Nitrosation of Amines in Non-Aqueous Solvents - Difference between N-N=O and O-N=O Nitroso Donors

Article abstract of DOI:10.1002/ejoc.200300482

A kinetic study has been carried out on nitroso group transfer from substituted N-methyl-N-nitroso-benzenesulfonamides to different secondary amines: pyrrolidine, piperidine, N-methylpiperazine, and morpholine in cyclohexane. The observed pseudo-first-order rate constant k_obs shows a linear and quadratic dependency on the amine concentration with the existence of a primary kinetic isotope effect. Experiments carried out at different temperatures show Arrhenius-type behavior. Addition of isopropylamine (iPrNH₂) to the reaction medium produces an increase in k _obs. In the presence of a high iPrNH₂ concentrations the influence of secondary amine concentration on k_obs shows the disappearance of the quadratic dependency of k_obs on the secondary amine. These results would be compatible with an addition-elimination mechanism, similar to that observed for the aminolysis of the alkyl nitrites in apolar solvents. The observed behavior in the presence of 18-crown-6 is very different, however. Addition of crown ether catalyses the reaction of aminolysis of alkyl nitrites insofar as it does not alter the rate of the nitroso group transfer from N-nitrososulfonamides. This behavior has been interpreted in terms of a concerted reaction mechanism through cyclical transition states, with four or six centers, involving one or two molecules of secondary amine. Addition of iPrNH₂ to the reaction medium causes the appearance of a third reaction path, which emerges through a mixed transition state formed by a molecule of a secondary amine and a molecule of isopropylamine. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300482

FULL PAPER
Nitrosation of Amines in Non-Aqueous Solvents ؊ Difference Between
[‡]
N؊N؍O and O؊N؍O Nitroso Donors
[a]
[a]
[b]
[a]
Luis Garc ´ı a-R ´ı o,* Jos e´ R. Leis, Jos e´ A. Moreira, and David Serantes
Keywords: Kinetics / Mechanism / Nitrosation / Solvent effect / Sulfonamide
A kinetic study has been carried out on nitroso group transfer
from substituted N-methyl-N-nitroso-benzenesulfonamides
to different secondary amines: pyrrolidine, piperidine, N-
methylpiperazine, and morpholine in cyclohexane. The ob-
served pseudo-first-order rate constant kobs shows a linear
and quadratic dependency on the amine concentration with
the existence of a primary kinetic isotope effect. Experiments
carried out at different temperatures show Arrhenius-type
alkyl nitrites in apolar solvents. The observed behavior in the
presence of 18-crown-6 is very different, however. Addition
of crown ether catalyses the reaction of aminolysis of alkyl
nitrites insofar as it does not alter the rate of the nitroso group
transfer from N-nitrososulfonamides. This behavior has been
interpreted in terms of a concerted reaction mechanism
through cyclical transition states, with four or six centers, in-
volving one or two molecules of secondary amine. Addition
behavior. Addition of isopropylamine (iPrNH
medium produces an increase in kobs. In the presence of a
high iPrNH concentrations the influence of secondary amine
concentration on kobs shows the disappearance of the quad-
ratic dependency of kobs on the secondary amine. These re-
sults would be compatible with an addition-elimination
mechanism, similar to that observed for the aminolysis of the
2
) to the reaction
2
of iPrNH to the reaction medium causes the appearance of
a third reaction path, which emerges through a mixed trans-
ition state formed by a molecule of a secondary amine and a
molecule of isopropylamine.
2
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
In 9:1 (w/w) dioxane/water[3] or THF/water[4] mixtures,
however, the rate-determining step is the attack on the sub-
The mechanism by which a reaction occurs can be altered strate by the nitrosating agent. When the reaction medium
[
5]
as the reaction medium varies, as has been clearly shown for is 90% acetonitrile, though, it is possible to observe a rate-
reactions involving the aminolysis of esters.[1] Nitrosation limiting step consisting of the rearrangement of the ni-
reactions generally display such behavior, and it has in fact trosourea, transferring the nitroso group from the more nu-
been shown that the mechanism of nitrosation of ureas can cleophilic O atom to the N atom. It has also been noted
be modified by changing the percentage of organic co-sol- that mechanism changes caused by the solvent occur in the
vent in the reaction medium. It is now known that the com- acid hydrolysis reaction of the alkyl nitrites. In an aqueous
[
2]
plete mechanism is in fact as shown in Scheme 1: attack medium the reaction takes place by a concerted mecha-
[
6]
by the nitrosating agent on the carbonyl oxygen atom, fol- nism (Scheme 2), while if the percentage of dioxane in the
lowed by a slow proton-transfer step and then by an in- medium is greater than 70% a stepwise reaction will take
[
7]
ternal rearrangement in which the NO group is transferred place, with prior protonation of the alkyl nitrite.
from oxygen to a nitrogen atom to afford the thermo-
The mechanism changes are more profound when the op-
erative reaction mechanisms in an aqueous medium and in
non-aqueous solvents are compared. Alkyl nitrites
dynamically stable N-nitroso compound.
(
RϪOϪNϭO) form a major group of nitrosating agents
[
‡]
a]
[8]
Nitrosation of Amines in Non-Aqueous Solvents, 4. Part 3: able to nitrosate amines. Nitroso group transfer can also
[
12b]
Ref.
[
take place with an N-nitroso donor, NϪNϭO, as in the
case of the N-nitrososulfonamides. In an aqueous medium
the mechanism of nitroso group transfer from alkyl ni-
trites or N-nitrososulfonamides to amines takes places
Departamento de Qu ´ı mica F ´ı sica, Facultad de Qu ´ı mica,
Universidad de Santiago
[
9]
1
5782 Santiago, Spain
Departamento de Qu ´ı mica
[
b]
e
Bioqu ´ı mica, Faculdade de
[
10]
[11]
Ciencias e Tecnolog ´ı a, Universidade do Algarbe, Campus de
Gambelas, 8005-139 Faro, Portugal
in a concerted manner (Scheme 3).
614
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300482
Eur. J. Org. Chem. 2004, 614Ϫ622

Nitrosation of Amines in Non-Aqueous Solvents
FULL PAPER
Scheme 1
If the polarity of the solvent, or its capacity to act as a
proton donor in hydrogen bond formation, are decreased,
the concerted mechanism observed in aqueous media is
gradually replaced by a stepwise mechanism, apparently be-
cause the more difficult solvation of the alkoxide leaving
group produces an energy barrier that delays cleavage of
[
13]
the ROϪN bond.
The objective of this study was to investigate the mecha-
nism of nitroso group transfer from N-nitrososulfonamides
to amines of different basicity in cyclohexane. The N-ni-
trososulfonamides used are shown in Scheme 5. By varying
the substituents on the aromatic ring it is possible to modu-
late its reactivity, in such a way that N-nitrososulfonamides
with electron-attracting groups show reactivities in aqueous
Scheme 2
The nitroso group transfer occurs in the slow step and
the protonation of X and deprotonation of N-nitrosamine
occur subsequently. The corresponding reaction mechanism
for nitroso group transfer from alkyl nitrites in non-aque-
ous solvents is different from that found in the aqueous me-
dium.
Ϫ
In non-aqueous solvents the reaction occurs through the
formation of a hydrogen bond complex (HBC) between the
amine and the alkyl nitrite. Subsequently this HBC evolves
0
to form a reaction intermediate (T ) that can decompose
quite spontaneously or by means of a process involving
[
12]
basic catalysis (Scheme 4).
Scheme 5
Scheme 3
Scheme 4
Eur. J. Org. Chem. 2004, 614Ϫ622
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
615

L. Garc ´ı a-R ´ı o, J. R. Leis, J. A. Moreira, D. Serantes
FULL PAPER
medium similar to those of the most activated alkyl nitrites. cases it is possible to observe both first- and second-order
The main difference between the behavior observed in the dependency of kobs on the amine concentration. In contrast
nitrosation of amines by alkyl nitrites and by N-nitrososul- with what occurred in the nitrosation of pyrrolidine by 2-
fonamides derives from the effect on the reaction mecha- bromoethyl nitrite, the results obtained with MN-4-Me-BS
nism exerted by crown ethers. 18-Crown-6 is an efficient and MN-4-MeO-BS do not suggest any change in the rate-
[
14]
catalyst in aminolysis reactions of carboxylic esters
and determining step when the amine concentration varies, nor
also in the nitrosation of amines by alkyl nitrites in cyclo- the existence of hydrogen bond complexes between the am-
hexane. However, addition of 18-crown-6 to the reaction ine and the N-nitrososulfonamide. A simplification of the
medium does not have any effect on the nitrosation of am- mechanism shown in Scheme 4 allows us to explain the ex-
ines by N-nitrososulfonamides. This difference in behavior perimental results shown in Figure 2, which would be com-
indicates a difference between the donors RϪNϪNϭO and patible with a nitroso group transfer mechanism through
RϪOϪNϭO in their nitroso group transfer reaction the formation of an addition intermediate, where the rate-
mechanisms in cyclohexane. The experimental results ob- determining step was the spontaneous or the base-catalyzed
tained in this study indicate that the transfer of the nitroso decomposition of the intermediate.
group from N-nitrososulfonamides to amines in cyclohex-
ane occurs through a concerted mechanism without the for-
mation of addition intermediates.
Results
1. Aminolysis of Alkyl Nitrites Catalyzed by Crown
Ethers: The results in Figure 1 show the influence of pyr-
rolidine on kobs in nitrosation by 2-bromoethyl nitrite. The
complex dependency of k
on amine concentration has
obs
[
12a]
been interpreted
in terms of the mechanism shown in
Scheme 4. For small amine concentrations the rate-limiting
step is the decomposition of the addition intermediate,
either spontaneously, or by a process involving basic cataly-
sis by a second amine molecule. This behavior is responsible
for the first- and second-order dependency of kobs on the sation by (·)MN-4-Me-BS and (o)MN-4-MeO-BS at 25 °C in cyclo-
pyrrolidine concentration. As the amine concentration in-
Figure 2. Influence of pyrrolidine concentration on kobs for nitro-
hexane; experimental data are fitted to Equation (1) (parameters
in Table 1)
creases, so too does the rate of decomposition of the inter-
mediate, in such a way that the rate-limiting step becomes
the formation of the intermediate. Finally, for high amine
Crown ethers and glymes catalyze the ester aminolysis in
concentrations, kobs tends to reach a maximum value due aprotic solvents such as chlorobenzene, and the catalytic
to the formation of the hydrogen bond complex between effect is due to complexation between the crown ether and
the amine and the alkyl nitrite.
the zwitterionic adduct. The rate law for butylaminolysis of
Figure 2 shows the experimental behavior inferred from phenyl acetates in the presence of 18-crown-6 is first order
study of the nitrosation of pyrrolidine by two N-nitrososul- both in butylamine and in 18-crown-6 concentration, which
fonamides: MN-4-Me-BS and MN-4-MeO-BS. In both requires the crown to be involved in the rate-limiting step
[
15]
and also in the transition state. The reaction mechanism
involves rate-limiting expulsion of phenolate ion from the
zwitterionic adduct-crown complex. Earlier studies on the
butylaminolysis of phenyl acetate and 4-nitrophenyl acetate
in acetonitrile show that the presence of 18-crown-6 cata-
lyses the first reaction but not the second. This difference
in behavior has been interpreted in terms of a mechanism
involving a common zwitterionic adduct, which presents
two decomposition pathways: (i) direct expulsion of the
phenolate ion leaving group and (ii) proton transfer prior
to phenolate ion expulsion. Formation of the zwitterionic
adduct is rate-limiting for path (i) and CϪOAr bond fission
[
16]
is rate-limiting for mechanism (ii).
Figure 3 shows the results obtained from examination of
the influence of the 18-crown-6 concentration on kobs in the
nitrosation of pyrrolidine by 2-bromoethyl nitrite and by
MN-4-Me-BS. A study on the influence of the concen-
Figure 1. Influence of pyrrolidine concentration on kobs for nitro-
sation by 2-bromoethyl nitrite at 25 °C in cyclohexane
616
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Eur. J. Org. Chem. 2004, 614Ϫ622

Nitrosation of Amines in Non-Aqueous Solvents
FULL PAPER
tration of 18-crown-6 on kobs in nitrosation of pyrrolidine sation by MN-4-Me-BS and MN-4-MeO-BS. In all cases
by 2-bromoethyl nitrite was carried out by use of a concen- we can observe the existence of linear and quadratic depen-
Ϫ3
Ϫ3
tration of pyrrolidine [PYR] of 1.43 ϫ 10 mol·dm . As dency of kobs on the [PYR] [Equation (1)].
shown in Figure 1, this concentration of pyrrolidine corre-
sponds with a situation in which the rate-limiting step of the
k
obs ϭ a[R
2
NH] ϩ b[R
2
NH]2
(1)
reaction is the decomposition of the addition intermediate,
either spontaneously or by basic catalysis. The results show
that the value of kobs increases as the [18-crown-6] does,
tending towards a maximum value. This maximum value
must correspond with experimental conditions under which
the rate-limiting step changes, which will give rise to the
formation of the addition intermediate. Moreover, its pro-
cess will not be catalyzed by the 18-crown-6. Figure 3 also
shows that there is no effect on kobs in the nitrosation of
pyrrolidine by MN-4-Me-BS derived from the addition of
Table 1 shows the values of the parameters a and b ob-
tained by variation of the nature of the amine and of the
nitrosating agent. As can be seen, the values of the param-
eters a and b increase together with the electron-attracting
substituents on the nitrosating agents, and also when the
basicity of the amine increases.
On studying the nitrosation of PYR and other less basic
amines by alkyl nitrites, similar experimental behavior was
found for small concentrations of amines. As the concen-
18-crown-6. This behavior is consistent with a rate-de-
termining step other than the decomposition of an addition
intermediate. The obtained results therefore show the differ-
ence between the nitroso group transfer mechanism from
donors RϪOϪNϭO and RϪNϪNϭO in cyclohexane.
Ϫ2
tration of the amine increases ([amine]Ͼ5 ϫ 10
Ϫ3
mol·dm ), however, it can be observed that kobs tends
towards a maximum value. This result had been interpreted
in terms of the formation of a hydrogen bond complex be-
tween the alkyl nitrite and the amine. In the nitrosation of
amines by N-nitrososulfonamides this tendency cannot be
observed even for concentrations of amines higher than
2. Influence of the Amine Concentration: Figure 2 shows
the experimental results obtained from examination of the
influence of the concentration of PYR on kobs in its nitro-
0.50 .
3. Influence of the Temperature: Figure 4 shows the re-
sults obtained from examination of the nitrosation of pip-
eridine by MN-4-Cl-BS at T ϭ 25 and T ϭ 35 °C. As can
be observed, the values of kobs increase together with the
temperature independently of the concentration of amine
used. The experimentally obtained values for kobs were fit-
ted to Equation (1), and the parameters are shown in
Table 1. The values of the parameters a and b increase with
Ϫ4
the temperature, providing [a ϭ (7.8Ϯ0.5) ϫ 10 and b ϭ
Ϫ3
Ϫ3
(
1.6Ϯ0.3) ϫ 10 ] at T ϭ 25 °C and [a ϭ (1.6Ϯ0.3) ϫ 10
Ϫ3
and b ϭ (3.9Ϯ0.5) ϫ 10 ] at T ϭ 35 °C.
The observed Arrhenius behavior contrasts with the re-
sults of previous studies of the nitrosation of amines by
[
12a]
alkyl nitrites in cyclohexane.
The existence of a hydro-
Figure 3. Influence of 18-crown-6 concentration on kobs for nitro-
sation of pyrrolidine by (o) 2-bromoethyl nitrite, [PYR] ϭ 1.43 ϫ
gen bond complex in the nitrosation of amines by alkyl ni-
trites had been shown kinetically by the existence of anti-
Arrhenius behavior when the influence of the temperature
Ϫ3
Ϫ3
Ϫ2
10
mol·dm , and (·) MN-4-Me-BS, [PYR] ϭ 8.00 ϫ 10
Ϫ3
mol·dm , at 25 °C in cyclohexane
Table 1. Values of the parameters a and b obtained from Equation (1) for the nitrosation of secondary amines by N-nitrososulfonamides
under different experimental conditions
Ϫ1 Ϫ1
Ϫ2 Ϫ1
Reaction
T/°C
a/
s
b/M s
PYR ϩ MN-4-MeO-BS
PYR ϩ MN-4-Me-BS
PYR ϩ MN-4-Me-BS
PYR ϩ MN-4-Cl-BS
25
25
25
25
25
25
25
25
25
25
35
(4Ϯ2) ϫ 10Ϫ5
(3.7Ϯ0.3) ϫ 10
(3.2Ϯ0.9) ϫ 10
(8.6Ϯ0.5) ϫ 10Ϫ4
(1.46Ϯ0.06) ϫ 10
Ϫ4
Ϫ4
Ϫ3
[
a]
Ϫ3
(1.0Ϯ0.2) ϫ 10
(1.84Ϯ0.07) ϫ 10
1.32Ϯ0.08
Ϫ2
Ϫ2
(1.18Ϯ0.03) ϫ 10
0.206Ϯ0.006
0.16Ϯ0.02
PYR ϩ MN-4-NO
PYR ϩ MN-4-NO -BS
2
-BS
2
[
a]
1.1Ϯ0.2
(7Ϯ1) ϫ 10
Ϫ2
Ϫ2
PIPER ϩ MN-4-NO
MePIP ϩ MN-4-NO
2
-BS
-BS
(4.3Ϯ0.3) ϫ 10
Ϫ3
Ϫ2
2
(6.2Ϯ0.9) ϫ 10
(1.4Ϯ0.2) ϫ 10
Ϫ3
Ϫ3
MOR ϩ MN-4-NO
2
-BS
(1.9Ϯ0.1) ϫ 10
(1.8Ϯ0.2) ϫ 10
Ϫ4
Ϫ3
PIPER ϩ MN-4-Cl-BS
PIPER ϩ MN-4-Cl-BS
(7.8Ϯ0.5) ϫ 10
(1.6Ϯ0.3) ϫ 10
Ϫ3
Ϫ3
(1.6Ϯ0.3) ϫ 10
(3.9Ϯ0.5) ϫ 10
[
a]
N-Deuterated amine.
Eur. J. Org. Chem. 2004, 614Ϫ622
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L. Garc ´ı a-R ´ı o, J. R. Leis, J. A. Moreira, D. Serantes
FULL PAPER
Figure 4. Influence of piperidine concentration on kobs for nitro-
sation by MN-4-Cl-BS at (·) T ϭ 35 °C and (o) T ϭ 25 °C in
cyclohexane; experimental data are fitted to Equation (1) (param-
eters in Table 1)
Figure 5. Influence of isopropylamine concentration on kobs for
nitrosation of piperidine by MN-4-Cl-BS at 25 °C; [PIPER] ϭ
Ϫ3
0.50 mol·dm
k
obs ϭ Intecept ϩ Slope[iPrNH
2
]
(2)
on the reaction rate is studied. This anti-Arrhenius behavior
is compatible with the tendency of kobs on reaching a maxi-
mum value for high concentrations of amine. The results
Figure 6 shows the influence of the concentration of
obtained from study of the nitrosation of amines by N-ni- morpholine on kobs in its nitrosation by MN-4-NO -BS in
2
Ϫ3
trososulfonamides therefore suggest the absence of hydro- the presence ([iPrNH ] ϭ 0.20 mol·dm ) and in the ab-
2
gen bond complexes between the N-methyl-N-nitrosoben- sence of iPrNH . The obtained results show that the quad-
2
zenesulfonamides and the amines.
ratic term of Equation (1) disappears. On the basis of the
Ϫ3
4. Influence of Isopropylamine Addition: A study on the linear dependence we can obtain a slope of 3.05 ϫ 10
Ϫ2
6 Ϫ1
influence of the addition of a highly basic and only slightly mol ·dm ·s . An analogous result was obtained from
reactive amine, such as isopropylamine (iPrNH ), to the re- investigation of the influence of the concentration of piperi-
2
action medium was carried out. Two types of experiments dine on kobs in its nitrosation by MN-4-Cl-BS in the pres-
Ϫ3
were carried out: firstly, on the influence of the addition of ence of [iPrNH ] ϭ 1.00 mol·dm (not shown). In this case
2
Ϫ3
isopropylamine to the reaction medium, during which the we obtain a linear plot with an slope of 2.23 ϫ 10
Ϫ2
6 Ϫ1
concentration of the secondary amine remained constant, mol ·dm ·s
and secondly, on the influence of the concentration of sec- 5. Influence of Isotopic Substitution: The results obtained
ondary amine in the presence of a high concentration of from study of the influence of the concentration of iPrNH2
isopropylamine. suggest that the rate-limiting step is susceptible to basic ca-
.
Figure 5 shows the influence of the concentration of talysis. To confirm this hypothesis we studied the effect of
iPrNH on the nitrosation of piperidine by MN-4-Cl-BS, isotopic substitution on kobs. Figure 7 shows the influence
2
the concentration of piperidine being kept constant of the concentration of pyrrolidine. The experimentally ob-
(
[PIPER] ϭ 0.5 mol·dmϪ3). We can observe a clear linear tained results were fitted to Equation (1), giving the values
dependency of kobs on the concentration of iPrNH added of the parameters a and b shown in Table 1. The results show
2
to the reaction medium [Equation (2)]. On the basis of this the existence of a primary isotopic effect on the terms a and
linear representation and other analogous plots obtained in b as much in the nitrosation of PYR by MN-4-Me-BS
the nitrosation of piperidine by MN-4ϪNO -BS (a /a ϭ 1.16 and b /b ؍1.4) as in the nitrosation of
2
H
D
H
D
Ϫ2
Ϫ3
(
[PIPER] ϭ 9.99 ϫ 10 mol·dm ) and for the nitrosation PYR by MN-4-NO -BS (a /a ϭ 1.29 and b /b ϭ 1.2).
of morpholine by MN-4ϪNO -BS ([MOR] ϭ 9.92 ϫ 10
2 H D H D
Ϫ2
These results are consistent with the existence of proton
transfer in the rate-limiting step.
2
Ϫ3
mol·dm ) we obtain the values shown in Table 2.
Table 2. Values of the slopes obtained from Equation (2) from study of the influence of the isopropylamine concentration on the
nitrosation of piperidine and morpholine by MN-4-Cl-BS and MN-4-NO
2
-BS at T ϭ 25 °C under different experimental conditions
Slope, molϪ1·dm ·s
3
Ϫ1
Ϫ3
Ϫ4
MN-4-Cl-BS
[PIPER] ϭ 0.50 mol·dm
(4.7Ϯ0.3) ϫ 10
Ϫ2
Ϫ3
Ϫ3
Ϫ4
MN-4-NO
MN-4-NO
2
-BS
-BS
[PIPER] ϭ 9.99 ϫ 10 mol·dm
[MOR] ϭ 9.92 ϫ 10 mol·dm
(3.2Ϯ0.3) ϫ 10
(6.4Ϯ0.3) ϫ 10
Ϫ2
Ϫ3
2
618
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 614Ϫ622

Nitrosation of Amines in Non-Aqueous Solvents
FULL PAPER
(Scheme 6), since no evidence has been found of the forma-
tion of a hydrogen bond complex between the amines and
the N-nitrososulfonamides.
The reaction mechanism may take place through an ad-
0
dition intermediate (T ), the decomposition of which, either
by a spontaneous pathway (k ) or by a base-catalyzed pro-
2
cess (k ), may be rate-limiting. However, the results shown
3
in Figure 3 indicate that there is no catalysis by 18-crown-
6, in contrast with what is found for the nitrosation of pyr-
rolidine by 2-bromoethyl nitrite.
The absence of catalysis by 18-crown-6 in the aminolysis
of carboxylic esters was interpreted by Williams[ as a
consequence of the existence of a reaction mechanism in
which the rate-limiting step is the formation of a reaction
16]
Figure 6. Influence of morpholine concentration on kobs for nitro-
sation of morpholine by MN-4-NO
2
-BS at 25 °C; (·) [iPrNH
2
] ϭ intermediate. This change in the rate-limiting step would be
compatible with an addition-elimination mechanism for the
amine nitrosation by N-nitrososulfonamide. If this is the
case it would be necessary that the formation of the inter-
mediate should show first- and second-order dependency
on the amine concentration. This behavior contrasts with
that observed in the nitrosation of pyrrolidine by 2-bromoe-
thyl nitrite, in which the formation of the addition inter-
mediate only shows first-order dependency on the amine
concentration.
Ϫ3
Ϫ3
1
2
.00 mol·dm and (o) [iPrNH ] ϭ 0 mol·dm in cyclohexane
These results lead us to propose a concerted reaction
mechanism, similar to that operating in an aqueous me-
dium, in which the amine attack on the nitroso group and
the expulsion of the sulfonamide take place simultaneously.
2
. Concerted Mechanism: In the nitrosation of amines by
alkyl nitrites in cyclohexane we can observe a change in
Figure 7. Influence of pyrrolidine concentration on kobs for nitro- the rate-limiting step as the amine concentration is varied
sation of pyrrolidine by MN-4-NO
2
-BS at 25 °C; (·) N-deuterated
[17]
(
Figure 1). For small amine concentrations, the rate-lim-
pyrrolidine and (o) non-deuterated pyrrolidine in cyclohexane
iting step is the decomposition of the addition intermediate
T . As the concentration of the amine increases, the rate-
limiting step is the formation of T . The anions of sulfona-
mides are much better leaving groups that the alkoxides,
0
0
Discussion
The reaction mechanism proposed for the nitroso group given that the pK values of the alcohols are 2Ϫ3 units
a
[
18]
transfer from N-methyl-N-nitrosobenzenesulfonamides to greater than those of the sulfonamides.
This weaker ca-
amines in cyclohexane must be compatible with the exper- pacity to act as a leaving group should be reflected in
imentally obtained results and with the reaction mecha- greater difficulty in the decomposition of the reaction inter-
nisms obtained for this reaction in water and for the nitro- mediate. The balance between the processes of formation
0
sation by alkyl nitrites in water and in non-aqueous sol- and decomposition of T is responsible for a change in the
vents.
rate-limiting step. In aqueous medium the transition states
1. Addition-Elimination Mechanism: The experimentally for amine nitrosation by alkyl nitrites and N-nitrososulfon-
obtained results might suggest the existence of an addition- amides are analogous, the extension of the bond formation
elimination mechanism, such as that presented by alkyl ni- (O···N and N···N) and the bond breaking (O···NϭO and
trites in cyclohexane. This mechanism can be simplified N···NϭO) being similar in the two cases. However, the
Scheme 6
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L. Garc ´ı a-R ´ı o, J. R. Leis, J. A. Moreira, D. Serantes
FULL PAPER
Scheme 7
2-ethoxyethyl nitrite and the MN-4-Me-BS present similar tively, are in the vicinity of the obtained value in aqueous
reactivities. The difference in the pK values of the leaving medium, βnucl. ϭ (0.55Ϯ0.01).
a
groups is approximately three units larger for the alcohol.
From this we can conclude that the nitroso group of the
alkyl nitrites must be more electrophilic that than of the N-
nitrososulfonamides. The inversion in the rate-limiting step
for the nitrosation of amines by alkyl nitrites in cyclohexane
should therefore also be observable for the nitrosation of
amines by N-nitrososulfonamides.
The greater capacity of the anion of the sulfonamide to
act as a leaving group leads us to propose a concerted
mechanism for this reaction. According to Scheme 7, the
nucleophilic attack on the nitroso group will occur con-
certedly with the protonation of the leaving group, through
the formation of a four-center, cyclical transition state,
which is responsible for the linear dependency of kobs on
the amine concentration, or by means of a six-center tran-
The rate constants k and k show a high sensitivity to
1
2
the nature of the leaving group. From the pK values of the
a
sulfonamides obtained in an aqueous medium we can ob-
tain the corresponding Brønsted slopes: α1g ؍ (Ϫ3.5Ϯ0.4)
and α1g ϭ (Ϫ3.1Ϯ0.5) for k and k respectively. These val-
1
2
ues show a greater sensitivity to the nature of the leaving
group than the values obtained in an aqueous medium, α1g
Х Ϫ1.5. The difference may be due to the low capacity of
the cyclohexane to solvate charges, and therefore a modifi-
cation of the pK values of the sulfonamides. The great sen-
a
sitivity of the rate constants k and k to the electron-with-
1
2
drawing substituents is additional evidence in favor of a
concerted mechanism, and against a stepwise mechanism.
Obtained values of α , α Ͻ Ϫ1 are interpreted on the
1g
1g
basis of a concerted nitroso group transfer. Such large val-
ues for Brønsted slopes are easy to explain by considering
that the transnitrosation reaction involves a change in
charge of close to two units at the sulfonamide nitrogen,
from partial positive in the nitroso compound
sition state, responsible for the quadratic dependency of kobs
on the amine concentration.
From the proposed mechanism we can obtain the rate
Equation (3).
ϩ
Ϫ
[
ArϪSO ϪN(CH ) ϭNϪO ] to partial negative in the
2 3
NH]2
Ϫ
k
obsd ϭ k
1
[R
2
NH] ϩ k
2
[R
2
(3) transition state [ArϪSO ϪN(CH ) ]. With a change of
2 3
charge of close to two units in the reaction, in contrast with
only one in the reference reaction (the acid dissociation),
these values become reasonable. This change of charge of
close to two units is only compatible with a concerted
mechanism for nitroso group transfer, so the stepwise
mechanism shown in Scheme 8 can be ruled out.
The existence of two transition states with one or two
amine molecules provides a satisfactory explanation for the
linear and quadratic dependency of kobs on the amine con-
centration. The terms a and b in Equation (1) and Table 1
correspond to the rate constants: a ϭ k and b ϭ k . The
1
2
H
D
The values of the isotopic effects (k /k ϭ 1.29 and
relationship k /k is always less than 1, which shows that
1
1
1
2
H
D
k /k ϭ 1.16 for the nitrosation of pyrrolidine by
MN-4-NO -BS and MN-4-Me-BS and k /k ϭ 1.2 and
k /k ϭ 1.4 for the same reactions) indicate that there is
the six-membered transition state is more favorable that
that with four.
1
1
H
D
2
2
2
H
D
From the data in Table 1 we can obtain the Brønsted
slopes for the rate constants k and k with varying nature
2
2
a proton transfer involved in the rate-limiting step of the re-
action.
1
2
of the amine. The values corresponding to the nitrosation
of piperidine are not included in this correlation, since, as
From study of the nitrosation of piperidine by MN-4-Cl-
also occurs in the aqueous medium, this amine presents a BS at 25 °C and 35 °C, we can estimate the values of the
reactivity very much lower than that which would be ex- activation parameters for the reaction. The obtained results:
pected in view of its pKa.[ The obtained values, βnucl.
10]
ϭ
[∆H ϭ 52.3 kJ·mol and ∆S ϭ Ϫ129 J·mol ·K ] for
#
Ϫ1
#
Ϫ1 Ϫ1
(
0.69Ϯ0.03) and βnucl. ϭ (0.9Ϯ0.1), for k and k , respec- the formation of the transition state in which only one am-
1
2
620
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Eur. J. Org. Chem. 2004, 614Ϫ622

Nitrosation of Amines in Non-Aqueous Solvents
FULL PAPER
Scheme 8
#
Ϫ1
ine molecule intervenes, k , and [∆H ϭ 65.4 kJ·mol and amine than the morpholine, so path k will be more favor-
1
3
#
Ϫ1 Ϫ1
∆
S ؍ Ϫ79 J·mol ·K ] for the transition state in which able than k . However, the iPrNH is less basic than piperi-
2 2
two amine molecules intervene, k , are compatible with the dine, which causes the reaction path k to be more favorable
2
2
existence of highly ordered transition states.[
19]
than k3.
The results in Figure 6 and the analogous results ob-
The proposed concerted mechanism is perfectly compat-
ible with the results obtained from investigation of the in- tained for the nitrosation of morpholine by MN-4-NO -BS
2
fluence of the concentration of iPrNH . As we have seen allow us to calculate the rate constant k thus: k ؍ (Slope
2
3
3
Ϫ3
previously, the formation of a six-centered transition state Ϫ k )/[iPrNH ]. The obtained values Ϫ k ϭ 1.45 ϫ 10
is more common than that with four members. In this way, mol ·dm ·s and k ϭ 5.75 ϫ 10 mol ·dm ·s Ϫ are
1
Ϫ2
2
Ϫ1
3
Ϫ2
6
Ϫ3
6 Ϫ1
3
the effect of the addition of iPrNH2 can be explained compatible with those obtained previously for the nitro-
through the formation of a cyclical transition state of six sation of piperidine and morpholine by MN-4-Cl-BS and
members, as shown below.
MN-4-NO -BS respectively.
2
It is therefore appropriate to adapt the mechanism pro-
posed in Scheme 7 by inclusion of a third path in which a
mixed transition state forms, such as that shown in
Scheme 9. The rate Equation (4) can be written thus:
Conclusions
2
k
obsd ϭ k
1
[R
2
NH] ϩ k
2
[R
2
NH] ϩ k
3
[R
2
NH][iPrNH
2
]
(4)
Nitroso group transfer from N-nitrososulfonamides to
amines in cyclohexane is not catalyzed by 18-crown-6, un-
like what is observed when alkyl nitrites are used as nitro-
sating agents. This behavior has been interpreted in terms
of a concerted reaction mechanism. This change in behavior
from an addition-elimination reaction (alkyl nitrites) to a
concerted mechanism (N-nitrososulfonamides) must be a
consequence of the greater stability presented by the sulfon-
amides as leaving groups.
The concerted mechanism occurs through two parallel
paths, with the formation of two cyclical transition states
of four and of six centers, in which one and two molecules
of the secondary amine are involved. In all cases the six-
Scheme 9
The experimentally obtained results clearly confirm this centered transition state has greater stability than that with
behavior and from the values in Table 2 we can calculate four centers. The reaction rate accelerates as the basicity of
Ϫ2
Ϫ2
6
Ϫ1
Ϫ4
k . The obtained results Ϫ k ϭ 3.2 ϫ 10 mol ·dm ·s
the amine is increased, with a Brønsted slope similar to
those obtained in an aqueous medium. At the same time
3
3
Ϫ2
Ϫ1
3 Ϫ1
(
k ϭ 7.1 ϫ 10 mol ·dm ·s ) and k ϭ 9.4 ϫ 10
2
3
Ϫ2
6
Ϫ1
Ϫ3
Ϫ1
3 Ϫ1
mol ·dm ·s (k ϭ 1.6 ϫ 10 mol ·dm ·s ) for the the reaction rate shows a much greater degree of sensitivity
2
nitrosation of piperidine by MN-4-NO -BS and MN-4-Cl- to the nature of the leaving group than that observed in an
2
Ϫ3
Ϫ2
6 Ϫ1
BS, respectively, and k ϭ 6.45 ϫ 10 mol ·dm ·s (k ϭ aqueous medium, which has been attributed to a variation
.8 ϫ 10 mol ·dm ·s ) for the nitrosation of morph- of two units of charge on the nitrogen atom of the sulfona-
3
2
Ϫ3
Ϫ1
3 Ϫ1
1
oline by MN-4-NO -BS Ϫ show that k Ͼ k for the nitro- mide during the course of the reaction.
2
3
2
sation of morpholine and k Ͻ k for the nitrosation of
The addition of isopropylamine to the reaction medium
3
2
piperidine. Similarly, the difference in reactivity between causes the appearance of a third reaction path through a
MN-4-NO -BS and MN-4-Cl-BS can also be translated to mixed transition state formed by a secondary amine mol-
2
the term catalyzed by iPrNH . The reason for the difference ecule and an iPrNH molecule. The experimental results
2
2
in reactivity between k and k in the nitrosation of piperi- show that the evolution through this six-centered transition
2
3
dine and morpholine should be interpreted by taking into state is either more or less favorable than that occurring
account the fact that the isopropylamine is a more basic through a transition state with two secondary amine mol-
Eur. J. Org. Chem. 2004, 614Ϫ622
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621

L. Garc ´ı a-R ´ı o, J. R. Leis, J. A. Moreira, D. Serantes
FULL PAPER
3
824. [1b] C. W. Su, J. W. Watson, J. Am. Chem. Soc. 1974,
6, 1854.
ecules, depending on the relative basicities of the iPrNH2
and of the secondary amine.
9
[
[
2] [2a]
A. Castro, E. Iglesias, J. R. Leis, M. E. Pe n˜ a, J. V a´ zquez
Tato, J. Chem. Soc., Perkin Trans. 2 1986, 1725. [ J. Casado,
A. Castro, F. Meijide, M. Mosquera, J. V a´ zquez Tato, J. Chem.
Soc., Perkin Trans. 2 1987, 1759.
2b]
Experimental Section
3]
C. Bravo, P. Herv e´ s, E. Iglesias, J. R. Leis, M. E. Pe n˜ a, J. Chem.
Soc., Perkin Trans. 2 1990, 1969.
P. Herv e´ s, J. R. Leis, J. Chem. Soc., Perkin Trans. 2 1995, 2035.
C. Bravo, P. Herv e´ s, J. R. Leis, M. E. Pe n˜ a, J. Chem. Soc.,
Perkin Trans. 2 1991, 2091.
N-Methyl-N-nitrosobenzenesulfonamides were synthesized as de-
[
[
4]
5]
scribed previously.[
11]
N-Methyl-N-nitroso-p-toluenesulfonamide
was supplied by Merck. Cyclohexane (nominal purity Ͼ 99.9%
from Aldrich) was used as supplied. Secondary amines: pyrrolidine
[6]
[
E. Iglesias, L. Garc ´ı a-R ´ı o, J. R. Leis, M. E. Pe n˜ a, D. Williams,
H. Lyn, J. Chem. Soc., Perkin Trans. 2 1992, 1673.
(PYR), piperidine (PIPER), N-methylpiperazine (MePIP) and
7] [7a]
[7b]
morpholine (MOR), all from Aldrich, were of the highest available
purity and were distilled under argon and used shortly afterwards.
N-Deuterated pyrrolidine was prepared by repeated fractional dis-
A. D. Allen, J. Chem. Soc. 1954, 1968.
Ind. J. Chem. Sect. B. 1981, 20, 526.
G. Bhattacharjee,
[
[
8]
9]
D. L. H. Williams, Nitrosation; Cambridge University Press:
Cambridge, 1988.
L. Garc ´ı a-R ´ı o, J. R. Leis, J. A. Moreira, F. Norberto, J. Phys.
Org. Chem. 1998, 11, 756.
tillation of a mixture of the amine with a tenfold molar excess of
O through a 20 cm Vigreux column.[ After at least three runs,
1a]
D
2
the product was dried with calcium hydride, from which it was later
[10]
L. Garc ´ı a-R ´ı o, E. Iglesias, J. R. Leis, M. E. Pe n˜ a, A. Rios, J.
Chem. Soc., Perkin Trans. 2 1993, 11, 756.
L. Garc ´ı a-R ´ı o, J. R. Leis, J. A. Moreira, F. Norberto, J. Org.
Chem. 2001, 66, 381.
12] [12a]
1
distilled. The H NMR spectra of the final product confirmed N-
deuteration. 2-Bromoethyl nitrite was prepared by treatment of the
parent alcohol with sodium nitrite in acid medium. 2-Bromoethyl
nitrite was stored over molecular sieves to prevent its hydrolysis.
[11]
[
L. Garc ´ı a-R ´ı o, J. R. Leis, E. Iglesias, J. Org. Chem. 1997,
12b]
6
2, 4701. [
J. C. Boni, L. Garc ´ı a-R ´ı o, J. R. Leis, J. A. Mor-
In all the kinetic experiments the nitrosating agent concentration
was in deficit, generally ranging from (1Ϫ2) ϫ 10 mol·dm . Re-
action kinetics were monitored by following changes in absorbance
eira, J. Org. Chem. 1999, 64, 8887.
L. Garc ´ı a-R ´ı o, J. R. Leis, E. Iglesias, J. Org. Chem. 1997, 62,
Ϫ4
Ϫ3
[13]
4712.
[
[
14] [14a]
(generally in the 250Ϫ270 nm range for MN-4-MeO-BS, MN-4-
R. D. Gandour, D. A. Walker, A. Nayak, G. R. Newkome,
J. Am. Chem. Soc. 1978, 100, 3608. [
14b]
J. C. Hogan, R. D.
Me-BS, MN-4-Cl-BS, and 2-bromoethyl nitrite and in the
[14c]
Gandour, J. Am. Chem. Soc. 1980, 102, 2865.[
J. C. Hogan,
J. C. Hogan,
290Ϫ340 nm range for MN-4ϪNO
2
-BS) by use of a Varian Cary
14d]
R. D. Gandour, J. Org. Chem. 1992, 57, 55.
500 spectrophotometer equipped with thermostatted cell holders.
R. D. Gandour, J. Org. Chem. 1991, 56, 2821.
The absorbance-time data always show first-order behavior, and
obs, the corresponding pseudo-first-order rate constant, could be
15]
A. B. Maude, A. Williams, J. Chem. Soc., Perkin Trans. 2
995, 691.
A. B. Maude, A. Williams, J. Chem. Soc., Perkin Trans. 2
1997, 179.
In the nitrosation of pyrrolidine by 2-bromoethyl nitrite, for
which the reactivity in water is similar to that of MN-4-Cl-BS,
k
1
reproduced within 3%. Identification of reaction products was con-
firmed from UV spectra of the reactions on completion and in
some cases by HPLC with acetonitrile/water (1:1) as the eluent,
retention times and peak areas being compared with those of the
pure N-nitrosamines. In every case we found quantitative N-nitro-
samine formation compatible with the spectral changes observed
in kinetic experiments.
[16]
[17]
we observe a change in the rate-determining step of the reac-
Ϫ3
tion for amine concentrations lower than 0.05 mol·dm
.
[
[
18]
19]
G. Dauphin, A. Kergomard, Bull. Soc. Chim. Fr. 1961, 5, 486.
As mentioned by one of the reviewers, the activation param-
eters obtained from just two temperatures (25 and 35 °C) are
not generally accurate mainly for the activation entropy. In
Acknowledgments
#
Ϫ1 Ϫ1
fact, a value of ∆S -129 J·mol
K
is obtained for the four-
#
membered transition state whereas a value of ∆S ϭ Ϫ79
Financial
PGIDT00PXI20907PR), Ministerio de Ciencia y Tecnolog ´ı a (Pro-
ject BQU2002Ϫ01184), is gratefully acknowledged.
support
from
the
Xunta
de
Galicia
Ϫ1 Ϫ1
J·mol
K
is obtained for the six-membered transition state.
(
We think that the temperature study showing Arrhenius be-
havior Ϫ in contrast with that observed in the amine nitro-
sation by alkyl nitrites Ϫ is important.
[
1] [1a]
F. M. Menger, J. H. Smith, J. Am. Chem. Soc. 1972, 94,
Received July 31, 2003
622
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