The kinetics and mechanisms of aromatic nucleophilic substitution reactions in liquid ammonia

Article abstract of DOI:10.1021/jo200170z

The rates of aromatic nucleophilic substitution reactions in liquid ammonia are much faster than those in protic solvents indicating that liquid ammonia behaves like a typical dipolar aprotic solvent in its solvent effects on organic reactions. Nitrofluorobenzenes (NFBs) readily undergo solvolysis in liquid ammonia and 2-nitrofluorobenzene is about 30 times more reactive than the 4-substituted isomer. Oxygen nucleophiles, such as alkoxide and phenoxide ions, readily displace fluorine of 4-NFB in liquid ammonia to give the corresponding substitution product with little or no competing solvolysis product. Using the pK_a of the substituted phenols in liquid ammonia, the Bronsted β_nuc for the reaction of 4-NFB with para-substituted phenoxides is 0.91, indicative of the removal of most of the negative charge on the oxygen anion and complete bond formation in the transition state and therefore suggests that the decomposition of the Meisenheimer σ-intermediate is rate limiting. The aminolysis of 4-NFB occurs without general base catalysis by the amine and the second-order rate constants generate a Bronsted β_nuc of 0.36 using either the pK_a of aminium ion in acetonitrile or in water, which is also interpreted in terms of rate limiting breakdown of the Meisenheimer σ-intermediate. Nitrobenzene and diazene are formed as unusual products from the reaction between sodium azide and 4-NFB, which may be due to the initially formed 4-nitroazidobenzene decomposing to give a nitrene intermediate, which may then give diazene or be trapped by ammonia to give the unstable hydrazine which then yields nitrobenzene.

Full text of DOI:10.1021/jo200170z

ARTICLE
pubs.acs.org/joc
The Kinetics and Mechanisms of Aromatic Nucleophilic Substitution
Reactions in Liquid Ammonia
Pengju Ji, John H. Atherton, and Michael I. Page*
IPOS, The Page Laboratories, Department of Chemical and Biological Sciences, The University of Huddersfield, Queensgate,
Huddersfield, HD1 3DH, United Kingdom
S Supporting Information
b
ABSTRACT: The rates of aromatic nucleophilic substitution reactions in liquid
ammonia are much faster than those in protic solvents indicating that liquid ammonia
behaves like a typical dipolar aprotic solvent in its solvent effects on organic reactions.
Nitrofluorobenzenes (NFBs) readily undergo solvolysis in liquid ammonia and 2-nitro-
fluorobenzene is about 30 times more reactive than the 4-substituted isomer. Oxygen
nucleophiles, such as alkoxide and phenoxide ions, readily displace fluorine of 4-NFB in
liquid ammonia to give the corresponding substitution product with little or no
competing solvolysis product. Using the pK of the substituted phenols in liquid
a
ammonia, the Brønsted βnuc for the reaction of 4-NFB with para-substituted phenoxides
is 0.91, indicative of the removal of most of the negative charge on the oxygen anion and complete bond formation in the transition
state and therefore suggests that the decomposition of the Meisenheimer σ-intermediate is rate limiting. The aminolysis of 4-NFB
occurs without general base catalysis by the amine and the second-order rate constants generate a Brønsted βnuc of 0.36 using either
the pK of aminium ion in acetonitrile or in water, which is also interpreted in terms of rate limiting breakdown of the Meisenheimer
a
σ-intermediate. Nitrobenzene and diazene are formed as unusual products from the reaction between sodium azide and 4-NFB,
which may be due to the initially formed 4-nitroazidobenzene decomposing to give a nitrene intermediate, which may then give
diazene or be trapped by ammonia to give the unstable hydrazine which then yields nitrobenzene.
’
INTRODUCTION
does not significantly solvate anions as it is not a good hydrogen
donor. We have recently shown that, contrary to common
6
A significant proportion of reactions carried out by the
understanding, liquid ammonia behaves similarly to dipolar
aprotic solvents and is potentially useful as a solvent for organic
pharmaceutical and agrochemical industries involve aromatic
nucleophilic substitution. The nature of the solvent used for
these reactions influences both the kinetics and mechanisms of
7
synthesis. Thus, the poor solvation of anions in liquid ammonia
1
makes them good nucleophiles but poor leaving groups com-
pared with similar reactions in water, which leads to a significant
impact on the kinetics and mechanisms of aliphatic nucleophilic
the process and when solvents are used in large quantities on an
industrial scale, their efficiency, cost, and environmental impact
are major factors involved in their selection. Ever increasing cost,
health, and environmental concerns have resulted in some
previously common solvents, for example chloroform, being
prohibited. Although a particular solvent may be used in research
syntheses, they are often avoided on the manufacturing scale.
Dipolar aprotic solvents (e.g., DMSO and DMF) are used in
around 10% of chemical manufacturing processes but they are
expensive, have toxicity concerns, and are difficult to recycle
due to their water miscibility and are frequently disposed by
8
substitution. Liquid ammonia is much easier to recover than
many conventional solvents and it is easily handled in small scale
laboratory glassware over a useful temperature range.
Herein, we report on the kinetics and mechanisms of aromatic
nucleophilic substitution, using nitrofluorobenzenes as substrates.
’
RESULTS AND DISCUSSION
2
incineration.
i. Meisenheimer Complexes and UVꢀVis Spectra of
3
Liquid ammonia (LNH ) is cheap and is a promising can-
3
Aromatic Compounds in Liquid Ammonia. The UVꢀvis extinc-
tion coefficients of compounds are generally greater in liquid
ammonia compared with those in water or ether under similar
conditions, although the maximum wavelength of absorption of
some nitrobenzene derivatives changes little on going from water
to liquid ammonia (Supporting Information, Table S1). The
wavelength of maximum absorption of 4-nitrofluorobenzene,
didate to replace dipolar aprotic solvents in a number of
industrial processes, although at present its use as a solvent is
uncommon. Ammonia is relatively weakly associated in the liquid
state as it has only one lone pair for three potential NꢀH
hydrogen bonds leading to a boiling point of ꢀ33 °C and a vapor
4
pressure of 10 bar at 25 °C. Although liquid ammonia has a low
5
dielectric constant (16.7 at 25 °C), many salts and organic
compounds are highly soluble. Cations are strongly solvated in
liquid ammonia by the nitrogen lone pair but liquid ammonia
Received: January 24, 2011
Published: March 21, 2011
r 2011 American Chemical Society
3286
dx.doi.org/10.1021/jo200170z
|J. Org. Chem. 2011, 76, 3286–3295

The Journal of Organic Chemistry
ARTICLE
Scheme 1
Scheme 2
Table 1. Solvolysis Rate Constants and Half-Lives of Some
a
Aromatic Compounds in LNH3
6
ꢀ1
substrate
temp (°C) 10 k
0
(s
)
t
1/2
2
2
3
4
2
2
4
2
3
2
4
2
2
2
2
-nitrofluorobenzene (2-NFB)
25
100
20
25
25
25
25
25
20
25
25
20
20
25
2.15 ꢁ 10
54 min
-nitrofluorobenzene
no reaction
b
-nitrofluorobenzene (4-NFB)
7.86
24.4 h
3
,4-difluoronitrobenzene (2,4-DFNB)
,4-dinitrofluorobenzene (2,4-DNFB)
-nitrochlorobenzene
6.72 ꢁ 10
1.7 min
5
>1.4 ꢁ 10 <5 s
exponential appearance of product and disappearance of reactant
using normalized areas from GC or HPLC analysis as a function
of time to give the first-order rate constants for solvolysis which
are dependent on the nature of the leaving group and aromatic
substituents and show the expected trends (Table 1). There is no
reaction of unsubstituted halobenzenes and 3-nitrohalobenzenes at
ambient temperature, but as expected, the 2- and 4-nitro-activated
derivatives and the substituted aryl fluorides are much more
no reaction
3
,4-dinitrochlorobenzene
6.18 ꢁ 10
no reaction
5.81
1.9 min
-nitroiodobenzene
-nitroazidobenzene (2-NAB)
33.1 h
37.7 h
b
-nitroazidobenzene (4-NAB)
5.11
5
,4-dinitroazidobenzene
-chloropyrimidine
-chlorobenzthiazole
-fluoropyridine
>1.4 ꢁ 10 <5 s
14.2
13.3 h
36.1 h
13
reactive. The introduction of additional fluoro- or nitro-groups
5.33
increases the solvolysis rates by more than 4 orders of magnitude.
Given the demonstration that nitro-substituted aromatic
compounds without a leaving group reversibly form Meisenhei-
mer complexes in liquid ammonia (Scheme 1), it seems reason-
able to postulate the complexes as intermediates in solvolysis and
nucleophilic substitution reactions of analogous compounds that
no reaction
a
b
The kinetics were measured by GC unless otherwise noted. Measured
by GC and UV, both methods gave similar pseudo-first-order rate
constants.
9
4
-nitroaniline, and 4-nitroazidobenzene is significantly smaller
do contain a leaving group (Scheme 2). However, an unpro-
than those of the corresponding ortho analogues and may
indicate a stronger resonance effect from the ortho nitro group,
which considerably decreases the energy gaps between ground
and excited states. The absorption spectrum of 2,4-dinitroaniline
in liquid ammonia shows several absorptions (257, 353, 387,
ductive intermediate 1 may also be formed by nucleophilic attack
9,14
on the C-3 unsubstituted position and in the case of dinitro-
substituted derivatives these complexes may actually be the
effective starting material as they are formed rapidly and are
9
often more stable than the reactants. Attack at the ipso C-
5
37 nm) which are more complicated than those in ether or
water (220 and 330 nm). A likely interpretation is that 2,
-dinitroaniline is attacked by a solvent molecule to form
1-fluoro-subtituted position generates the reactive intermediate 2
with a charged ammonium ion but product formation probably
requires deprotonation to form the anionic intermediate 3 before
the leaving group can be expelled, especially as liquid ammonia is
a poor solvent for anions. We have shown that aminium ions in
liquid ammonia are invariably deprotonated by the vast excess of
4
9
stable Meisenheimer complexes (Scheme 1), which are written
as anions rather than zwitterions, as we have shown that
aminium ions exist as free bases in liquid ammonia. The
formation of Meisenheimer complexes between highly activated
8
8
basic solvent and so exist in their free base form. It is therefore
benzenes and nucleophiles is well-known, and has been shown
likely that the zwitterionic intermediate 2 is rapidly converted to
the thermodynamically more stable anionic intermediate 3 by
1
0
11
spectroscopically, including NMR. The UVꢀvis absorp-
tion of a typical Meisenheimer complex is in the range 450ꢀ
proton transfer to the solvent (k step in Scheme 2 where B =
2
1
2
6
00 nm, and therefore often color is observed with the
NH ). In fact the intermediate 3 may be formed directly from the
3
formation of the σ-adducts. The absorption of 2,4-dinitroaniline
in liquid ammonia at 537 nm can be assigned to one or both of
the intermediates shown in Scheme 1. There is no new product
formed after vaporization of liquid ammonia from a solution of
either 2,4-dinitroaniline or 1,3-dinitrobenzene and it appears that
the Meisenheimer complex is formed rapidly but reversibly and
removal of the ammonia solvent results in its reversion to starting
material.
ii. Solvolysis of Aromatic Compounds in Liquid Ammonia.
Aryl halides and aromatic heterocyclic halides undergo solvolysis
in liquid ammonia to give the corresponding aromatic amines.
The rates of these reactions were determined by monitoring the
reactants by general base catalysis by solvent ammonia. The rate-
limiting step for solvolysis is therefore likely to be the breakdown
of the intermediate 3, step k (Scheme 2), which is also
3
compatible with the observations for other aromatic nucleophilic
substitutions in liquid ammonia (vide infra).
The solvolysis rates of 4-nitrofluorobenzene and 2-nitrofluor-
obenzene (4-NFB and 2-NFB, respectively) show relatively small
salt effects (Figures 1 and 2); however, it is worth noting that 2 M
salt increases the rate for the 4-isomer nearly 3-fold but by only
28% for the 2- isomer (Supporting Information, Table S2).
The solvolysis rate of 4-nitroazidobenzene (4-NAB), in the
absence of salts, is similar to that for 4-NFB, but that for 2-NFB is
3
287
dx.doi.org/10.1021/jo200170z |J. Org. Chem. 2011, 76, 3286–3295

The Journal of Organic Chemistry
ARTICLE
Table 2. The Rates and Activation Parameters for the Sol-
volysis of 2-NFB, 4-NFB, and 2,4-DFNB in LNH at 25 °C
3
q
q
q
ΔG /
ΔH /
ΔS /
6
ꢀ1
ꢀ1
ꢀ1
ꢀ1
ꢀ1
substrate
10 kobs/s
k
rel.
kJ mol
kJ mol
J K mol
4
-NFB
7.86
215
6717
1
101.1
94.1
87.7
53.0
51.3
40.0
ꢀ161.3
ꢀ143.4
ꢀ151.6
2
2
-NFB
27
,4-DFNB
852
Scheme 4
Figure 1. The dependence of the solvolysis rate of 4-NFB on the salt
concentration in LNH
3
4 3
at 25 °C: (Δ) NH Cl and (0) NaNO .
of 2-NFB is better solvated than 4-NFB in both aprotic and
1
7
dipolar aprotic solvents according to DFT calculations, prob-
ably due to the relatively larger molecular dipole of 2-NFB than
4
2
-NFB. It is therefore likely that the enhanced reactivity of
-NFB over 4-NFB is due to a transition state effect. The entropy
of activation for the ortho-isomer is less negative than that for the
para-isomer (Table 2, and in the Supporting Information Tables
S4ꢀS6 and Figures S1ꢀS3). Although this is compatible with
some interaction between the ortho substituents such as the
formation of an intramolecular hydrogen bond within the
1
8
activated complex to stabilize the intermediate 5, it would
Figure 2. The dependence of the solvolysis rate of 2-NFB on the salt
concentration in LNH3.
not explain why this favorable interaction cannot occur with
2
-NAB. The generation of negative charge on the nitro group
oxygens in the Meisenheimer σ-adduct formed from 4-NFB
requires solvation and restriction of solvent molecules giving rise
to a slightly more negative entropy of activation.
Scheme 3
The additional fluorine in 2,4-DFNB compared with 2-NFB
increases the solvolysis rate by about 30-fold presumably due to
the inductive effect of fluorine, which normally shows an additive
effect on the reactivity of the polyfluorobenzenes. Introduction
of a second nitro group causes the solvolysis of 2,4-DNFB in
liquid ammonia to be too fast to measure with our present
equipment.
iii. Aromatic Nucleophilic Substitution by Oxygen Nucleo-
philes. Oxygen nucleophiles, such as alkoxide and phenoxide
ions, react readily with 4-NFB in liquid ammonia to give the
corresponding substitution product (Scheme 4). There is little
solvolysis product formed as the background rate of reaction of
4-NFB with ammonia is too slow to compete with the rates of
substitution by anionic O-nucleophiles. The rate of the latter
reaction shows a first-order dependence on the concentration of
the anion and the associated second-order rate constants
(Table 3) were obtained from the slope of these plots
(Figure 3). The rate of the reaction between 4-NFB and
phenoxide is reduced by about 2-fold as the concentration of
nearly 2 orders of magnitude greater than that for 2-NAB
(
Table 1). As well as a significant difference in salt effects,
-NFB is nearly 30 times more reactive toward solvolysis than
its 4-substituted isomer, whereas the reactivities of 2- and
-nitroazidobenzenes are similar. This ortho effect for 2-NFB,
19
2
4
but not 2-NAB, is also seen in the solvolysis of the more reactive
disubstituted 2,4-DFNB, which gives almost exclusively the
ortho-substituted derivative 4 as product in liquid ammonia at
2
5 °C (Scheme 3). The product ratio of ortho to para isomers is
compatible with the rate differences observed between 2-NFB
and 4-NFB (Table 1).
Preferential substitution ortho to the nitro group is sometimes
observed in the reactions of nitrohalobenzenes with neutral
1
5
15f,g
nucleophiles, and even with sterically hindered nucleophiles.
However, some calculations indicate that the Meisenheimer
σ-complex formed by nucleophilic addition of anionic nucleo-
ꢀ
1
philes to the para position is generally about 10ꢀ20 kJ mol
16
more stable than the ortho one. Furthermore, the ground state
3
288
dx.doi.org/10.1021/jo200170z |J. Org. Chem. 2011, 76, 3286–3295

The Journal of Organic Chemistry
ARTICLE
Table 3. The Second-Order Rate Constants for the Nucleo-
philic Substitution of 4-NFB by Oxygen Anions in Different
Solvents at 25 °C
Table 4. Activation Parameters for the Nucleophilic Substi-
tution of 4-NFB by Oxygen Anions in LNH and Methanol
3
q
ꢀ1
q
ꢀ1
ꢀ1
nucleophile solvent ΔH /kJ mol
ΔS /J K mol
ref
ꢀ1
ꢀ1
O-nucleophile
solvent
2
k /M
s
k
rel.
ref
ꢀ
PhO
PhO
LNH
3
38.1
102.9
88.6
ꢀ141.3
ꢀ19.7
ꢀ27.6
present work
15e, 15f
ꢀ
a
ꢀ
MeO
LNH
3
>3.5
>20 000 present work
2 100 21
MeOH
MeOH
ꢀ
b
ꢀ1
ꢀ
MeO
DMSO-MeOH 3.77 ꢁ 10
MeO
15a, 26
ꢀ
ꢀ4
MeO
MeOH
1.79 ꢁ 10
1
22
ꢀ
energies of activation in liquid ammonia appear as much lower
enthalpies of activation which more than compensate for un-
favorable large negative entropies of activation compared with
those in the protic solvent methanol (Table 4, and in the
Supporting Information Table S8 and Figure S4).
PhO
LNH
3
0.0528
0.52
41 000 present work
400 000 23
ꢀ
c
PhO
DMSO
MeOH
ꢀ
ꢀ6
PhO
1.29 ꢁ 10
1
15e, 15f, 24
a
b
Rate is too fast to be measured accurately. 80% (% v/v)
DMSOꢀMeOH solution. 20 °C.
c
This suggests that the oxygen anions are strongly hydrogen
bonded to the solvent molecules in methanol so that the large
2
7
negative entropy loss expected for the bimolecular process is
partially compensated by the release of solvent molecules on
going from the initial reactant state to the transition state. By
contrast, in liquid ammonia, the poor solvation of the oxygen
anions leads to a smaller contribution to the entropy of activation
from the solvent and consequently there is a large negative loss of
entropy as a result of covalently linking two molecules together.
The good solvation of metal cations in liquid ammonia through
electron donation from ammonia presumably also increases the
nucleophilicity and reactivity of the counteranion in this solvent,
which is reflected in the low enthalpy of activation compared with
that in methanol.
A rigorous interpretation of linear free-energy relationships for
reactions in liquid ammonia requires a knowledge of the effect of
substituents on equilibria in this solvent. We have previously
reported the ionization constants for substituted phenols in
liquid ammonia and that these show a linear relationship with
Figure 3. The dependence of the observed pseudo-first-order rate
constants for the reaction between 4-NFB and sodium phenoxide on
the concentration of phenoxide ion (I = 0.3 M, KClO
C (Supporting Information, Table S7).
4 3
) in LNH at 25
°
8
the corresponding values in water. The Brønsted plot for the
the salt is changed from 0 to 1.5 M (Supporting Information,
Table S10 and Figure S5) in common with the general observa-
tion that salt effects have very limited influence on the rate of
reaction of 4-NFB with para-substituted phenoxides in liquid
ammonia using the aqueous pK for the phenols gives an
a
apparent βnuc of 1.49, but a more meaningful βnuc of 0.91 is
20
aromatic nucleophilic substitutions.
obtained using the pK of the substituted phenols in liquid
a
The rates of reactions of 4-NFB with O-nucleophiles are 4ꢀ5
orders of magnitude faster in liquid ammonia than in methanol
and are similar to those in DMSO. This large rate enhancement is
probably due to the differences in solvation of the nucleophilic
anions in dipolar aprotic and protic solvents, giving rise to
enhanced nucleophilicity of anions in liquid ammonia. The
second-order rate constant for the reaction of phenoxide with
ammonia (Figure 4). These values are much larger than those
for the reaction of 4-NFB with phenoxides or thiophenoxides in
28
protic solvents which are around 0.5. The large value is
indicative of significant, if not total, removal of the negative
charge on the oxygen anion and complete bond formation in the
transition state and therefore suggests that the decomposition of
the σ-complex is the rate limiting step or possibly formation with
a very late transition state. This is probably due to the difficulty of
expelling and solvating the leaving fluoride anion from the
Meisenheimer σ-complex (Scheme 2) in liquid ammonia.
iv. Aromatic Nucleophilic Substitution by Nitrogen Nu-
cleophiles. The kinetics and mechanisms of secondary amines
reacting with activated aryl halides have been extensively
ꢀ
7
ꢀ1 ꢀ1
4
-nitrochlorobenzene, 2.51 ꢁ 10
M
s
at 25 °C, is 5 orders
of magnitude smaller than that of 4-NFB (Table 3), which
probably reflects the less favorable formation of the σ-complex.
It is usually assumed that the mechanism of S Ar reactions
N
involves a charge delocalized Meisenheimer intermediate, the
σ-complex (Scheme 2), in which negative charge of an incoming
nucleophile is spread into the aromatic ring and substituents
through the resonance, and so any stabilizing influence of the
solvent is expected to be less in the transition state than in the
relatively localized reactant anion. Liquid ammonia, in common
16a,29
studied.
Solvent effects on those reactions are often com-
plicated by base catalysis, which depends on the reaction medium
and substrate structure. Normally, general base catalysis occurs in
nonpolar aprotic solvents especially when proton removal is
required from the attacking nucleophile before the leaving group
is expelled, although it may also occur coupled with the decom-
25,39
with dipolar aprotic solvents and unlike protic ones,
in-
creases the rate of aromatic nucleophilic substitution by anions
by several orders of magnitude primarily due to the less solvated
but more reactive nucleophile.
30
position of the σ-complex. However, in dipolar aprotic solvents
2
9eꢀg
the general base catalysis is generally not observed.
The
There are some interesting differences in the activation
parameters for oxygen anions reacting with 4-NFB in liquid
ammonia compared with those in methanol. The lower free
observed pseudo-first-order rate constants for the reaction of
secondary amines with 4-NFB in liquid ammonia (Scheme 5) are
first order in amine concentration (Figure 5), indicating the
3
289
dx.doi.org/10.1021/jo200170z |J. Org. Chem. 2011, 76, 3286–3295

The Journal of Organic Chemistry
ARTICLE
Figure 4. Brønsted type plot for the reactions between para-substituted phenoxides and 4-NFB in LNH (Supporting Information, Table S9).
3
Scheme 5
Figure 6. Brønsted type plot for the substitution of 4-NFB by nitrogen
nucleophiles in LNH
aminium ion.
3 a
using the corresponding aqueous pK of the
thermodynamically more stable than its conjugate acid 2 in liquid
ammonia and other amines are unlikely to be able to compete
with solvent ammonia in converting 2 to 3 and so the absence of
general base catalysis by amines is not surprising.
There is no nucleophilic substitution of 4-NFB with aniline,
DABCO [(1,4-diazabicyclo(2.2.2)octane], and triethylamine in
liquid ammonia and only the solvolysis product, 4-nitroaniline, is
formed. The rate of solvolysis was not significantly increased by
these amines, again indicating no general base catalysis by these
amines. The rates of reaction of sodium azide and piperidine with
Figure 5. The dependence of the pseudo-first-order reaction between
4
-NFB and morpholine on the concentration of morpholine in LNH at
3
25 °C (Supporting Information, Table S11).
4
-NFB are similar to those in some typical dipolar aprotic
Table 5. The Second-Order Rate Constants for the Substi-
31
solvents such as acetonitrile, DMSO, and DMF. The reaction
between 1,2,4- triazolate and 4-NFB in liquid ammonia gives
only the 1-substituted product 6.
tution of 4-NFB by Nitrogen Nucleophiles in LNH at 25 °C
3
3
ꢀ1 ꢀ1
N-nucleophile
pK
a
(aq)
10 k
2
(M
s
)
a
sodium azide
morpholine
4.70
8.50
0.382
0.401
0.560
2.23
1,2,4-triazolate
10.3
piperidine
pyrrolidine
imidazolate
10.4
11.4
14.5
5.01
As already stated, all amines exist in their free base unproto-
5.73
8
nated form in liquid ammonia and so it has not been possible to
a
Reaction conditions: 0.1 M 4-NFB with 0.01 M sodium azide.
evaluate the pK of aminium ions in this solvent. Nonetheless, the
a
second-order rate constants (Table 5) do increase with increas-
ing aqueous basicity of the amine, and there is actually a reason-
able correlation between the second-order rate constants for
absence of general base catalysis by a second molecule of amine.
The corresponding second-order rate constants for secondary
amines and other nitrogen nucleophiles reacting with 4-NFB
are shown in Table 5. As discussed in the solvolysis section,
aminium ions exist only in their free base unprotonated form in
liquid ammonia, i.e., the latter is more basic than amines. The
anionic Meisenheimer σ-intermediate 3 (Scheme 2) therefore is
aminolysis of 4-NFB in liquid ammonia and aqueous pK values
a
of the amines which generates an apparent Bronsted βnuc = 0.36
(Figure 6). A plot of the pK values of aminium ions in
a
3
2
acetonitrile against those in water is a linear slope of 1.0 and
so using the pK values in this aprotic solvent would generate the
a
3
290
dx.doi.org/10.1021/jo200170z |J. Org. Chem. 2011, 76, 3286–3295

The Journal of Organic Chemistry
ARTICLE
Scheme 6
Figure 7. The dependence of the observed pseudo-first-order rate
constant for the reaction of 4-NFB on sodium azide concentration in
Figure 9. The dependence of the observed pseudo-first-order rate
constant for the reaction of 4-NAB on potassium perchlorate concen-
LNH
3
at 25 °C (I = 3 M, NaNO
3
).
tration in LNH at 25 °C.
3
discussed earlier, due to the lack of a removable proton. An
alternative mechanism could involve proton transfer to solvent
being coupled to expulsion of the fluoride ion in a concerted
breakdown of the σ-complex.
In addition to the enhanced reactivity of azide ion compared
with its aqueous basicity (Table 5) there are some unusual
observations with the reactions of this nucleophile with 4-NFB
in liquid ammonia. The reaction between sodium azide and
4
4
-NFB in other solvents affords, as expected, the corresponding
-nitroazidobenzene (4-NAB). However, in liquid ammonia the
reaction gives no 4-NAB after 4-NFB has completely reacted.
The final reaction products are 4-nitroaniline, nitrobenzene (7),
diazene (8), and nitrogen (Scheme 6). The molar ratio of 7 and 8
in the products is independent of whether the reaction vessel is
covered in aluminum foil or not. In the absence of air, with
Figure 8. Reaction profile for 4-FBN reacts with sodium azide in LNH
at 25 °C.
3
control of ionic strength (I = 3 M, NaNO ), the apparent first-
3
order rate constant, based on the disappearance of 4-NFB in
liquid ammonia, is proportional to the azide concentration at
25 °C (Figure 7, and Table S12 in the Supporting Information).
An investigation by GC and HPLC of the reaction of azide ion
with 4-NFB shows that 4-NAB is, in fact, a reactive intermediate
and its concentration initially increases, reaches a maximum, and
then decreases (Figure 8). Consequently, we investigated, in
separate experiments, the solvolysis of 4-NAB in liquid ammonia.
In the absence of salts, 4-NAB has a half-life of 38 h and yields the
same products as does 4-NFB with azide anion (Scheme 6).
Unlike the other aromatic substitution reactions, the rate of
decomposition of 4-NAB in liquid ammonia is very dependent
upon salt concentration. For example, it is 35-fold faster in the
presence of 1.0 M perchlorate and the observed pseudo-first-
order rate constant for the decomposition of 4-NAB is propor-
tional to the concentration of potassium perchlorate (Figure 9,
and Table S13 in the Supporting Information). The rate of
same Brønsted βnuc. The small Brønsted βnuc contrasts with the
βnuc of 0.91 observed with phenoxide anions, which was obtained
by using pK values for phenols determined in ammonia. With-
a
out the knowledge of the relative pK values in liquid ammonia it
a
is not possible to interpret the small values of Brønsted βnuc for
amines reacting with 4-NFB with any certainty, but it is indicative
of only a small amount of positive charge development on the
amine nitrogen nucleophile in the transition state. This small
value is compatible with the rate limiting breakdown of the
σ-complex 3, following the deprotonation of the aminium ion in
the Meisenheimer intermediate 2 (Scheme 2). This proton
transfer step to the solvent ammonia is probably thermodyna-
mically favorable given the effect of the adjacent fluorine in
reducing the pK of the aminium ion and the fact that all aminium
a
ions are deprotonated in liquid ammonia. This suggestion is
further supported by the lack of reactivity of tertiary amines,
3
291
dx.doi.org/10.1021/jo200170z |J. Org. Chem. 2011, 76, 3286–3295

The Journal of Organic Chemistry
ARTICLE
Scheme 7
Scheme 8
8, with no crossover product formed, which was seen as evidence
for dimerization of the triplet nitrene in preference to nitrene
35b
attack on the azide.
reaction of 4-NAB is independent of the nature of salt, whether
sodium nitrate, sodium azide, or potassium perchlorate.
The unusual products nitrobenzene 7 and diazene 8 formed
from 4-NFB and azide ion (Scheme 6) could be explained by the
formation of an intermediate nitrene that is trapped by ammonia
to form 4-nitrophenyl hydrazine. Interestingly, the reaction of
hydrazine with 4-NFB in liquid ammonia gives, after workup with
sodium hydroxide and extraction with dichloromethane, a mix-
ture of nitrobenzene, 4-nitroaniline, and aniline in a molar ratio
No ring enlargement products, such as 5-nitro-1,2-didehy-
droazepine (9) or its amination derivative 10, were found from
the solvolysis of 4-NAB in liquid ammonia, and the molar ratio
between 4-nitroaniline and nitrobenzene is about 5:1 in the
product mixture. The diazene compound 8 is quite stable in
liquid ammonia at room temperature. The possible routes for the
decomposition of 4-NAB in liquid ammonia are therefore
summarized as in Scheme 7.
3
3
of 12:5:1. The formation of nitrobenzene and aniline in this
reaction suggests that 4-nitrophenyl hydrazine could be an
unstable intermediate formed in the reaction of 4-NFB with
azide ion in liquid ammonia. This is further substantiated by the
observation that 4-nitrophenyl hydrazine in liquid ammonia does
indeed give nitrobenzene and aniline, but no diazene 8 is formed.
It is also worth noting that there is no cross-coupling reactions
between phenyl azide or benzyl azide with 4-NAB in the presence
of KClO or NaN in liquid ammonia at room temperature, and
The nitrene could undergo insertion into the NꢀH bond of
solvent ammonia to form 4-nitrophenylhydrazine, which decom-
poses into nitrobenzene and a small amount of 4-nitroaniline.
Given the expected low concentration of the nitrene, it is unlikely
to dimerize to form the diazene 8, but the latter could be formed
from the nitrene reacting with 4-NAB and releasing nitrogen.
Most of the 4-nitroaniline formed may come from the direct
solvolysis of 4-NAB by displacement of azide ion. Interestingly,
similar results were observed when 4-NAB was dissolved in
DMSO together with an excess of tetraethylammonium azide,
followed by passing ammonia gas into the solution for several
hours; however, no reaction was observed in methanol.
v. Nucleophilic Substitution by Sulfur Nucleophiles.
4-NFB reacts rapidly with thiophenoxide anion in liquid ammo-
nia to give 4-nitrophenyl sulfide (Scheme 8) and a trace amount
of diphenyl thioether, probably due to the oxidation of thiophen-
oxide by air during the sample processing stage. The rate of
reaction between thiophenoxide and 4-NFB in liquid ammonia is
significantly greater than that in methanol, and is similar to that in
DMSO (Table 6). The rate difference of this reaction in liquid
ammonia and in methanol is more pronounced in aromatic than
in aliphatic nucleophilic substitution, which suggests the poten-
tial benefit of using liquid ammonia as solvent in aromatic
substitution reactions.
4
3
only the self-coupling diazene product of 4-NAB (8) is formed.
So a possible origin of nitrobenzene 7 and diazene 8 from the
reaction of azide ion with 4-NFB in liquid ammonia is the
decomposition by the loss of nitrogen of the initially formed
azide, 4-NAB, to give 4-nitrophenyl nitrene, which is trapped by
ammonia to form 4-nitrophenyl hydrazine. The generation of the
nitrene from 4-NAB by the release of nitrogen does occur under
34
thermal, photolytic conditions and electrochemically, and
singlet aromatic nitrenes with electro-withdrawing groups are
known to undergo insertion into the NꢀH bonds of amines to
35
give the corresponding hydrazines. The major product of
4
-nitrophenyl nitrene trapped by diethylamine is 4-nitroaniline,
with the minor product being 4-nitrophenyl hydrazine under
photoirradiation. However, photolysis of 4-NAB in acetonitrile
in the presence of a 3-fold excess of phenyl azide, under
conditions where only the 4-NAB absorbs, gives only the diazene
3
292
dx.doi.org/10.1021/jo200170z |J. Org. Chem. 2011, 76, 3286–3295

The Journal of Organic Chemistry
ARTICLE
Table 6. The Second-Order Rate Constants for the Reaction
of Thiophenoxide Ion with 4-NFB in Various Solvents at
thus the cell can be connected with the reactor and allows the reaction
mixture to be transferred from it to the cell. For the determination of
extinction coefficients and the rates of relatively slow reactions, the
reactants were normally premixed in the reactor and the reaction
mixture was quickly transferred from it to the chamber between the
windows of the cell for the measurement of maximum absorbance
wavelength (λmax) and extinction coefficient (εmax). The concentration
2
5 °C
ꢀ
1
ꢀ1
nucleophile
solvent
MeOH
k
2
/M
s
k
rel.
ref
ꢀ4
PhSNa
2.1 ꢁ 10
3.1
1
36
a
4
PhSNH
4
LNH
3
1.5 ꢁ 10
5 ꢁ 10
present work
37
ꢀ5
ꢀ4
of the compounds in liquid ammonia normally varied from 10 to 10 M.
Generally, a standard ether solution of solute (0.02 M) was prepared,
4
PhSNa
DMSO
10.4
a
a
Thiophenol (aqueous pK = 6.5) is completely self-ionized in liquid
0.05 to 0.1 mL of this standard solution was injected though a syringe
ammonia at room temperature, for detail, see ref 38.
into the reactor, then 10 mL of liquid ammonia was released into the
vessel, and liquid ammonia solution was transferred into the pressure
UV cell.
’
CONCLUSION
For kinetic studies, the nucleophile was precharged in the reaction
vessel and dissolved in 10 mL of liquid ammonia. The concentration of
nucleophile varied from 0.1 to 1 M depending on the nature of the
reaction. Normally the substrate concentration was 0.01ꢀ0.015 M and
the internal standard was biphenyl or phenetole. The substrate standard
ether solution was injected into the vessel through an Omnifit septum
after the precharged nucleophile in liquid ammonia had been equili-
brated at the required temperature. At suitable time intervals, a reaction
aliquot was carefully released into a 3 mL sample vial by controlling the
Omnifit 2-way valves which connected to an ID 0.8 mm PTFE tube that
dips into the bottom of the reaction vessel. After rapid evaporation of
ammonia, saturated ammonium chloride solution, 1 M HCl or 1 M
NaOH, was added as a quenching agent, then the sample was extracted
with dichloromethane or toluene and dried over anhydrous Na SO .
The rates of S Ar reactions in liquid ammonia are much
N
greater than those in protic solvents and are similar to those in
dipolar aprotic solvents. In many cases the nucleophilic substitu-
tion reactions are sufficiently faster than the background solvo-
lysis reaction so that useful synthetic procedures are possible in
liquid ammonia. The rates of S Ar reactions with neutral amines
N
in liquid ammonia are slower than those for anionic O- and
S-nucleophiles of similar aqueous basicity. Liquid ammonia can
increase the regioselectivity of some reactions compared with
more conventional solvents. These results indicate that liquid
ammonia has potential as an easily recoverable solvent in many
reactions usually carried out in dipolar aprotic solvents by the
chemical industry.
2
4
The kinetics of some reactions were measured by a competition method,
so that the rate constants were obtained from the molar ratio of products.
The samples from the reaction were analyzed by GC or HPLC and the
data were processed with commercial data-fitting software.
The pseudo-first-order rate constants for the reactions of NFBs with
anionic oxygen and nitrogen nucleophiles and for the reaction between
’
EXPERIMENTAL SECTION
Materials. Liquid ammonia was 99.98% pure with moisture levels
<
200 ppm and other impurities <5 ppm. It was used directly as reaction
medium without further purification. All the organic chemicals were
purchased from commercial source with at least 98% purity; all the
inorganic salts were either analytical or laboratory grade. They were used
without further purification unless otherwise noted. Sodium phenoxide
salts were prepared from sodium metal and the corresponding
4
4
-NFB and azide, under constant ionic strength, and the solvolysis of
-NAB under different salt concentration were obtained by a general
sampling method measuring the formation of the product and the
disappearance of the reactant by GC analysis. The kinetics for the
reactions of 4-NFB with sulfur nucleophiles were too fast to be measured
by this method, and the rate constants for these reactions were measured
by a competition method.
39
phenols; sodium triazolate and imidazolate were prepared as pre-
viously reported; 4-nitroazidobenzene, 2-nitroazidobenzene, and 2,
40
41,42
4-dinitroazidobenzene were prepared in DMF
and recrystallized in
The reactions in liquid ammonia above 45 °C were carried out in a
stainless steel tube (ammonia resistant) that had a total volume of
15 mL. Both ends of the tube could be sealed with standard Swagelok
caps. Normally the reactants were premixed in a glass pressure vessel,
and then transferred into the tube by cooling the tube with liquid
nitrogen. The end of the tube was quickly sealed after the reaction
mixture was transferred into the tube, and then the reactor was placed in
a GC oven where the required temperature can be controlled accurately.
Calculations. The calculation of ground state solvation energy for
the nitrofluorobenzenes in different solvents was performed by using
Spartan 08 software (Spartan 08, Wave function, Inc., Irvine, CA, USA,
waterꢀethanol twice. N-(4-Nitrophenyl)pyrrolidine, piperidine, and
43
44
morpholine; 1-substituted-4-(4-nitrophenoxy)benzene; 1-(4-nitro-
4
5
46
phenyl)-1H-imidazole, and 1-(4-nitrophenyl)-1H-1,2,4-triazole
were prepared and purified by recrystallization or general flash column
methods; the structures of those compounds were confirmed by DSC,
GC-MS, and NMR analysis. The general solvents were laboratory grade
and were used without further purification. For HPLC analysis, HPLC
grade acetonitrile, methanol, and toluene were used as eluent.
Kinetics. Ammonia gas was condensed from a liquid ammonia
cylinder into a glass ammonia tank cooled by liquid nitrogen or dry ice,
then transferred into a glass graduated buret (maximum volume 30 mL).
The buret was connected to a glass reactor (15 mL) through several
Omnifit 3-way and 2-way valves in order to keep the pressure balanced
between the reactor and the buret during the liquid ammonia transfer.
Generally, one of the reactants was precharged into the reactor and the
system maintained at the required temperature by a thermostat. Liquid
ammonia (normally 10 mL) was released into the reactor and equili-
brated for an hour, before another reactant was injected by a pressure
2008). The calculation was carried on the HF and DFT/B3LYP method,
both with 6-31þG* as the basis set.
’
ASSOCIATED CONTENT
S
Supporting Information. Tables and figures that con-
b
taining the UV absorbance and extinction coefficient of aromatic
nitro compounds; the rate constants of the individual kinetic
experiments in liquid ammonia; calculation of solvation energy
for 2-NFB and 4-NFB in typical protic and dipolar aprotic
solvents; and F NMR spectra for the solvolysis of 2,4-DFNB.
This material is available free of charge via the Internet at http://
pubs.acs.org.
47
syringe through an Omnifit septum.
48
The pressure UV cell was based on a design by Gill. The body of the
pressure UV cell is made of PTFE, and with an inlet and outlet controlled
19
by Kel-F valves; the windows of the UV cell are made from CaF
2
, with
the path length between two windows being 10 mm. The top of the UV
cell has a standard Swagelok that can be connected to the Omnifit valves,
3
293
dx.doi.org/10.1021/jo200170z |J. Org. Chem. 2011, 76, 3286–3295

The Journal of Organic Chemistry
ARTICLE
’
AUTHOR INFORMATION
Cima, F. J. Org. Chem. 1968, 33, 1411–1416. (h) Pietra, F.; Del Cima, F.
Tetrahedron Lett. 1966, 37, 4453–4457.
Corresponding Author
(16) For examples, see: (a) Nudelman, N. S.; MacCormack, P.
*E-mail: m.i.page@hud.ac.uk.
Tetrahedron 1984, 40, 4227–4235. (b) Birch, A. J.; Hinde, A. L.; Radom,
L. J. Am. Chem. Soc. 1980, 102, 6430–6437. (c) Politanskaya, L. V.;
Malykhin, E. V.; Shteingarts, V. D. Russ. J. Org. Chem. 1997, 33, 644–651.
(
17) The Gibbs solvation energy of nitrofluorobenzenes in typical
’
ACKNOWLEDGMENT
protic and dipolar aprotic solvents was calculated based on the HF
method with 6-31þG* as the basis set; similar results were also obtained
from DFT calculation at the B3LYP/6-31þG* level. For details, see
Table S3 in the Supporting Information.
(18) Wang, X.; Salaski, E. J.; Berger, D. M.; Powell, D. Org. Lett.
009, 11, 5662–5664.
P.J. acknowledges a postgraduate scholarship from the Uni-
versity of Huddersfield. We also thank the IPOS (Innovative
Physical Organic Solutions) group of the university for financial
support.
2
(
19) For examples, see: (a) Burger, K.; Tremmel, S.; Schickaneder,
’
REFERENCES
H. J. Fluorine Chem. 1976, 7, 471–480. (b) Nishida, S. J. Org. Chem. 1967,
32, 2695–2697. (c) Bolton, R.; Sandall, J. P. B. J. Chem. Soc., Perkin Trans.
2 1978, 141–144.
(
1) Reichardt, C. Solvents and Solvent Effects in Organic Chemistry, 3rd
ed.; Wiley-VCH: Weinheim, Germany, 2003.
2) Constable, D. J. C.; Jimenez-Gonzalez, C.; Henderson, R. K. Org.
Process Res. Dev. 2007, 11, 133–137.
3) For examples, see: (a) Appl, M. Ammonia: Principles and
(
(20) Indeed, with the exception of lithium salts, the added electro-
lytes decrease the rate constant for the decomposition of σ-complexes,
but the effect is not very pronounced. For examples, see: (a) Fendler,
J. H.; Findler, E. J.; Merritt, M. V. J. Org. Chem. 1971, 36, 2172–2176.(b)
Hostetler, W.; Reinheimer, J. D. J. Org. Chem. 1968, 33, 3510ꢀ3513. In
liquid ammonia, the solvolysis rate of 2-chlorobenzothiazole also shows
insensitivity toward the added salt; for details, see: Lemons, J. F.;
Anderson, R. C.; Watt, G. W. J. Am. Chem. Soc. 1941, 63, 1953–1956.
(21) Kingsbury, C. A. J. Org. Chem. 1964, 29, 3262–3270.
(22) (a) Bevan, C. W. L.; Foley, A. J.; Hirst, J.; Uwanu, W. O. J. Chem.
Soc. B 1970, 794–797. (b) Annulli, A.; Mencarelli, P.; Stegel, F. J. Org.
Chem. 1988, 49, 4065–4067.
(
Industrial Practice; Wiley-VCH: Weinheim, Germany, 1999. (b) Appl,
M. Ammonia; Elvers, B. et al. , Eds.; Ullmann’s Encyclopedia of Industrial
Chemistry; Wiley-VCH: Weinheim, Germany, 2006.
(
4) Nicholls, D. Inorganic chemistry in liquid ammonia; Clark, R. J. H.,
Ed.; Topic in Inorganic and General Chemistry, Monograph 17; Elsevier
Scientific Publishing Company: Amsterdam, The Netherlands, 1979.
(
(
W. Science 1987, 238, 1670–1674. (b) Luehurs, D. C.; Brown, R. E.;
Godbole, K. A. J. Solution Chem. 1989, 18, 463–469. (c) Swift, T. J.;
Marks, S. B.; Sayre, W. G. J. Chem. Phys. 1966, 44, 2797–2801. (d)
Tongraar, A.; Kerdcharoen, T.; Hannongbua, S. J. Phys. Chem. A 2006,
5) Billaud, G.; Demortler, A. J. Phys. Chem. 1975, 79, 3053–3055.
6) For examples, see: (a) Nelson, D. D., Jr.; Fraser, G. T.; Klemperer,
(23) (a) Bartoli, G.; Todesco, P. E. Tetrahedron Lett. 1968,
9, 4867–4870. (b) Bartoli, G.; Ciminale, F.; Todesco, P. E. J. Org. Chem.
1975, 40, 872–874.
1
2
1
10, 4924–4929.
7) Ji, P.; Atherton, J. H.; Page, M. I. J. Chem. Soc., Faraday Discuss.
010, 145, 15–25.
8) Ji, P.; Atherton, J. H.; Page, M. I. J. Org. Chem. 2011, 76,
425–1435.
9) (a) Terrier, F. Nucleophilic Aromatic Displacement: The Influence
(24) Cox, B. G. Morden Liquid Phase Kinetics. In Oxford Chemistry
Primers; Compton, R. G., Ed.; Oxford University Press: New York, 1994.
(25) For examples, see: (a) Bowden, K.; Cook, R. S. Tetrahedron
Lett. 1970, 11, 249–250. (b) Shtark, A. A.; Kizner, T. A.; Shteingarts,
V. D. Russ. J. Org. Chem. 1981, 18, 2321–2327.
(26) Ho, K. C.; Miller, J.; Wong, K. W. J. Chem. Soc. B 1966,
310–314.
(27) Page., M. I.; Jencks, W. P. Proc. Natl. Acad. Sci. 1971,
68, 1678–1683.
(
(
(
of the Nitro Group; Feuer, H., Ed.; Organic Nitro Chemistry; Wiley-
VCH: New York, 1991. (b) Terrier, F. Chem. Rev. 1982, 82, 77–152.
(10) For examples, see: (a) Norris, A. R. Can. J. Chem. 1967,
4
5, 2703–2709. (b) Sauer, A.; Wasgestian, F.; Barabasch, B. J. Chem.
(28) Nudelman, N. S. SNAr reactions of amines in aprotic solvents;
Patai, S., Ed.; The Chemistry of Amino, Nitroso, Nitro and Related
Groups, Supplement F2; John Wiley & Sons: New York, 1996; Chapter
26.
Soc., Perkin Trans. 2 1990, 1317–1320. (c) Sekiguchi, S.; Fujisawa, S.;
Ando, Y. Bull. Chem. Soc. Jpn. 1976, 49, 1451–1452. (d) Hasegawa, Y.;
Abe, T. Chem. Lett. 1972, 1, 985–988.
(
11) For examples, see: (a) Chudek, J. A.; Foster, R. J. Chem. Soc.,
(29) For examples, see: (a) Durantini, E.; Zingaretti, L.; Anunziata,
J. D.; Silber, J. J. J. Phys. Org. Chem. 1992, 5, 577–566. (b) Nudelman,
N. S.; Silvana Alvaro, C. E.; Savini, M.; Niotra, V.; Yankelevich, J. Collect.
Czech. Chem. Commun. 1998, 64, 1583–1593. (c) Bamkole, T. O.; Hirst,
J.; Onyido, I. J. Chem. Soc., Perkin Trans. 2 1982, 889–893. (d) Hirst, J.;
Onyido, I. J. Chem. Soc., Perkin Trans. 2 1984, 711–715. (e) Crampton,
M. R.; Emokpae, T. A.; Isanbor, C. Eur. J. Org. Chem. 2007, 1378–1383.
(f) Isanbor, C.; Emokpae, T. A. Int. J. Chem. Kinet. 2008, 40, 125–135.
(g) Akinyele, E. T.; Onyido, I. J. Chem. Soc., Perkin Trans. 2
1988, 1859–1861.
Perkin Trans. 2 1979, 628–633. (b) Chudek, J. A.; Foster, R. J. Chem. Soc.,
Perkin Trans. 2 1982, 511–512. (c) Chudek, J. A.; Ellingham, R. A.;
Foster, R. J. Chem. Soc., Perkin Trans. 2 1985, 1477–1978. (d) Chudek,
J. A.; Foster, R.; Marr, A. W. J. Chem. Soc., Perkin Trans. 2 1987,
341–1344.
(
P. J. Org. Chem. 1979, 44, 3189–3196. (b) Miller, R. E.; Wynne-Jones,
W. F. K. J. Chem. Soc. 1959, 2375–2384. (c) Foster, R.; Mackie, R. K.
Tetrahedron 1961, 16, 119–129. (d) Foster, R.; Mackie, R. K. Tetra-
hedron 1962, 18, 161–168. (e) Bernasconi, C. F. J. Org. Chem. 1970,
5, 1214–1216.
(
1
12) For examples, see: (a) Bernasconi, C. F.; Muller, M. C.; Schmid,
(30) (a) Mancini, P. M. E.; Martinez, R. D.; Vottero, L. R.; Nudel-
man, N. S. J. Chem. Soc., Perkin Trans. 2 1984, 1133–1138. (b) Mancini,
P. M. E.; Martinez, R. D.; Vottero, L. R.; Nudelman, N. S. J. Chem. Soc.,
Perkin Trans. 2 1987, 951–954.
3
13) Vlasov, V. M. Russ. Chem. Rev. 2003, 72, 681–703.
(14) (a) Makosza, M.; Winiarski, J. Acc. Chem. Res. 1987, 20,
2
2
82–289. (b) Makosza, M.; Wojciechowski, K. Chem. Rev. 2004, 104,
631–2666.
(31) For examples, see: (a) Parker, A. J. Chem. Rev. 1969, 69, 1–32.
(b) Parker, A. J. Q. Rev. Chem. Soc. 1962, 16, 163–187. (c) Miller, J.;
Parker, A. J. J. Am. Chem. Soc. 1961, 83, 117–123. (d) Suhr, H. Liebigs
Ann. Chem. 1967, 701, 101–106.
(15) For examples, see: (a) Bevan, C. W. L.; Bye, G. C. J. Chem. Soc.
1
951, 3091–3094. (b) Bolto, B. A.; Miller, J.; Williams, V. A. J. Org.
Chem. 1955, 2926–2929. (c) Bolto, B. A.; Miller, J. Aust. J. Chem. 1956,
(32) Coetzee, J. F; Padmanabhan, G. R. J. Am. Chem. Soc. 1965,
87, 5005–5010.
(33) The oxidative decomposition of aromatic hydrazine is known,
for details, see: (a) Stroh, H.; Ebert, B. Chem. Ber. 1964, 97, 2335–2341.
(b) Hoffman, R. V.; Kumar, A. J. Org. Chem. 1984, 49, 4014–4017.
9
7
, 74–82. (d) Bunnett, J. F.; Morath, R. J. J. Am. Chem. Soc. 1955,
7, 5051–5055. (e) Bamkole, T. O.; Hirst, J.; Udoessien, I. J. Chem. Soc.,
Perkin Trans. 2 1972, 110–114. (f) Bamkole, T. O.; Hirst, J.; Udoessien,
I. J. Chem. Soc., Perkin Trans. 2 1973, 2114–2119. (g) Pietra, F.; Del
3
294
dx.doi.org/10.1021/jo200170z |J. Org. Chem. 2011, 76, 3286–3295

The Journal of Organic Chemistry
ARTICLE
(
3
c) Itoh, T.; Matsuya, Y.; Nagata, K.; Ohsawa, A. Tetrahedron Lett. 1997,
8, 4117–4120.
34) For examples, see: (a) Gritsan, N. P.; Pritchina, E. A. Russ.
Chem. Rev. 1992, 61, 500–516. (b) Budyka, M. F. Russ. Chem. Rev. 2008,
(
7
5
7, 709–723. (c) Herbranson, D. E.; Hawley, M. D. J. Org. Chem. 1990,
5, 4297–4303.
(35) For examples, see: (a) Liang, T. Y.; Schuster, G. B. J. Am. Chem.
Soc. 1986, 108, 546–548. (b) Liang, T. Y.; Schuster, G. B. J. Am. Chem.
Soc. 1987, 109, 7803–7810. (c) Albini, A.; Bettinetti, G.; Minoli, G.
J. Chem. Soc., Perkin Trans. 2 1999, 2803–2807. (d) Liang, T. Y.;
Schuster, G. B. Tetrahedron Lett. 1986, 26, 3325–3328. (e) Odum,
R. A.; Wolf, G. J. Chem. Soc., Chem. Commun. 1973, 360–361. (f) Odum,
R. A.; Aaronson, A. M. J. Am. Chem. Soc. 1969, 91, 5680–5681.
(
(
36) Bartoli, G.; Todesco, P. E. Acc. Chem. Res. 1977, 10, 125–132.
37) Bordwell, F. G.; Hughes, D. L. J. Am. Chem. Soc. 1986,
108, 5991–5997.
(
(
38) Kraus, C. A.; White, G. F. J. Am. Chem. Soc. 1922, 45, 768–778.
39) Kunert, M.; Dinjus, E.; Nauck, M.; Sieler, J. Chem. Ber./Recl.
1
997, 130, 1461–1465.
40) Kazhemekaite, M.; Yuodvirshis, A.; Vektarene, A. Chem.
Heterocycl. Compd. 1998, 34, 252–253.
41) (a) Cox, B. G.; Parker, A. J. J. Am. Chem. Soc. 1973, 95, 402–407.
b) Cox, B. G.; Parker, A. J. J. Am. Chem. Soc. 1973, 95, 408–410.
(
(
(
(42) Dyall, L. K. Aust. J. Chem. 1986, 39, 89–101.
(43) Tangallapally, R. P.; Yendapally, R.; Lee, R. E.; Lenaerts,
A. J. M.; Lee, R. E. J. Med. Chem. 2005, 48, 8261–8269.
44) Bunce, R. A.; Eastons, K. M. Org. Prep. Proced. Int. 2004,
6, 76–81.
45) Kitazaki, T.; Ichikawa, T.; Tasaka, A.; Hosono, H.; Matsushita,
Y.; Hayashi, R.; Okonogi, K.; Itoh, K. Chem. Pharm. Bull. 2000, 48,
935–1946.
46) (a) United States Patent Publication No. 6987158. (b) United
States Patent Application Publication No. 2005/0143384.
(
3
(
1
(
(
47) A 0.1ꢀ0.2 mL standard diethyl ether solution of reactant and
internal standard was injected by a pressure syringe into 10 mL of liquid
ammonia for all the kinetic measurement, so the reaction system under
investigation contained 1ꢀ2% (v/v) diethyl ether.
(
48) Gans, P.; Gill, J. B.; Maclnnes, Y. M.; Reyner, C. Spectrochim.
Acta 1986, 42A, 1349–1354.
3
295
dx.doi.org/10.1021/jo200170z |J. Org. Chem. 2011, 76, 3286–3295