Hydrogen-bonded nucleophile effects in ANS: The reactions of 1-chloro and 1-fluoro-2,4-dinitrobenzene with 2-guanidinobenzimidazole, 1-(2-aminoethyl) piperidine and N-(3-aminopropyl)morpholine in aprotic solvents

Article abstract of DOI:10.1002/poc.1712

The kinetics of the reactions of 2,4-dinitrofluorobenzene (DNFB) and 2,4-dinitrochlorobenzene (DNClB) with 2-guanidinobenzimidazole (2-GB) at 40±0.2°C in dimethylsulphoxide (DMSO), toluene, and in toluene-DMSO mixtures, and with 1-(2-aminoethyl)piperidine (2-AEPip) and N-(3-aminopropyl) morpholine (3-APMo) in toluene at 25±0.2°C were studied under pseudo first-order conditions. For the reactions of 2-GB carried out in pure DMSO, the second-order rate coefficients were independent of the amine concentration. In contrast, the reactions of 2-GB with DNFB in toluene, showed a kinetic behaviour consistent with a base-catalysed decomposition of the zwitterionic intermediate. These results suggest an intramolecular H-bonding of 2-GB in toluene, which is not present in DMSO. To confirm this interpretation the reactions were studied in DMSO-toluene mixtures. Small amounts of DMSO produce significant increase in rate that is not expected on the basis of the classical effect of a dipolar aprotic medium; the effect is consistent with the formation of a nucleophile/co-solvent mixed aggregate. For the reactions of 3-APMo with both substrates in toluene, the second-order rate coefficients, k_A, show a linear dependence on the [amine]. 3-APMo is able to form a six-membered ring by an intramolecular H-bond which prevents the formation of self-aggregates. In contrast, a third order was observed in the reactions with 2-AEPip: these results can be interpreted as a H-bonded homo-aggregate of the amine acting as a better nucleophile than the monomer. Most of these results can be well explained within the frame of the 'dimer nucleophile' mechanism. The shown polyamines were selected to examine its ability to form inter- or intra-molecular hydrogen-bonds. The reactions of 2-AEPip with both halodinitro-benzenes in toluene are third order in amine, consistently with the dimer nucleophile mechanism. On the contrary, the intramolecularly hydrogen-bonded structures of 2-GB and 3-APMo prevent formation of dimeric aggregates, the reactions are 2^nd.order in amine as expected for the classical base-catalysed ANS. Copyright

Full text of DOI:10.1002/poc.1712

Research Article
Received: 26 January 2010,
Revised: 19 February 2010,
Accepted: 22 February 2010,
Published online in Wiley Online Library: 21 July 2010
(wileyonlinelibrary.com) DOI 10.1002/poc.1712
Hydrogen-bonded nucleophile effects in ANS:
the reactions of 1-chloro and
1-fluoro-2,4-dinitrobenzene with
2-guanidinobenzimidazole,
1-(2-aminoethyl)piperidine and
N-(3-aminopropyl)morpholine in aprotic
solvents
a
b
c
*
Cecilia E. Silvana Alvaro , Alicia D. Ayala and Norma S. Nudelman
The kinetics of the reactions of 2,4-dinitrofluorobenzene (DNFB) and 2,4-dinitrochlorobenzene (DNClB) with
2-guanidinobenzimidazole (2-GB) at 40 W 0.2 -C in dimethylsulphoxide (DMSO), toluene, and in toluene–DMSO
mixtures, and with 1-(2-aminoethyl)piperidine (2-AEPip) and N-(3-aminopropyl)morpholine (3-APMo) in toluene at
25 W 0.2 -C were studied under pseudo first-order conditions. For the reactions of 2-GB carried out in pure DMSO, the
second-order rate coefficients were independent of the amine concentration. In contrast, the reactions of 2-GB with
DNFB in toluene, showed a kinetic behaviour consistent with a base-catalysed decomposition of the zwitterionic
intermediate. These results suggest an intramolecular H-bonding of 2-GB in toluene, which is not present in DMSO. To
confirm this interpretation the reactions were studied in DMSO–toluene mixtures. Small amounts of DMSO produce
significant increase in rate that is not expected on the basis of the classical effect of a dipolar aprotic medium; the
effect is consistent with the formation of a nucleophile/co-solvent mixed aggregate. For the reactions of 3-APMo with
both substrates in toluene, the second-order rate coefficients, kA, show a linear dependence on the [amine]. 3-APMo is
able to form a six-membered ring by an intramolecular H-bond which prevents the formation of self-aggregates. In
contrast, a third order was observed in the reactions with 2-AEPip: these results can be interpreted as a H-bonded
homo-aggregate of the amine acting as a better nucleophile than the monomer. Most of these results can be well
explained within the frame of the ‘dimer nucleophile’ mechanism. Copyright ß 2010 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this paper.
Keywords: aprotic solvents; aromatic nucleophilic substitution; dimer nucleophile mechanism; hydrogen bond;
hydrogen-bonded nucleophiles; mixed aggregates
5-amino-1H-4-pyrazolecarbonitrile has been recognised as a
new leaving group.[11]
INTRODUCTION
There has been an active research in the last two decades to
elucidate how the aggregation state of reactants can influence
the mechanisms of organic reactions.[1,2] Aromatic nucleophilic
substitutions (ANS) have been extensively studied because of
their importance in fundamental Organic Chemistry; in the
syntheses of pharmaceuticals and other bioactive agents,
the interest stems from the fact that they can proceed in a
great variety of ways.[3–5] Lately, Crampton and colleagues.
have reported additional data about ring substitution[6] and
leaving-group[7] effects in ANS of substituted nitrobenzenes
with aliphatic amines, as well of electronic and steric effects
in reactions with aniline[8,9] and with substituted anilines,[8,10]
all of them realised in dipolar aprotic solvents. ANS of a
2,4-dinitrophenyl substituted pyrazole with primary amines leads
to the substitution of the pyrazolo substituent; thus the
´
Correspondence to: N. S. Nudelman, Depto Qu´ımica Organica, Facultad de
*
Ciencias Exactas, Universidad de Buenos Aires, Ciudad Universitaria, (1428)
Buenos Aires, Argentina.
E-mail: nudelman@qo.fcen.uba.ar
a
b
c
C. E. S. Alvaro
Depto Qu´ımica, Facultad de Ingenier´ıa, Universidad Nacional del Comahue,
´
Buenos Aires 1400 (8300), Neuquen, Argentina
A. D. Ayala
Instituto de Investigaciones en Qu´ımica Organica, Universidad Nacional del
´
Sur, Avda Alem 1253 (8000), Bah´ıa Blanca, Argentina
N. S. Nudelman
Depto Qu´ımica Organica, Facultad de Ciencias Exactas, Universidad de
´
Buenos Aires, Ciudad Universitaria, (1428) Buenos Aires, Argentina
J. Phys. Org. Chem. 2011, 24 101–109
Copyright ß 2010 John Wiley & Sons, Ltd.

C. E. S. ALVARO, A. D. AYALA AND N. S. NUDELMAN
On the other hand, ANS by amines has been recognised to be
extremely affected by the solvent.[1,2,12] Their study is currently
receiving increased interest since they constitute a suitable
model that contributes to the understanding of the microscopic
properties of solvent in reactions, due to the complex interactions
between the amine, the substrate and/or the intermediate
that can occur involving the solvent molecules.[13–20] A specific
solvent effect has been recently demonstrated in the solvent-
controlled leaving group selectivity in ANS carried out on a highly
functionalised substituted xanthone, giving rise to a useful
synthesis for the xanthone core of a new antibiotic.[21] Similarly,
experimental and theoretical exploration of acid-catalysed
multi-step ANS showed that the mechanisms in polar and
non-polar solvents (i.e. toluene) are different.[22] When the
reactions are carried out in solution, noncovalent-binding
interactions of different types are established that can be
involved in the general concept of ‘solvent effects’, of which
hydrogen bonding is one of the most important specific
microscopic interactions.[1,2,13–15]
obtained were well explained within the frame of the ‘dimer
nucleophile’ mechanism. In a thorough examination of nucleo-
phile structure effect regarding its self-aggregation states,
the present paper describes a kinetic and spectroscopic
study of the reactions between 2,4-dinitrofluorobenzene
(DNFB) and 2,4-dinitrochlorobenzene (DNClB) with 2-
guanidinobenzimidazole (2-GB) in dimethylsulphoxide (DMSO),
in toluene and in binary toluene–DMSO mixtures. Likewise,
the reactions of the same substrates with diamines having
an alicyclic amino group near the nucleophilic nitrogen
in the lateral chain having two or three methylene groups,
such as 1-(2-aminoethyl)piperidine (2-AEPip) and N-(3-
aminopropyl)morpholine (3-APMo), were studied in toluene.
The observed results afford evidence concerning the critical role
that hydrogen-bond interactions and formation of ‘mixed
aggregates’ play in the kinetics of these reactions.
The inter- and intramolecular hydrogen bonding are one of the
principal types of weak non-covalent interactions that play a role
in defining the physical properties and reactivity of a large variety
of structures in chemical and biological systems.[23,24] This subject
is currently receiving increased interest and a growing number
of studies in gas phase as well as theoretical calculations are
being undertaken to understand the influence of the internal
(structural) and external (solvent) effects on the hydrogen
bonded configurations. Raczynska and co-workers reported the
features of hydrogen bonding in the gas phase of polyfunctional
compounds such as cyclic and acyclic substituted diamines,
vinamidines and guanidines,[25] substituted formamidines
and amidinazines,[26] all of which can develop intramolecular
hydrogen bonding called ‘internal solvation’. The observed
enhancement of gas-phase basicity of these compounds was
interpreted as due to the intramolecular hydrogen bonding
cyclisation.[25] Intramolecular hydrogen bonding also plays an
important role in biological molecules involving polyfunctional
groups. It was found that a six-membered ring cyclic structure
is formed in the protonated histamine[27] and Na, Na-
dimethylhistamine.[28] Within this context, it is worth mentioning
that part of the high basicity of the arginine is due to the ‘internal
solvation’ of the guanidinium cation moiety as shown by a careful
ab initio study,[29] which confirmed earlier conjectures.[25]
We recently published atypical findings in ANS carried out in
aprotic solvents using diamines that were purposefully selected
due to their special structures able to form intra- or
intermolecular hydrogen bonds such as ethylendiamine;
3-dimethylamino-1-propylamine and histamine.[30] The results
RESULTS AND DISCUSSION
There is at present considerable interest in the experimental and
theoretical studies of hydrogen bonding effects on the
conformation and stability of organic molecules.[31–37]
Intramolecular hydrogen bonds are involved in the control of
the conformation of many biological molecules and they
contribute to the interactions needed for efficient molecular
recognition.[38,39] It has been shown[1,2,19,20] that for ANS
reactions of nitro-activated substrates and amines in non-polar
aprotic solvents, auto-association of amines is very important
because of the low permittivity of the media. Self-association of
amines to form mainly dimers by hydrogen bonding interactions
increases its nucleophilicity; consequently the dimer is a better
nucleophile, as it was confirmed by semi-empirical[1] and ab initio
calculations.[40] On the other hand, when two amino groups are in
an appropriate geometry, like in 2-guanidinobenzimidazole
(2-GB), intramolecular H-bonding is easily established, and those
compounds exhibit unusually high basicity.[41]
2-GB has important biological properties,[42–45] it is
a
polyfunctional planar molecule with a delocalised p electronic
system, in which the formation of an intramolecular hydrogen
bond was determined in solid state by X-ray diffraction.[46,47] Due
to the intramolecular H-bonds, guanidine systems have strong
basicity; some of them constitute the new ‘proton sponges’. Thus,
1,8-bis(tetramethylguanidino)naphthalene
(TMGN)[48]
and
4,5-bis(tetramethylguanidino)-fluorene (TMGF)[49] are stronger
bases than the 1,8-bis(dimethylamino)naphthalene (DMAN), due
to the more favourable intramolecular H-bond effect.
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J. Phys. Org. Chem. 2011, 24 101–109

HYDROGEN-BONDED NUCLEOPHILE EFFECTS IN ANS
To examine the importance of hydrogen bonding
interactions in ANS with amines, the reactions of DNFB
and DNClB with a polifunctionalised amine, 2-GB, in DMSO,
toluene, and DMSO–toluene binary solvents and with
diamines as 1-(2-aminoethyl)piperidine (2-AEPip) and N-(3-
aminopropyl)morpholine (3-APMo) in toluene were studied.
The selected amines were chosen for their potential ability
to form inter- and/or intramolecular H-bonds. The reactions
proceed straightforwardly to give the expected N-substituted
2,4-dinitroaniline, in almost quantitative yield. The determi-
nations were carried out under pseudo-first order conditions;
the rate dependence with amine concentration was studied
and good kinetic behaviour was observed throughout the work.
Table 2. Reaction of 2,4-dinitrochlororobenzene, DNClB,a
with 2-guanidinobenzimidazole (2-GB) in dimethylsulphoxide
(DMSO) at 40.0 ꢀ 0.2 8C. Pseudo first-, kc, and second-order
rate coefficients, kA
102[2-GB]/M
107 kc (sꢁ1
)
106 kA (sꢁ1Mꢁ1
)
0.50
1.08
3.22
4.00
5.00
6.08
8.01
0.59
1.25
3.87
4.75
6.37
7.73
10.1
11.8
11.6
12.0
11.9
12.7
12.7
12.7
a [DNClB] ¼ 5.02 ꢂ 10ꢁ4 M.
Reactions of DNFB and DNClB with 2-GB in DMSO
The kinetics of the reactions of DNFB and of DNClB, with 2-GB
in DMSO, were studied at 40 ꢀ 0.2 8C in the presence of
variable amounts of the nucleophile. Table 1 presents the
pseudo-first, kc, and the bimolecular rate coefficients kA for
the reactions with DNFB. It can be observed that the
pseudo-first order rate coefficients, kc, increase linearly with
amine concentration, [B], in the whole range studied. On the
other hand, no dependence of the bimolecular rate coefficients,
kA, on [B] was observed.
Table 2 shows the corresponding kc and kA values for the
reactions of 2-GB with DNClB in DMSO at 40 ꢀ 0.2 8C in the
presence of variable amounts of the nucleophile. As expected for
a less-activated substrate, the reactions of DNClB are slower than
those of DNFB; the kinetic behaviour is very similar. With both
substrates, the plot (not shown) of kc versus [2-GB] is a straight
line with null intercept; the correlation coefficients being
R2 ¼ 0.999 for DNFB and R2 ¼ 0.998 for DNClB, respectively.
These results are consistent with a mechanism in which a
molecule of amine attacks the substrate in the first step, and this
becomes the rds. This is likely due to an increase in kꢁ1 coupled to
the inability of 2-GB to assist proton transfer from the zwitterionic
intermediate. Thus, decomposition of the zwitterionic intermedi-
ate by DMSO (a well known hydrogen-bond acceptor (HBA), b
value ¼ 0.76, ET(30) ¼ 45.0)[5], becomes thermodynamically more
favorable than a potential base-catalysed decomposition. The
2-GB steric hindrance attempts to catalyze.
Though from the present results is not possible to infer that the
intramolecular hydrogen bond is present in 2-GB, they are in
agreement with 1H, 13C and 15N NMR spectroscopy studies
carried out in DMSO-d6 solutions.[50] The authors proposed that
2-GB exhibits an open structure in DMSO solution, where all NH
moieties form H-bonds with the solvent. The kinetic results also
agree with the studies of proton exchange of 15N12/15N13 of
15N1/15N3 of 2-GB (refer Scheme 1) in solution with protic and
dipolar aprotic solvents.[51] It was shown that the equivalent
conformers 1 and 2 are the principal contributors[52] (Scheme 1).
These conformers are in equilibrium and may be stabilised by
intramolecular hydrogen bonding. The impact that this intra-
molecular H-bond has on the bond order of the neutral guanidine
group and on the dynamic conformations was related to the
concept of ‘resonance-assisted hydrogen bond’ (RAHB).[53,54]
The results indicate that the 15N12/15N13 exchange is rapid
and accelerated by protic solvents. The exchange of 15N1/15N3 in
2-GB at the imidazole ring correlates with proton exchange, but it
is not mechanistically related to guanidino 15N12/15N13
exchange. In 2-GB dissolved in CD3OD, both processes are fast
on the NMR time scale; however, DMSO-d6 inhibits the 15N1/15N3
exchange and allows 15N12/15N13 exchange. This behaviour
indicates that proton exchange is a bimolecular process in the
absence of protic polar species, while in DMSO-d6 the
intramolecular homo-aggregation of 2-GB is inhibited.
Table 1. Reaction of 2,4-dinitrofluorobenzene, DNFB,a with
2-guanidinobenzimidazole (2-GB) in dimethylsulphoxide
(DMSO) at 40.0 ꢀ 0.2 8C. Pseudo first-, kc, and second-order
rate coefficients, kA
102[2-GB]/M
105 kc (sꢁ1
)
104 kA (sꢁ1Mꢁ1
)
Reactions of DNFB with 2-GB in toluene
0.54
0.71
0.90
1.08
2.00
3.00
5.00
0.62
0.82
1.08
1.19
2.23
3.31
5.56
11.4
11.5
12.0
11.0
11.1
11.0
11.1
To examine the effects of an apolar aprotic solvent on the kinetics
behaviour, the reactions of 2-GB with DNFB were studied in
toluene. Table 3 shows that the bimolecular rate coefficients, kA,
increase steadily with [B]; and the plot of kA versus [B] is a straight
line with a null intercept with a correlation coefficient of
R2 ¼ 0.988 (Fig. 1).
a [DNFB] ¼ 5.019 ꢂ 10ꢁ4 M.
Contrary to the observations in DMSO, the reactions with DNFB
in toluene showed a kinetic behaviour consistent with a
J. Phys. Org. Chem. 2011, 24 101–109
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C. E. S. ALVARO, A. D. AYALA AND N. S. NUDELMAN
Scheme 1. Principal conformers of 2-GB
base-catalysed decomposition of the zwitterionic intermediate.
These results suggest the formation of a strong intramolecular
hydrogen bond in 2-GB that prevails over the formation of
intermolecular 2-GB dimers, and an ‘atypical’ base-catalysed
decomposition of the zwitterionic intermediate SB due to an
‘intramolecular dimer’ is obeyed. The null intercept indicates
that the spontaneous decomposition of SB is negligible, as
expected from the poor nucleofugacity of fluorine in an aprotic
solvent.
preferential solvation was observed as described below. Table 4
shows the observed second-order rate coefficients, kA, for the
reactions of DNFB with 2-GB in DMSO–toluene binary solvents.
Figure 2 shows the significant increase in rate observed with
small additions of DMSO to toluene up to 15%; then the increase
diminishes. The dramatic effect caused by small additions of
DMSO to toluene suggests that a specific effect must be involved.
This effect is consistent with the formation of nucleophile/
co-solvent mixed aggregates that prevents the self-aggregation of
the nucleophile. The mixed aggregate increases the reaction rate
since the amine now acts as a hydrogen-bond donor (HBD)
and therefore increases its nucleophilicity. The observed
results afford new evidence to the ‘dimer nucleophile’ mechanism.
In that mechanism, the homo- or mixed dimer of the amine
(a hydrogen-bonded molecular complex) acts as the true
nucleophile forming an intermediate-complex, and a third
molecule of amine assists the decomposition step, Eqn (2). For a
Reactions of DNFB and DNClB with 2-GB in solvent mixtures
To analyse how specifically changes in the reaction media
influence the kinetic behaviour, an HBA co-solvent was added to
toluene, a non-hydrogen bonding aromatic solvent (NHBA). The
reactions were studied in DMSO–toluene binary mixtures;
starting from small additions of DMSO to toluene, evidence for
HBA co-solvent > 20% the reactions show the kinetic
behaviour found in pure DMSO; it is likely that a preferential
solvation by DMSO molecules occurs in the 2–3 solvent shells
around the cibotactic zone.
Table 3. Reaction of 2,4-dinitrofluorobenzene, DNFB,a with
2-guanidinobenzimidazole (2-GB) in toluene at 40.0 ꢀ 0.2 8C.
Second-order rate coefficients, kA
Although the specific effect of the aggregation of the
nucleophile with DMSO could also operate in the second step,
the above interpretation is preferred since it also explains the
early reported ‘anomalous’ effect of small additions of DMSO
observed when the first step is rate determining.[55] Similar rate
accelerations due to the addition of small amounts of a HBA
co-solvent were found in the reactions of 1,2-dinitrobenzene with
butylamine in benzene. While the reaction is almost insensitive
to other additives, the accelerations observed upon the addition
of DMSO to benzene exceed expectations based only on
considerations of the polarity of the medium,[56] in line with the
present finding for the reactions studied in toluene/DMSO binary
solvents. To support this interpretation of the experimental
results, theoretical semi-empirical and ab initio calculations were
performed to investigate the likelihood of 2-GB: DMSO hydrogen
bond formation. It was found that 2-GB exhibits intra- and
102[2-GB]/M
105 kA (sꢁ1Mꢁ1
)
0.61
0.75
0.92
1.08
1.21
1.51
2.02
2.50
3.00
0.64
0.84
1.09
1.42
1.51
1.71
2.32
2.91
3.80
a [DNFB] ¼ 5.15 ꢂ 10ꢁ4 M.
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J. Phys. Org. Chem. 2011, 24 101–109

HYDROGEN-BONDED NUCLEOPHILE EFFECTS IN ANS
4
12
10
3
2
1
8
6
4
2
0
0
20
40
60
80
100
0
1
2
3
4
% DMSO (v/v)
102 [2-GB]/M
Figure 2. Second-order rate coefficients, kA, for the reactions of
2,4-dinitrofluorobenzene (DNFB) with 2-guanidinobenzimidazole (2-GB)
in dimethylsulphoxide (DMSO)–toluene binary solvents as a function of
percentage of DMSO in the binary solvent at 40.0 ꢀ 0.2 8C
Figure 1. Second-order rate coefficients, kA, for the reaction of dinitro-
fluorobenzene (DNFB) with 2-guanidinobenzimidazole (2-GB) in toluene
at 40.0 ꢀ 0.2 8C as a function of [2-GB]
intermolecular hydrogen bond formation leading to homo 2-GB
and mixed solute–solvent dimers.[57]
25.0 ꢀ 0.2 shown in Table 7 and plotted as Figs 5 and 6, shows a
straightline;thisresultisconsistentwithathird-orderinamineterm
in the kinetic law. This kinetic behaviour has been observed
previously in other systems[1,2,13–15,58,59] and can be interpreted by
the mechanism shown in Eqns (3)–(5) where the dimer (B:B) of the
nucleophile attacks the substrate, S, forming the intermediate, SB2;
then a third molecule of amine assists the decomposition step. The
intermediate in Eqn (4) is highly zwitterionic; the extra amine
molecule is needed to stabilise the developing charge in this
solvent of very low permitivity. The kinetic law is given by Eqn (5),
where K ¼ [B:B]/[B]2 stands for the amine self-association constant.
Reactions of DNFB and DNClB with 2-(AEPip) and 3-(APMo)
in toluene
The kinetics of the reactions of DNFB and DNClB, both with 2-(AEPip)
and 3-(APMo), in toluene, were studied at 25 ꢀ 0.2 8C in the
presence of variable amounts of the nucleophile. Table 5 shows the
observed results for the reactions of 2,4-dinitrofluorobenzene,
DNFB, with 1-(2-aminoethyl)piperidine, 2-(AEPip), and N-(3-amino-
propylmorpholine, 3-(APMo): the bimolecular rate coefficients, kA,
are given. Table 6 shows the corresponding values for the reactions
of both amines with 2,4-dinitrochlorobenzene, DNClB, in toluene. It
can be observed that the second-order rate coefficients, kA, for the
reactions with 2-(AEPip) increase rapidly [B], and the plots of kA
versus [B] (refer Figs 3 and 4) show a quadratic dependence (for Fig. 4
different scales for the kA values should be used in the plot due to
the reactivity difference of the two amines in DNClB). On the
other hand, the corresponding third-order rate coefficient values for
the reactions of 2-(AEPip) with DNCIB and DNFB in toluene at
2BB : B
(3)
2
k1k2K½Bꢃ þ k1k3K½Bꢃ
kA ¼
(5)
k
ꢁ1 þ k2 þ k3½Bꢃ
Table 4. Reaction of 2,4-dinitrofluorobenzene, (DNFB,
5.019 ꢂ 10ꢁ4 M) with 2-guanidinobenzimidazole (2-GB)a in
dimethylsulphoxide (DMSO)-toluene binary solvents at
40.0 ꢀ 0.28C. Second-order rate coefficients, kA
Table 5. Reaction of 2,4-dinitrofluorobenzene, DNFB, with
1-(2-aminoethyl)piperidine 2-(AEPip) and
N-(3-aminopropylmorpholine, 3-(APMo), in toluene at
25.0 ꢀ 0.2 8C. Second-order rate coefficients, kA
% DMSO (v/v)
104kA (sꢁ1Mꢁ1
)
3-APMo
kA (sꢁ1Mꢁ1
2-AEPip
kA (sꢁ1Mꢁ1
)
2
5
7
9
10
20
40
60
80
100
4.21
6.70
7.80
8.74
9.38
9.45
9.83
9.98
10.2
11.0
103[B] (M)
)
103[B] (M)
5.05
6.10
7.00
8.04
9.01
10.2
12.0
1.36
1.72
2.05
2.29
2.51
2.85
3.49
5.02
5.97
6.96
7.98
8.95
9.94
1.59
2.34
3.15
4.18
5.85
6.57
a [2-GB] ¼ 0.0108 M.
[DNFB] ¼ 5.15 ꢂ 10ꢁ4 M.
J. Phys. Org. Chem. 2011, 24 101–109
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C. E. S. ALVARO, A. D. AYALA AND N. S. NUDELMAN
30
20
10
10.0
Table 6. Reaction of 2,4-dinitrochlorobenzene, DNClBa with
1-(2-aminoethyl)piperidine, 2-(AEPip), and
N-(3-aminopropylmorpholine, 3-(APMo), in toluene at
25.0 ꢀ 0.2 8C. Second-order rate coefficients, kA
7.5
5.0
2.5
0.0
3-APMo
103kA (sꢁ1Mꢁ1
2-AEPip
103kA (sꢁ1Mꢁ1
)
[B] (M)
)
[B] (M)
0.300
0.537
0.604
0.805
0.900
1.01
1.20
1.48
1.75
2.01
1.53
2.54
3.44
4.02
4.54
4.94
5.59
6.89
7.97
9.25
0.496
0.597
0.791
0.999
1.20
1.51
1.73
2.01
2.31
1.92
2.48
3.12
4.88
5.98
8.73
0
1
2
3
[Amine]/M
Figure 4. Second-order rate coefficients, kA, for the reactions of
2,4-dinitrochlorobenzene (DNClB) with ^ 1-(2-aminoethyl)piperidine,
2-(AEPip) (103 left Y-axis scale) and & N-(3-aminopropylmorpholine
3-(APMo) (103 right Y-axis scale) at 25.0 ꢀ 0.2 8C as a function of [amine]
10.9
15.4
22.9
26.4
2.54
a [DNClB] ¼ 5.09 ꢂ 10ꢁ4 M.
The magnitudes of the rates of both amines with the same
substrate are similar; in all the reactions studied in the present
work, DNFB reacts faster than DNClB. These results are consistent
with those reported in the literature.[20]
On the other hand, for the reactions of 3-APMo with both
substrates in toluene, the second-order rate coefficients, kA,
exhibit a linear dependence on amine concentration as expected
for a classical mechanism of base-catalysed decomposition of the
zwitterionic intermediate; the plot of kA versus [B] is a straight line
with a null intercept and a correlation coefficient of R2 ¼ 0.992 for
the reactions with DNFB (Fig. 3) and R2 ¼ 0.991 for the reactions
with DNClB (Fig. 4). Because of the ability of 3-APMo to form
a six-membered ring, an intramolecular hydrogen bond is
established which prevents the formation of self-aggregates. It
can be observed in Fig. 6 that the straight line for the reaction of
2-(AEPip) with DNClB has a no null intercept. This indicates that
both the monomer and the dimer nucleophile mechanisms occur
in the reaction with this substrate, while the reaction with DNFB
proceeds entirely through the ‘dimer nucleophile mechanism’.
The present kinetics results that indicate inter- and intra-
molecular hydrogen bonds in flexible structure bifunctionalisated
amines with two and three methylene groups are in agreement
with studies of gas phase basicity of bidentate ligands reported.
Raczynska and Wozniak[60] studied the gas phase basicity of
rigid and flexible conformation bidentate ligands and
concluded that intramolecular hydrogen bonding called ‘internal
solvation’ is responsible for an enhancement of gas phase
basicities. The thermodynamic parameters and proton affinities
for compounds of general formula Y(CH2)nX (X,Y ¼OR, NR2; R ¼ H
or alkyl; n ¼ 2) have been determined; the results suggest that
when n ¼ 2, the intramolecular H-bond is partial or does not
exist.[61]
10
8
8
6
4
2
0
6
4
2
0
3
6
9
12
15
103 [Amine]/M
0
3
6
9
12
103 [2-AEPip]/M
Figure 3. Second-order rate coefficients, kA, for the reactions of
2,4-dinitrofluorobenzene (DNFB) with 1-(2-aminoethyl)piperidine,
^
Figure 5. Third-order rate coefficient, kA/[B], for the reactions of
2,4-dinitrofluorobenzene (DNFB) with 1-(2-aminoethyl)piperidine, 2-(AEPip),
in toluene at 25.0 ꢀ 0.2 8C as a function of [amine]
2-(AEPip) and & N-(3-aminopropylmorpholine, 3-(APMo) at 25.0 ꢀ
0.2 8C as a function of [amine]
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J. Phys. Org. Chem. 2011, 24 101–109

HYDROGEN-BONDED NUCLEOPHILE EFFECTS IN ANS
12
Table 7. Reactions of 2,4-dinitrofluorobenzene, DNFB, and
2,4-dinitrochlorobenzene, DNClB, with
1-(2-aminoethyl)piperidine, 2-(AEPip), in toluene at
25.0 ꢀ 0.2 8C. Third-order rate coefficient, kA/[B]
8
4
0
DNFBa
DNClBb
103[B]/M 10ꢁ2 kA/[B] (sꢁ1Mꢁ2
)
[B]/M 103 kA/[B] (sꢁ1Mꢁ2
)
5.02
5.97
6.96
7.98
8.95
9.94
3.17
3.92
4.52
5.24
6.54
6.61
0.496
0.597
0.791
0.999
1.20
1.51
1.73
2.01
2.31
3.87
4.15
3.95
4.88
4.98
5.78
6.30
7.66
9.91
0
1
2
3
[2-AEPip]/M
Figure 6. Third-order rate coefficient, kA/[B], for the reactions of
2,4-dinitrochlorobenzene (DNClB) with 1-(2-aminoethyl)piperidine,
2-(AEPip) in toluene at 25.0 ꢀ 0.2 8C as a function of [2-AEPip]
2.54
10.4
a [DNFB] ¼ 5.15 ꢂ 10ꢁ4 M.
b [DNClB] ¼ 5.09 ꢂ 10ꢁ4 M.
expected are prone to react in the monomeric state, while those
in which no intramolecular hydrogen bonds are possible can
react by the ‘dimer nucleophile’ mechanism. In HBA solvents, such
as DMSO, the role of mixed aggregates is clearly demonstrated.
EXPERIMENTAL
The general procedures for spectroscopic determinations and for
the purification of reagents and solvents are given as
Supplementary Materials.
2-guanidinobenzimidazole, (2-GB, Aldrich) was crystallised
twice from ethyl acetate. To assure fully removal of the solvent,
the crystals were dissolved in chloroform and vacuum was
applied until a dried residue was obtained; it was reduced to
powder in a mortar and the procedure was repeated until no
impurities were detected by thin-layer chromatography. Finally, it
was kept in a desiccator protected from light under dry nitrogen
The proposed structures for the intramolecular H-bonded
3-APMo and the intermolecular dimer 2-AEPip that should act as
the respective nucleophiles in the present ANS reactions are
shown above.
atmosphere (mp 242–244 8C, lit,[50] 242.8–244.5 8C). IR. n cmꢁ1
:
—
—
—
3448, 3210 (N—H), 1648 (C N), 1600, 1542 (C C), 1392, 1274
—
(C—N).
1-(2-aminoethyl)piperidine, (2-AEPip, Aldrich): the commercial
product was kept over sodium strings during several days,
distilled by reduced pressure fractional distillation over zinc
powder and then twice over sodium strings under reduced
pressure. The fraction 78–80 8C at 20 mmHg was collected. It was
kept in a desiccator under dry nitrogen atmosphere, protected
from light, and it was re-distilled before using
N-(3-aminopropyl)morpholine, (3-APMo, Aldrich): the commer-
cial product was kept over sodium strings during several days,
distilled by reduced pressure fractional distillation over zinc
powder and then twice over sodium strings under reduced
pressure. The fraction 96–97 8C at 20 mmHg was collected. It was
kept in a desiccator under dry nitrogen atmosphere, protected
from light, was re-distilled before using 2,4-dinitrochlorobenzene
(DNClB, Sigma), and was crystallised twice from absolute ethanol
(mp 52–53 8C, lit.[62] 52–53 8C).
CONCLUSIONS
The present results show that for ANS reactions of nitro-activated
substrates and polyamines in aprotic solvents, homo-(or hetero-)
association of amines is very important because of the low
permitivity of the media and the strong involvement of
hydrogen-bonding interactions. Because of the higher electron
density on the hydrogen-bond donor nitrogen, hydrogen
bonded amines are better nucleophiles than those in which
no hydrogen-bonding interactions are possible. So, the reactions
with intramolecular homo-aggregate, as well as mixed (hetero-)
aggregates with other hydrogen-bond acceptor present in the
reaction media, are faster than with the non-hydrogen-bonded
nucleophile. The hydrogen bonded nucleophile structure is
crucial: bi- and polyamines for which internal hydrogen bond is
J. Phys. Org. Chem. 2011, 24 101–109
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C. E. S. ALVARO, A. D. AYALA AND N. S. NUDELMAN
2,4-dinitrofluorobenzene, (DNFB, Merck), was distilled at
reduced pressure under nitrogen (b.p. 122–123 8C at 5 mmHg,
lit,[62] 119 8C at 2 mmHg) and was kept in a desiccator protected
from light under dry nitrogen atmosphere.
from the application of Beer’s law to solutions of the product
independently prepared in the desired solvent. In all cases,
pseudo-first-order kinetics were observed. Pseudo-first-order
coefficients, kC, were obtained by the least-squared method as
1-N-(2-benzimidazol)-3-N-(2,4-dinitrophenyl)guanidine, N-(2,4-
dinitrophenyl)-1-(2-aminoethyl)piperidine and N-(2,4-dinitropheny)-
N-(3-aminopropyl)morpholine were prepared from 2,4-
dinitrochlorobenzene and 2-guanidinobenzimidazole, N-(3-
aminopropyl)morpholine and 1-(2-aminoethyl)piperidine, respect-
ively, following the general procedure reported for N-(2,4-
dinitrophenyl)-2-methoxyaniline.[63] In all cases, the compounds
were obtained in almost quantitative yields as dark orange, the
former, and yellow crystals the other two products, respectively.
[1-N-(2-benzimidazol)-3-N-(2,4-dinitrophenyl)guanidine (mp 218–
the slope of the correlation ln (A1 ꢁ At)/A against time, where
1
is the optical density of the reaction mixture measured at
A
1
‘infinity’ (more than ten half-lives). The second-order rate
coefficients, kA, were obtained by dividing kC by the amine
concentrations. Rate coefficients were reproducible to ꢀ 2%. No
corrections for expansion coefficients were applied to the
concentration values.
Acknowledgements
1
220 8C), H NMR (DMSO-d6): d 11.12 (s, 1H), 9.03 (s, 1H), 8.25 (d,
The authors gratefully acknowledged financial support from the
Universidad Nacional del Comahue (grant no. I123-UNCo) and
from the National Research Council (CONICET) from Argentina
(grant no. PIP 6019).
1H), 7.20 (m, 2H), 7.10 (d, 1H), 6.92 (m, 2H), 2.30 (s, 1H), 2.10 (s, 2H). 13
C
NMR (DMSO-d6): d 160.00, 152.00, 149.90, 148.48, 147.80, 140.80,
128.87, 125.80, 123.70, 121.30, 120.30, 119.34, 114.34, 110.20. IR (KBr)
ncmꢁ1: 3439 and 3196 (N—H),. 1640 (N—H) and (NH2), 1626
—
(C N), 1510, (NO2), 1340, (NO2), 780 (NH2)]. [N-(2,4-
—
dinitrophenyl)-1-(2-aminoethyl)piperidine (mp 122–123 8C), 1H
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