Acid-catalysed chlorine transfer from N-chloramines to iodide ion: Experimental evidence for a predicted change in mechanism

Article abstract of DOI:10.1039/c004976j

Rate constants for acid catalysis of the reactions of N-chlorodimethylamine (1), N-chloro-2,2,2-trifluoroethylamine (2) and N,N-dichlorotaurine (3) with iodide ion were determined in H₂O at 25°C and I = 0.5 (NaClO ₄). The failure to detect significant catalysis by general acids of chlorine transfer from 1 to the nucleophile, together with the observed inverse solvent deuterium isotope effect on the hydronium ion-catalysed reaction (k _H/k_D = 0.37), indicates that this process occurs by protonation of 1 in a fast equilibrium step, followed by rate determining chlorine transfer to iodide ion. The appearance of general acid catalysis for the reactions of 2 and 3 shows that increasing the leaving group ability leads to a change to a concerted mechanism, which is suggested to be enforced by the absence of a significant lifetime of the protonated chloramine intermediate in the presence of iodide ion.

Full text of DOI:10.1039/c004976j

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Acid-catalysed chlorine transfer from N-chloramines to iodide ion:
experimental evidence for a predicted change in mechanism†
Paula Calvo, Juan Crugeiras* and Ana R ´ı os
Received 8th April 2010, Accepted 18th June 2010
First published as an Advance Article on the web 22nd July 2010
DOI: 10.1039/c004976j
Rate constants for acid catalysis of the reactions of N-chlorodimethylamine (1),
N-chloro-2,2,2-trifluoroethylamine (2) and N,N-dichlorotaurine (3) with iodide ion were determined in
◦
H
2
O at 25 C and I = 0.5 (NaClO
4
). The failure to detect significant catalysis by general acids of
chlorine transfer from 1 to the nucleophile, together with the observed inverse solvent deuterium isotope
effect on the hydronium ion-catalysed reaction (k /k = 0.37), indicates that this process occurs by
H
D
protonation of 1 in a fast equilibrium step, followed by rate determining chlorine transfer to iodide ion.
The appearance of general acid catalysis for the reactions of 2 and 3 shows that increasing the leaving
group ability leads to a change to a concerted mechanism, which is suggested to be enforced by the
absence of a significant lifetime of the protonated chloramine intermediate in the presence of iodide ion.
Introduction
chlorotaurine (4) with iodide ion and less reactive nucleophiles
proceeds by a stepwise mechanism, with proton transfer to the
The amino groups in amino acids and in protein side chains
are believed to be potential targets for electrophilic halogenating
compounds generated as microbiocidal agents at the active site of
leaving nitrogen atom taking place in an initial equilibrium step
13
(
Scheme 1). However, chlorination of highly reactive nucle-
ophiles, such as the anion of 2-mercaptoethanol, undergoes a
concerted mechanism of general acid catalysis. This shows that
increasing the reactivity of the nucleophile results in a change from
a two step mechanism, that proceeds through a N-protonated
chloramine intermediate, to a concerted mechanism involving
protonation of the chloramine at nitrogen and chlorine transfer
in a single step (Scheme 1). The observed change in mechanism
appears to be enforced by the lack of a significant lifetime for the
intermediate in the presence of very reactive nucleophilic species.
1–3
heme-dependent peroxidases present in phagocytic cells. The
N-haloamines formed as a result of these reactions retain a
significant oxidizing activity, being able to transfer the halogen to
a wide range of nucleophilic groups present in biological systems.
A lysine chloramine intermediate has also been postulated as
the chlorinating agent in the formation of 7-chlorotryptophan
4,5
catalysed by a flavin-dependent halogenase. The important role
6
played by chloramines in the human immune defense system,
together with their proposed involvement as intermediates in
7
biological pathways to chlorinated molecules, shows the need
for a detailed understanding of their chemical reactivity, which is
the basis for their biological activity.
The chemistry of N-chloramines in aqueous solution has been
8
explored extensively, but comprehensive mechanistic studies of
their chlorine transfer reactions are scarce. It has been shown,
9–11
mainly through the work of Margerum et al.,
that chlorine
transfer from chloramines to electron rich substrates is subject to
acid catalysis, and this reflects the fact that protonation at nitrogen
before or during the rate determining step is required to avoid the
formation of an unstable amine anion. However, there is currently
no clear understanding of the mechanism, stepwise or concerted,
by which assistance to leaving group departure occurs in each case
and the conditions that determine a change from one mechanism
to the other.
Scheme 1
We suggest here that it should be possible to find experimental
evidence for a similar change in mechanism for chlorine transfer
to iodide ion on moving from the chloramines of basic amines to
less stable chloramines bearing electron-withdrawing substituents.
This is because a decrease in the basicity of the leaving amine
will result in an increasing destabilisation of the protonated
chloramine, which should favour reaction through a concerted
mechanism that avoids its formation. In earlier studies of this
reaction, the observation of weak buffer catalysis for chloramines
with poor amine leaving groups led to the conclusion that
We are interested in characterizing the mechanisms of chlorine
12–14
transfer from N-chloramines to nucleophilic reagents
and
have recently reported that the acid-catalyzed reaction of N-
Departamento de Qu ´ı mica F ´ı sica, Facultad de Qu ´ı mica, Universidad de
Santiago de Compostela, 15782 Santiago de Compostela, Spain. E-mail:
juan.crugeiras@usc.es
simultaneous chlorine and proton transfer occur in the rate
In contrast to these results, we were unable
to detect general acid catalysis of the reaction of 4 with iodide
†
Electronic supplementary information (ESI) available: Tables S1–S3:
Second-order rate constants for chlorine transfer from the N-chloramines
O. See
10,15,16
determining step.
1
, 2 and 3 to iodide ion in the presence of buffer solutions in H
2
13
DOI: 10.1039/c004976j
ion.
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We describe here a study of chlorine transfer to iodide ion from
Table 1 Third-order rate constants for the acid-catalyzed reaction of
a
iodide ion with the N-chloramines 1–4 in water
N-chlorodimethylamine (1), N-chloro-2,2,2-trifluoroethylamine
◦
(
2) and N,N-dichlorotaurine (3) (Scheme 2) in H
2
O at 25
C
b
k
or kAH/M-2 s-1
Acid catalyst
pK
a
Chloramine
H
and I = 0.5 (NaClO
4
). These experiments were carried out for
+
3
10
the purpose of examining possible changes in mechanism brought
about by changes in leaving group ability.
H O
-1.7
1
2
(2.69 ± 0.08) ¥ 10
1
0
(
7.24 ± 0.12) ¥ 10
(D
2
2
O)
O)
8
(1.52 ± 0.07) ¥ 10
8
(
1.795 ± 0.013) ¥ 10 (D
5
3
4
(2.05 ± 0.10) ¥ 10
9
9
c
c
(4.6 ± 0.1) ¥ 10
8.5 ± 0.2) ¥ 10
(
(D
2
O)
4
3
3
2
Cl
ClCH
CH
CH
2
CHCOOH
COOH
OCH
COOH
1.1
2.6
3
3
3
3
2
3
3
(5.32 ± 0.13) ¥ 10
(3.54 ± 0.05) ¥ 10
(1.79 ± 0.04) ¥ 10
(3.58 ± 0.04) ¥ 10
2
3
3
2
COOH 3.4
4.6
6.5
-
2
H
2
PO
4
(3.8 ± 0.2) ¥ 10
Scheme 2
2
(1.21 ± 0.02) ¥ 10
(2.27 ± 0.14) ¥ 10
-
1
H
2
O
15.7
a
◦
b
At 25 C and I = 0.5 (NaClO
4
). Apparent pK
a
of the acid catalyst in
Results and discussion
◦
c
2
H O at 25 C. Data from ref. 13
1
Observed second-order rate constants, (k
2
)
obsd (M- s-1), for the
-
reaction of I with 1, 2 and 3, in aqueous perchloric acid solutions
Fig. 1 (᭺) also shows the pD-rate profile for the reaction of iodide
◦
◦
or in the presence of buffers at 25 C and I = 0.5 (NaClO
4
), were
ion with 1 in D
2
O at 25 C and I = 0.5 (NaClO
4
). The solid line
-
1
determined as the slopes of linear plots of kobsd (s ) against the
through the data shows the fit to eqn (1) (L = D), which gives k =
D
-
1
0
-2 -1
-
concentration of iodide ion (not shown) or as (k
Table S1 of the ESI† shows the dependence of (k
transfer from 1 to iodide ion on the concentration of acetate (pH =
.5 or 5.1), phosphate (pH = 5.5 or 6.5) or borate (pH = 8.3)
buffers. No general acid catalysis of this reaction was observed in
.02–0.2 M acetate and 0.01–0.1 M phosphate or borate buffers.
2
)
obsd = kobsd/[I ].
(
1
7.24 ± 0.12) ¥ 10 M s for the acid-catalysed reaction of I with
in D O (Table 1). Combination of the two rate constants gives a
solvent deuterium isotope effect on the hydronium ion-catalysed
reaction of k /k = (0.37 ± 0.01). The absence of detectable
2
)obsd for chlorine
2
4
H
D
catalysis by general acids, together with the inverse nature of this
isotope effect, indicates that chlorine transfer to iodide ion occurs
through a mechanism involving pre-equilibrium protonation of
0
Small changes in the observed rate constants with increasing the
buffer concentration were accounted for by parallel small changes
1
followed by the reaction of the protonated chloramine with
-
1
-1
in solution pH. The second-order rate constants (k
are therefore equal to the rate constants (k for catalysis of this
reaction by solvent species only. Fig. 1 (᭹) shows the pH-rate
2
)obsd (M s )
the nucleophile (Scheme 3). The observed isotope effect is the
consequence of a large inverse solvent isotope effect on the pre-
equilibrium combined with a small isotope effect on the rate
)
2 o
17
profile of (k
2
)
o
for the reaction of iodide ion with 1, where (k
2
) =
o
determining chlorine transfer. A second-order rate constant,
+
-2 -1
9
-1 -1
-
k
H
[H
3
O ] and k (M s ) is the third-order rate constant for the
H
k
I
= 5.4 ¥ 10 M s , for the reaction of I with protonated N-
chlorine transfer reaction catalysed by hydronium ion. The solid
chlorodimethylamine (1-H) was determined from the relationship
line shows the fit of the data to eqn (1) (L = H), which gives k
H
=
k
H
= k
I
/K
= 0.2 M
a
, derived for Scheme 3, using the observed value of k
H
1
0
-2 -1
-
18,19
(
2.69 ± 0.08) ¥ 10
M
s
for the acid-catalysed reaction of I
and K
a
for ionization of 1-H.
with 1 (Table 1). This value agrees, to within 24%, with a value
16
reported in earlier work.
log(k
2
)
o
= logk
L
- pL
(1)
Scheme 3
We have recently reported that the reaction of N-chlorotaurine
4) with iodide ion proceeds by a stepwise mechanism through a
(
N-protonated chloramine intermediate (4-H) (Scheme 3), which
is consistent with the inverse solvent deuterium isotope effect
13
+
k
H
/k
D
= 0.54 observed for this reaction. Catalysis by H O of
3
chlorine transfer from 4 to iodide ion must correspond to specific
acid catalysis because proton transfer from the catalyst to the
chloramine nitrogen atom is thermodynamically favourable.
A change in the leaving group from taurine to the more basic
dimethylamine results in a larger stability of the protonated
chloramine that will favour the reaction through a stepwise
mechanism. We suggest that the reaction of iodide ion with
1
Fig. 1 pL-rate profiles of (k
2
)
o
(M- s-1) for the reaction of iodide ion with
20,21
◦
N-chloramines at 25 C and I = 0.5 (NaClO
4
). The solid symbols show
O. The open
data for 1 (᭹), 2 (ꢀ), 3 (ꢀ) and 4 (᭢, data from ref. 13) in H
2
symbols show data for 1 (᭺), 2 (ꢀ) and 4 (ꢁ, data from ref. 13) in D
2
O.
The solid lines through the data show the fits to eqn (1) for 1, 2 and 4, and
to eqn (4) for 3 (see text).
4
138 | Org. Biomol. Chem., 2010, 8, 4137–4142
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chloramines of amines more basic than taurine must involve spe-
cific acid catalysis, because the pK of the protonated chloramine
intermediate is larger than pK = -1.7 for H
a
+
a
3
O . The experimental
data reported here for N-chlorodimethylamine are consistent with
-
this conclusion. The reactions of 1-H and 4-H with I are diffusion
9
-1 -1
limited, with k
I
ª 5 ¥ 10 M s . An estimate of the rate constant
for the reaction of protonated chlorodimethylamine with iodide
ion in an encounter complex, k
I
¢, can be made from an association
Scheme 5
-
1
22
constant Kass £ 1 M for formation of the ion pair, which gives
9
-1
11
-1
Table S2 of the ESI† gives the dependence of (k2)obsd
for the
k
-d ≥ 5 ¥ 10 s and, therefore, k
I
¢ ≥ 10
s
for the reaction
reaction of 2 with iodide ion on the concentration of buffers.
An increase in the total concentration of buffer from 0.01 to
0.1 M results in small changes in solution pH (DpH £ 0.08)
which complicate the detection of weak general acid catalysis.
After correction of the observed rate constants for these changes
in pH, small catalytic effects of up to 9% over the background
hydronium ion-catalysed reaction were found in the presence of
substituted acetic acids in the concentration range 0.01–0.1 M.
The observed rate enhancements were too small to obtain reliable
to be diffusion limited (Scheme 4). This suggests that decreasing
the basicity of the leaving amine could make this rate constant
1
3
-1
larger than 10
s
for a bond vibration. In this situation, the
ion pair has no lifetime and the reaction must proceed through
23
a pre-association concerted mechanism. We predict a change
in mechanism from stepwise to concerted on going from N-
chlorotaurine to chloramines with less basic leaving groups.
-
2
-1
values of the catalytic rate constants, kHA (M s ), for these acids.
A somewhat larger effect was observed for the weaker catalyst,
phosphate monoanion (ca. 40% in 0.01–0.1 M buffers, 50% acid).
Scheme 4
Fig. 2 (᭹) shows a plot of the normalised rate constant krel
=
1
+
Table S2 of the ESI† gives values of (k
2
)
obsd (M- s-1) for chlorine
(k
[H
2
)
obsd/k
H
[H
3
O ] for the reaction of 2 with iodide ion against
-
+
transfer from 2 to iodide ion in the presence of chloroacetate
pH 3.2), methoxyacetate (pH 3.3), acetate (pH 4.5), phosphate
pH 6.5) and borate (pH 8.3) buffers at 25 C and I = 0.5 (NaClO
2
PO
4
]/[H
3
O ] according to eqn (3). A value of kHA = (3.8 ±
2
-2
-1
(
(
0.2) ¥ 10 M
phosphate monoanion was determined from the slope of this plot
and the value of k given in Table 1.
s
for general acid catalysis of this reaction by
◦
4
).
The values of (k
2
)
obsd for the reaction in the presence of 0.01 M
for the
H
buffer are essentially equal to the rate constants (k
)
2 o
(
k2 )obsd
kHA [HA]
reaction catalysed by solvent species only, because there is no
significant general acid catalysis of chlorine transfer at this low
krel
=
=1+
(3)
+
+
k [H O ]
kH [H O ]
H
3
3
buffer concentration ((k
that (k
2
)
o
ꢀ kHA[HA], eqn (2)). Fig. 1 (ꢀ) shows
+
2
)
o
increases with increasing [H
3
O ] due to the acid-catalysed
nature of the chlorine transfer reaction. A value of k
H
= (1.52 ±
8
-2 -1
0.07) ¥ 10 M
s
for the acid-catalysed reaction of iodide ion
with 2 was calculated from the fit of the data to eqn (1) (L = H),
which is shown as a solid line through the data in Fig. 1. Similarly,
8
-2 -1
a value of k
D
= (1.795 ± 0.013) ¥ 10 M
s
for this acid-catalysed
reaction in D
2
O was determined from the fit of the data in this
solvent (Fig. 1, ꢀ) to eqn (1) (L = D).
(
k
2
)
obsd = (k
2
)
o
+ kHA[HA]
(2)
The acidity constant of protonated 2 is not known, but there
is good evidence that the introduction of a chlorine atom at
2
4
the nitrogen of an amine lowers its pK
combination of the observed rate constant k
a
by ca. 9–10 units.
A
s
8
-2 -1
H
= 1.52 ¥ 10 M
for the hydronium ion-catalysed reaction of 2 with an estimated
25
11
-1 -1
pK
a
of -3 for 2-H leads to k ª 10 M s for chlorine transfer
I
from 2-H to iodide ion (Scheme 3), which is an order of magnitude
Fig.
2
Dependence of the normalised rate constant
k
]/[H
rel
=
O ]
9
-1 -1
above the experimentally observed value of 5 ¥ 10 M
s for the
+
-
+
(
k
2
)
obsd/k
H
[H
3
O ] for chlorine transfer to iodide ion on [H
2
PO
4
3
encounter-limited reactions of 1-H and 4-H with this nucleophile.
This shows that 2-H is not involved as a free solvent-equilibrated
intermediate in the acid-catalysed reaction of this chloramine
and it suggests that the reaction is forced to proceed through a
mechanism involving an initial association of the reactants and
catalyst into a ternary encounter complex (Kass, Scheme 5). This
◦
in phosphate buffers at 25 C and I = 0.5 (NaClO
pH 5.6–6.5. (᭹) Reaction of 2 at pH 6.5.
4
). (ꢀ) Reaction of 1 at
The lack of significant general acid catalysis of chlorine transfer
from 1 to iodide ion (see data for phosphate monoanion in
Fig. 2, ꢀ) is consistent with a stepwise pathway through the
protonated intermediate 1-H (Scheme 3). The detection of weak
general acid catalysis for the reaction of 2 provides evidence for
a change to a mechanism in which proton transfer occurs in the
pre-association mechanism may be stepwise (through k
p
and k¢Nu)
or concerted (through kNu) depending on the lifetime of the triple
-
@
+
-
21,23
ion complex [I · NHCl ·A ].
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rate determining step. These results show that the acid-catalysed
transfer of chlorine from 2 to iodide ion proceeds through either a
stepwise pre-association mechanism, with protonation at nitrogen
(k , Scheme 5) rate limiting, or a concerted mechanism (kNu,
p
Scheme 5). The observed weak catalytic effect suggests that proton
transfer is well advanced in the transition state. A lower limit of
the Brønsted coefficient a ≥ 0.72 was calculated as the slope of a
+
Brønsted line through the statistically corrected data for H
3
O and
-
H
2
PO
4
. However, the nitrogen atom of the chloramine is likely
to take on a partial positive charge in the transition state. This
would result in significant electrostatic interactions between the
developing positive charge at nitrogen and the charges on these
catalysts in the transition state, leading to a negative deviation of
-
k
H
and a positive deviation of k 2
H
PO from the Brønsted correlation
4
for protonation of the chloramine by neutral acids. Therefore, the
a value for neutral catalysts may be significantly larger than the
estimated value of 0.72.
Additional evidence for a change in mechanism comes from
the observed increase in solvent deuterium isotope effect from
k
to k
H
/k
D
= 0.37 and 0.54 for the reactions of 1 and 4, respectively,
/k = (0.85 ± 0.04) for the reaction of 2. The latter is
H
D
larger than the isotope effect in the range 0.3–0.5 that would be
expected if protonation of the substrate occurs in a fast equilibrium
26,27
preceding the rate determining step.
The value of k
H
D
/k =
0
.85 is in accord with a mechanism involving rate determining
proton transfer from the hydronium ion to the nitrogen atom of
the chloramine. The inverse nature of this isotope effect comes
from the combination of a weak primary isotope effect in the
normal direction for a product-like transition state with a large
inverse secondary component due to the tightening of the two
+
17
non-reacting bonds in L
3
O on moving to a late transition state.
Table S3 in the ESI† shows that the second-order rate constants,
(k )
obsd (M- s ), for the reaction of iodide ion with 3 increase with
1
-1
2
increasing the concentration of substituted acetate or phosphate
buffers in the range 0.04–0.4 M and 0.02–0.15 M, respectively.
Fig. 1 (ꢀ) gives the dependence on pH of the second-order
Fig. 3 General acid catalysis by substituted acetic acids of the reaction
◦
of iodide ion with 3 at 25 C and I = 0.5 (NaClO
4
). (A) Catalysis by
-
1
-1
Cl
(B) Catalysis by ClCH
Catalysis by CH OCH
by CH CO
2
CHCO
2
H. Fraction of buffer acid, f AH = 0.8 (᭹), 0.5 (ꢀ), 0.2 (ꢀ).
rate constants for the solvent-catalysed reaction, (k
2
) (M s ),
o
-
1
-1
2
CO
CO
2
H. f AH = 0.7 (᭹), 0.5 (ꢀ), 0.3 (ꢀ), 0.2 (᭜). (C)
H. f AH = 0.8 (᭹), 0.5 (ꢀ), 0.2 (ꢀ). (D) Catalysis
obtained as the intercepts of linear plots of (k )obsd (M s ) against
2
3
2
2
the total buffer concentration (not shown). The pH-rate profile
shows a region of slope -1.0 at pH < 3.5 which corresponds to
3
2
H. f AH = 0.8 (᭹), 0.7 (ꢀ), 0.5 (ꢀ), 0.3 (᭜), 0.2 (᭢).
the hydronium ion-catalysed chlorine transfer to iodide ion. A
+
value of the third-order rate constant for catalysis by H
3
O of the
the slopes of the linear plots in Fig. 3. This set of rate constants
follows a Brønsted plot with a = 0.61, as shown in Fig. 4. A
similar treatment of the data for catalysis by phosphate buffers
5
-2
-1
reaction of iodide ion with 3, k
Table 1), was determined from the fit of the data at pH < 3.5 to
eqn (1) (L = H). At higher pH, chlorine transfer proceeds by a
pH-independent pathway and the average value of (k at pH >
as the second-order rate constant
H
= (2.05 ± 0.10) ¥ 10 M
s
(
2
-2 -1
gives kHA = (1.21 ± 0.02) ¥ 10 M
monoanion. This catalytic rate constant and that for H O show
s
(Table 1) for phosphate
+
2
)
o
3
-
1
-1
4
.5 gives k
o
= (12.6 ± 0.8) M
s
significant deviations from the Brønsted correlation defined by
the neutral substituted acetic acids, which can be attributed to
electrostatic interactions between these charged catalysts and the
developing positive charge on nitrogen in the transition state.
for the solvent-catalysed reaction. The solid line through the data
in Fig. 1 shows the fit to the logarithmic form of eqn (4) using the
k
H
and k
o
values given above.
= k
Fig. 3 shows plots of (k
A pK
a
ª -7 for 3-H can be estimated by assuming that the effect
+
(
k
2
)
0
0
+ k
H
[H
3
O ]
(4)
of a second chlorine for hydrogen substitution on the acidity of
1
2
28
2
)
obsd - (k
2
)
o
against the concentration
of the acid form of substituted acetate buffers, according to eqn
2). The data obtained at different buffer ratios fall on the same
correlation line, which shows that there is no significant catalysis
of this reaction by the basic form of the buffer. Table 1 gives
4-H (pK
a
= -0.1) is ª 80% of the 9 unit effect of the first chlorine
of the parent amine taurine
for hydrogen substitution on the pK
a
12
5
-2 -1
(
(pK
a
= 9.0). The value of k
H
= 2.05 ¥ 10 M s for the hydronium
= -7 for 3-H, gives
for chlorine transfer from 3-H to
iodide ion (Scheme 3). This is much larger than the value of 5 ¥
ion-catalysed reaction of 3, combined with pK
a
1
2
-1 -1
a value of k = 2 ¥ 10 M s
I
-
2
-1
third-order rate constants kAH (M s ) for general acid catalysis
of the addition reaction by substituted acetic acids, determined as
9
-1 -1
10 M
s
for the encounter-controlled reactions of 1-H and 4-H,
4
140 | Org. Biomol. Chem., 2010, 8, 4137–4142
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through a protonated chloramine intermediate, with therefore
full protonation at nitrogen in the transition state (a = 1). The
protonated intermediate reacts with iodide ion at the diffusion
limit, which means that chlorine transfer within the ion pair is
faster than diffusional separation and therefore occurs with a
1
1
-1
rate constant ≥10
s
(Scheme 4). When electron-withdrawing
substituents are introduced in the leaving amine, a point is reached
at which the protonated intermediate becomes so reactive that it
no longer has a significant lifetime when it is in contact with
iodide ion. When this occurs, the reaction mechanism is forced
to become concerted and the reaction is subject to general acid
catalysis. There is a progressive decrease in the amount of proton
transfer to nitrogen, and consequently in the Brønsted a value,
with decreasing the base strength of the amine, which reflects an
increasingly smaller requirement for assistance to leaving group
expulsion by protonation.
Fig. 4 Statistically corrected Brønsted correlation for general acid
catalysis of chlorine transfer from 3 to iodide ion, where p and q are
equal to the number of chemically equivalent acidic hydrogens in the acid
and equivalent basic sites in the conjugate base, respectively.
Conclusions
N-Protonated chloramines derived from basic amines have pK ’s
a
so that 3-H cannot form as a reaction intermediate. The observed
general acid catalysis of the reaction of 3 supports a concerted
mechanism of catalysis in which the acid assists chlorine transfer
in water in the range 0–2 and therefore are sufficiently basic
to exist as free solvent-equilibrated intermediates in aqueous
solution. These chloramines transfer the chlorine atom to weak
nucleophiles through a stepwise mechanism involving protonation
at nitrogen in an initial equilibrium step. As the leaving amine
is made more acidic or the nucleophile stronger, a change to a
concerted mechanism of catalysis is observed which appears to be
enforced by the absence of a significant lifetime of the protonated
chloramine in the presence of the nucleophilic reagent.
to iodide ion by partial protonation at nitrogen (Scheme 5).
+
Protonation of 3 by H
3
O or substituted acetic acids is expected
to be thermodynamically unfavourable due to the strong electron-
withdrawing character of chlorine. Therefore, this reaction meets
the requirements for concerted general acid catalysis, which avoids
the formation of the highly unstable protonated intermediate 3-H.
3
There is a positive deviation of ~10 -fold of the rate constant
for H
acetic acids, which suggests that this reaction follows a different
mechanism. Although the pK for ionization of 4 to give an amine
anion is not known, the introduction of a chlorine atom at nitrogen
is expected to bring the pK of the amine down by ca. 9–10 units,
so that the pK of 4 is probably not very much larger than pK
15.7 for H O. A small DpK would make concerted protonation
2
O from the extrapolated Brønsted line for substituted
Experimental
a
The sodium salt of N-chlorotaurine (4) was prepared by reaction
of taurine with chloramine-T in ethanol. N-Chlorodimethylamine
a
(
1) was synthesized by treating the amine with a basic solution
a
a
=
of sodium hypochlorite. The chloramine separated as an or-
ganic phase, which was isolated and dried over sodium sulfate.
Deuterium oxide (99.9% D) and deuterium chloride (35% w/w,
+
2
a
30
by water insignificant, so that the uncatalysed reaction is likely
to proceed through a stepwise mechanism involving nucleophilic
99.5% D) were purchased from Aldrich. Commercially available
attack of iodide ion at 3 and expulsion of the chloramine anion
-
inorganic salts and organic chemicals were reagent grade or better
and were used without further purification.
4
in the slow step (Scheme 6). The failure of water to act as a
general acid catalyst through the concerted mechanism provides a
plausible explanation for the observed large deviation of the water
point from the Brønsted plot.
Solutions of N-chloro-2,2,2-trifluoroethylamine (2) were pre-
pared daily by mixing aqueous solutions of NaOCl and the amine
-
3
to give a 2 ¥ 10 M solution of 2 at pH 6–6.5. Solutions of N,N-
dichlorotaurine (3) were prepared by disproportionation of 4 at pH
2
–2.5 and used immediately after preparation. The concentration
of 3 was determined spectrophotometrically at 302 nm using a
-
1
-1 31
molar absorption coefficient of 332.9 M cm .
Buffer solutions and pH measurements
The following buffers were used to maintain constant pH in studies
of the reaction of 1, 2 and 3 with iodide ion: dichloroacetate,
pH < 2; chloroacetate, pH 2.2–3.3; methoxyacetate, pH 2.8–4.0;
acetate, pH 3.9–5.1; phosphate, pH 5.5–7.1; borate, pH 8.3. With
dichloroacetate buffers, the required hydronium ion concentration
was comparable to the concentration of the acid component of the
Scheme 6
In summary, the results described here show that there is a
transition from specific acid catalysis to general acid catalysis
of chlorine transfer to iodide ion as the amine leaving group
becomes more acidic. The reaction of basic chloramines proceeds
buffer and an appropriate amount of HClO was added to each
4
solution to ensure constant pH. Solution pH was measured at
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◦
2
5
C using a Radiometer PHM82 pH-meter equipped with a
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GK3401C combined glass electrode. Values of pD were obtained
by adding 0.40 to the observed reading of the pH meter. In
reactions monitored by conventional UV spectroscopy, the pH
was determined at the end of the reaction. In kinetic experiments
involving fast reactions, that were monitored using a stopped-flow
device, the pH was measured for control solutions prepared to be
identical to the solutions used in the stopped-flow experiments.
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1
1
1
4
344–4350.
Kinetic studies
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◦
All reactions were carried out in water at 25 C and I = 0.5
NaClO ). Kinetic experiments always employed at least a 10-fold
(
4
excess of nucleophile over substrate, with iodide ion concentrations
in the range 0.5–5 mM. Reactions with half-times of less than
13 P. Calvo, J. Crugeiras, A. Rios and M. A. Rios, J. Org. Chem., 2007,
2, 3171–3178.
7
1
1
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1
5 s were studied by using the DX17MV stopped-flow device
from Applied Photophysics. An aqueous solution of the substrate
and a buffered solution of the nucleophile were mixed in a ratio
16 J. M. Antelo, F. Arce, J. Crugeiras, C. Miraz and M. Parajo, Gazz.
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-
5
of 1 : 1 to give a final reaction mixture containing 2 ¥ 10
M
1
1
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substrate. The reactions were monitored by following the increase
-
in absorbance at 287 nm due to the appearance of I
3
. The slower
19 J. M. Antelo, F. Arce, J. Franco, M. Sanchez and A. Varela, Bull. Soc.
Chim. Belg., 1989, 98, 85–89.
reactions of 3 were monitored at 270 nm using a conventional
UV spectrophotometer and were initiated by making a 100-fold
dilution of a solution of substrate into the reaction mixture to give
2
2
2
0 W. P. Jencks, J. Am. Chem. Soc., 1972, 94, 4731–4732.
1 W. P. Jencks, Acc. Chem. Res., 1976, 9, 425–432.
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-
5
a final concentration of 2 ¥ 10 M. First-order rate constants,
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1
k
obsd (s ), were determined from the fit of the absorbance data to
1
979, 82, 264–277.
5 The pK for 2-H is estimated from pK
the assumption that the introduction of a chlorine atom at nitrogen
causes the same 9-unit decrease on this pK as for chlorine substitution
a single-exponential function and were reproducible to ±5%.
+
2
a
a
= 5.8 for CF
3
CH
2
NH
3
with
a
Acknowledgements
+
+
at CH
3
NH
3
(pK
a
= 10.9) to give CH
3
NH
2
Cl (pK = 1.6).
a
2
6 P. M. Laughton and R. E. Robertson, in Solute–Solvent Interactions,
ed. J. F. Coetzee and C. D. Ritchie, Marcel Dekker, New York, 1969,
pp. 399–538.
This research was supported by a grant from the Ministerio de
Ciencia y Tecnolog ´ı a (BQU2001-2912).
2
2
7 R. P. Bell, The Proton in Chemistry, Chapman and Hall, London, 1973.
8 The value of 80% was determined from an analysis of the effect of
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142 | Org. Biomol. Chem., 2010, 8, 4137–4142
This journal is © The Royal Society of Chemistry 2010