 19.0, 30.2, 55.5, 75.5, 113.9, 119.4, 125.3, 128.2, 129.1,
131.9, 132.2, 132.6, 164.3 (ester C=O), 174.7 (amide C=O).
m/z 366.1 (M + 23).
Accessory Publication
[29] W. Forster, R. M. Laird, J. Chem. Soc., Perkin Trans. 2 1982, 135.
doi:10.1039/P29820000135
DFT computational data: structures, energies and electrostatic
group charges are available on the Journal’s website. NMR
spectra are also available.
[30] A. Pross, Theoretical and Physical Principles of Organic Chemistry
1995, p. 142 (John Wiley & Sons, Inc.: New York, NY).
[31] F. A. Carrol, Perspectives on Structure and Mechanism in Organic
Chemistry 1998, p. 489 (Brooks/Cole Publishing Company: New
York, NY).
Acknowledgement
[32] A. Halvorsen, J. Songstad, J. Chem. Soc. Chem. Commun. 1978, 327.
doi:10.1039/C39780000327
The authors are grateful to Dr David Tucker for assistance with recording of
15N NMR spectra.
[33] D. J. McLennan, A. Pross, J. Chem. Soc., Perkin Trans. 2 1984, 981.
doi:10.1039/P29840000981
[34] N. De Kimpe, R. Verhé, The Chemistry of α-Haloketones, α-
Haloaldehydes and α-Haloimines (Eds S. Patai, Z. Rappoport) 1988,
p. 38 (John Wiley & Sons: Chichester).
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