Kinetic and thermodynamic barriers to chlorine transfer between amines in aqueous solution

Article abstract of DOI:10.1021/jo900876f

(Chemical Equation Presented) Third-order rate constants for the acid-catalyzed reversible reaction of N-chlorotaurine with benzylamine and dimethylamine were determined in water at 25°C and I = 0.5 (NaClO ₄). The reaction with benzylamine shows inverse solvent deuterium isotope effects of k_H/k_D = 0.57 and 0.47 in the forward and reverse directions, respectively. These isotope effects, together with the absence of detectable general acid catalysis for this reaction, provide evidence for a stepwise mechanism involving fast equilibrium protonation of N-chlorotaurine followed by rate-determining chlorine transfer from the protonated chloramine to benzylamine. The observation of strong catalysis by general acids of the reaction of dimethylamine with N-chlorotaurine suggests a change to a concerted mechanism with proton and chlorine transfer occurring in a single step. This change in mechanism is enforced by the absence of a significant lifetime for protonated chlorotaurine in contact with this strongly nucleophilic amine. The kinetic and thermodynamic parameters for the reaction between protonated chlorotaurine and benzylamine are used to estimate a Marcus intrinsic reaction barrier of ΔG₀^? = 4.1 kcal/mol for chlorine transfer between amines. Comparison of this intrinsic barrier with those reported previously for bromine transfer between carbanions points to the existence of certain similarities between halogen and proton transfer reactions.

Full text of DOI:10.1021/jo900876f

pubs.acs.org/joc
Kinetic and Thermodynamic Barriers to Chlorine Transfer between
Amines in Aqueous Solution
Paula Calvo, Juan Crugeiras,* and Ana Rıos
´ ´ ´
Departamento de Quımica Fısica, Facultad de Quımica, Universidad de Santiago, 15782 Santiago de
Compostela, Spain
juan.crugeiras@usc.es
Received April 28, 2009
Third-order rate constants for the acid-catalyzed reversible reaction of N-chlorotaurine with
benzylamine and dimethylamine were determined in water at 25 ꢀC and I = 0.5 (NaClO4). The
reaction with benzylamine shows inverse solvent deuterium isotope effects of kH/kD =0.57 and 0.47
in the forward and reverse directions, respectively. These isotope effects, together with the absence of
detectable general acid catalysis for this reaction, provide evidence for a stepwise mechanism
involving fast equilibrium protonation of N-chlorotaurine followed by rate-determining chlorine
transfer from the protonated chloramine to benzylamine. The observation of strong catalysis by
general acids of the reaction of dimethylamine with N-chlorotaurine suggests a change to a concerted
mechanism with proton and chlorine transfer occurring in a single step. This change in mechanism is
enforced by the absence of a significant lifetime for protonated chlorotaurine in contact with this
strongly nucleophilic amine. The kinetic and thermodynamic parameters for the reaction between
protonated chlorotaurine and benzylamine are used to estimate a Marcus intrinsic reaction barrier of
ΔGq0 = 4.1 kcal/mol for chlorine transfer between amines. Comparison of this intrinsic barrier with
those reported previously for bromine transfer between carbanions points to the existence of certain
similarities between halogen and proton transfer reactions.
Introduction
reaction of HOCl with amino groups of amino acids, pep-
tides, and proteins.6 These N-chloro compounds are longer
lived than HOCl but retain an effective oxidizing and
chlorinating capacity, being able to react with a variety of
nucleophilic groups in biological substrates. In the past few
years, significant efforts have been made to identify possi-
ble targets for N-chloramines in biological systems.7-12
However, relatively little is known about the mechanisms
N-Chloramines play a significant role in important biolo-
gical processes. They have been implicated as intermediates
in the myeloperoxidase/H2O2/Cl- initiated oxidation of
biomolecules, which is involved in the microbiocidal re-
sponse of phagocytic cells.1-3 More recently, it has been
suggested that a lysine chloramine is the chlorinating species
responsible for conversion of free tryptophan to 7-chloro-
tryptophan at the active site of the flavin-dependent halo-
genase RebH.4,5 N-Chloramines are formed in vivo by
(6) Hawkins, C. L.; Pattison, D. I.; Davies, M. J. Amino Acids 2003, 25,
259–274.
(7) Peskin, A. V.; Winterbourn, C. C. Free Radical Biol. Med. 2001, 30,
572–579.
(1) Takeshita, J.; Byun, J.; Nhan, T. Q.; Pritchard, D. K.; Pennathur, S.;
Schwartz, S. M.; Chait, A.; Heinecke, J. W. J. Biol. Chem. 2006, 281, 3096–3104.
(2) Kulcharyk, P. A.; Heinecke, J. W. Biochemistry 2001, 40, 3648–3656.
(3) Pattison, D. I.; Davies, M. J. Curr. Med. Chem. 2006, 13, 3271–3290.
(4) Yeh, E.; Blasiak, L. C.; Koglin, A.; Drennan, C. L.; Walsh, C. T.
Biochemistry 2007, 46, 1284–1292.
(8) Peskin, A. V.; Winterbourn, C. C. Free Radical Biol. Med. 2003, 35,
1252–1260.
(9) Peskin, A. V.; Midwinter, R. G.; Harwood, D. T.; Winterbourn, C. C.
Free Radical Biol. Med. 2004, 37, 1622–1630.
(10) Prutz, W. A.; Kissner, R.; Koppenol, W. H. Arch. Biochem. Biophys.
2001, 393, 297–307.
(5) Flecks, S.; Patallo, E. P.; Zhu, X.; Ernyei, A. J.; Seifert, G.; Schneider,
A.; Dong, C.; Naismith, J. H.; van Pee, K.-H. Angew. Chem., Int. Ed. 2008,
47, 9533–9536.
(11) Pattison, D. I.; Davies, M. J. Biochemistry 2005, 44, 7378–7387.
(12) Summers, F. A.; Morgan, P. E.; Davies, M. J.; Hawkins, C. L. Chem.
Res. Toxicol. 2008, 21, 1832–1840.
DOI: 10.1021/jo900876f
r
Published on Web 06/25/2009
J. Org. Chem. 2009, 74, 5381–5389 5381
2009 American Chemical Society

Calvo et al.
JOCArticle
of chlorine transfer from N-chloramines to other substra-
tes.13-16
of the protonated chloramine in the presence of a
sufficiently nucleophilic amine. We show here that an
expected transition from a stepwise to a concerted
mechanism, where protonation of the chloramine and
chlorine transfer to the amine occur in a single step, is
observed as the amine becomes more reactive.
We have recently reported that chlorine transfer from
N-chloramines to sulfur nucleophiles and halide ions re-
quires protonation of the chloramine at nitrogen before or
during the rate-limiting step, to avoid the formation of an
unstable nitranion.16 Most of these reactions proceed with
specific acid catalysis, consistent with protonation of the
chloramine in an initial equilibrium step. However, some of
them are subject to general acid catalysis, which indicates
that chlorine transfer is assisted by proton transfer to the
chloramine nitrogen in the rate-limiting step. We have
followed the suggestion of Jencks17-19 that reaction mechan-
isms are dictated by the lifetimes of possible reaction inter-
mediates and have analyzed the observed change in
mechanism in terms of the estimated lifetime of the proto-
nated chloramine in the presence of the nucleophile. The
results show that as the nucleophile becomes stronger, a
point is reached where there is no chemical barrier for
(2) Chlorine transfer between the nitrogen atoms of
amines is a reversible reaction for which it is possible
to experimentally determine the corresponding rate
and equilibrium constants. This allows for an estima-
tion of the Marcus intrinsic barrier for chlorine trans-
fer between amines, which can be compared with the
very small intrinsic barrier of ca. 1 kcal mol-1 for
direct proton transfer between electronegative
atoms.24 To the best of our knowledge, there is only
one report in the literature providing values of intrin-
sic barriers for halogen transfer reactions.25 This study
surprisingly reveals that bromine transfer between
carbanions is intrinsically faster than the parallel
proton transfer reaction and shows the nitro anomaly,
a typical feature of proton transfer. We report here
that the intrinsic barriers for halogen transfer between
electronegative atoms are much lower than those for
halogen transfer involving carbon. These results leave
an open question about the origin of the observed
similarities between proton and halogen transfer reac-
tions.
collapse of the complex [RNH2Clþ Nu] to products, and
3
therefore, the reaction becomes concerted. We have now
extended this work and report here the results of a study of
the reaction of N-chlorotaurine (-O3S(CH2)2NHCl) with
amines, designed to provide evidence for a similar change in
mechanism with increasing the strength of the nitrogen
nucleophile. This work was undertaken for the following
reasons:
(1) An analysis of the mechanistic information available
in the literature on the reaction of chloramines with
amines in aqueous solution shows important discre-
pancies between the conclusions reached in different
studies. Snyder and Margerum13 have reported spe-
cific acid catalysis of chlorine transfer from chlora-
mine (NH2Cl) to methylamine and amino acids and
have concluded that these reactions occur through a
stepwise mechanism involving the protonated chlor-
amine. Limited studies by Isaac and Morris20,21 de-
scribe the reaction of chloramine with amines, but the
presence or absence of general acid catalysis was not
investigated. In later studies, Ferriol et al.22,23 re-
ported general acid catalysis of the reaction of chlor-
amine with methylamine and other amines and
suggested that these reactions follow a concerted
mechanism, which could occur concurrently or not
with a stepwise process involving the protonated
chloramine. We therefore conclude that there is cur-
rently not a clear understanding of the mechanism of
these reactions. The available data provide no evi-
dence for the disappearance of the barrier for collapse
(3) A detailed elucidation of the mechanisms of reaction
of N-chloramines with small nucleophilic molecules,
as models for the reactive groups in the more complex
biomolecules, could help to understand the roles that
N-chloramines play in biological systems.
Results
Chlorine Transfer to Benzylamine. The observed first-
order rate constants, kobsd (s-1), for the reaction of N-
chlorotaurine with benzylamine in the presence of 5 mM
taurine at pH 6.5 (buffered by 0.1 M phosphate) show a
linear dependence on the total concentration of benzyl-
amine. The linear plot of kobsd against [RNH2]T (b,
Figure 1A) has a positive intercept characteristic of a rever-
sible reaction, first-order in both directions, and this indi-
cates that the reaction proceeds to an equilibrium mixture of
N-chlorotaurine and N-chlorobenzylamine. The rate con-
stants kobsd (s-1) for the reversible chlorine transfer reaction
are therefore equal to the sum of the rate constants for
reaction in the forward and reverse directions (eq 1).
Figure 1A shows the dependence of kobsd (s-1) for chlorine
transfer approaching equilibrium on the concentration of
benzylamine in the presence of fixed concentrations of
taurine. The slopes of these linear correlations give the same
(13) Snyder, M. P.; Margerum, D. W. Inorg. Chem. 1982, 21, 2545–2550.
(14) Kumar, K.; Day, R. A.; Margerum, D. W. Inorg. Chem. 1986, 25,
4344–4350.
(15) Yiin, B. S.; Walker, D. M.; Margerum, D. W. Inorg. Chem. 1987, 26,
3435–3441.
second-order rate constant (kRNH
)
obsd =(6.0 ( 0.2) ꢀ 10-2
2
M-1 s-1 for formation of N-chlorobenzylamine in the for-
ward direction. The intercepts, (kr)obsd (s-1), increase with
increasing the concentration of taurine according to eq 2,
and the slope of a linear plot of (kr)obsd against [TauNH2]T
(16) Calvo, P.; Crugeiras, J.; Rios, A.; Rios, M. A. J. Org. Chem. 2007,
72, 3171–3178.
(17) Jencks, W. P. Acc. Chem. Res. 1976, 9, 425–432.
(18) Jencks, W. P. Acc. Chem. Res. 1980, 13, 161–169.
(19) Jencks, W. P. Chem. Soc. Rev. 1981, 10, 345–375.
(20) Isaac, R. A.; Morris, J. C. Environ. Sci. Technol. 1983, 17, 738–742.
(21) Isaac, R. A.; Morris, J. C. Environ. Sci. Technol. 1985, 19, 810–814.
(22) Ferriol, M.; Gazet, J.; Rizk-Ouaini, R.; Saugier-Cohen Adad, M. T.
Inorg. Chem. 1989, 28, 3808–3813.
(Figure 1B) gives (kTauNH
)
obsd=(7.4 ( 0.2) ꢀ 10-2 M-1 s-1
2
(24) Guthrie, J. P. J. Am. Chem. Soc. 1996, 118, 12886–12890.
(25) Grinblat, J.; Ben-Zion, M.; Hoz, S. J. Am. Chem. Soc. 2001, 123,
10738–10739.
(23) Ferriol, M.; Gazet, J.; Saugier-Cohen Adad, M. T. Int. J. Chem.
Kinet. 1991, 23, 315–329.
5382 J. Org. Chem. Vol. 74, No. 15, 2009

Calvo et al.
JOCArticle
FIGURE 1. (A) Dependence of kobsd (s-1) for the reaction of N-chlorotaurine with benzylamine on the concentration of amine at pH 6.5 in the
presence of different concentrations of taurine and phosphate buffer in H2O at 25 ꢀC and I = 0.5 (NaClO4). Key: (O) [buffer] = 0.03 M; (0)
[buffer] = 0.05 M; (b, 1, 9, 2, `) [buffer] = 0.1 M; (4) [buffer] = 0.15 M. (B) Dependence of (kr)obsd (s-1) for the reaction of N-
chlorobenzylamine with taurine on the total concentration of taurine at pH 6.5 (buffered by 0.1 M phosphate) in H2O at 25 ꢀC and I = 0.5
(NaClO4).
TABLE 1. Third-Order Rate Constants for Reversible Acid-Catalyzed Chlorine Transfer from N-Chlorotaurine to Aminesa
b (M-2 s-1
)
(kTauNH
)
c (M-2 s-1
)
)
-
d (M-2 s-1
)
(kTauNH )
2
-
e (M-2 s-1
)
H2PO4
0
(kRR NH H
0
(kRR NH H PO
amine
)
H
2
2
4
C6H5CH2NH2 (in H2O)
C6H5CH2ND2 (in D2O)
(CH3)2NH
(1.87 ( 0.06) ꢀ 108
(3.3 ( 0.3) ꢀ 108
(9.0 ( 1.3) ꢀ 107
b
(8.84 ( 0.06) ꢀ 107
(1.9 ( 0.3) ꢀ 108
(1.1 ( 0.2) ꢀ 105
(2.63 ( 0.08) ꢀ 103
(3.91 ( 0.12)
aAt 25 ꢀC and I = 0.5 (NaClO4). Third-order rate constant for the hydronium ion catalyzed chlorine transfer from N-chlorotaurine to amines.
cThird-order rate constant for the hydronium ion catalyzed chlorine transfer from the corresponding N-chloramine to taurine in the reverse direction.
dThird-order rate constant for catalysis by phosphate monoanion of chlorine transfer from N-chlorotaurine to amines. eThird-order rate constant for
catalysis by phosphate monoanion of chlorine transfer from the corresponding N-chloramine to taurine in the reverse direction.
SCHEME 1
for formation of N-chlorotaurine from N-chlorobenzyla-
mine and taurine in the reverse direction.
kobsd ¼ ðkRNH
Þ
½RNH2ꢁT þ ðkrÞobsd
ð1Þ
ð2Þ
2
obsd
ðkrÞobsd ¼ ðkTauNH
Þ
½TauNH2ꢁT
2
obsd
0.06) ꢀ 108 M-2 s-1 (Table 1) for the acid-catalyzed reaction
of benzylamine with N-chlorotaurine was determined from
Figure 1A also shows that kobsd does not depend on the
concentration of 50% free base phosphate buffer at pH 6.5
and 25 ꢀC (I = 0.5, NaClO4). The absence of a significant
increase in kobsd upon increasing the buffer concentration
from 30 to 150 mM shows that there is no general acid-base
catalysis of chlorine transfer in the forward or reverse
directions. Table S1 of Supporting Information gives sec-
this equation, using the average of the values of (kRNH
þ
)
obsd
= 3.31 ꢀ
2
determined at different pH values and (Ka)RNH
3
10-10 M for the apparent acidity constant of proto-
nated benzylamine. Similarly, a third-order rate constant
(kTauNH
the acid-catalyzed reaction of taurine with N-chloro-
)
= (8.84 ( 0.06) ꢀ 107 M-2 s-1 (Table 1) for
H
2
ond-order rate constants (kRNH
)
)
(M-1 s-1, eq 1) and
obsd
2
(kTauNH
(M-1 s-1, eq 2) obtained from the slope and
obsd
benzylamine in the reverse direction was calculated as
2
intercept, respectively, of linear plots of kobsd against
[RNH2]T at pH 5.8, 6.5, and 7.1. An analysis of the data
reported in this table shows that there is no significant
change in these second-order rate constants with changing
pH in the interval 5.8-7.1. This pH-independent pathway is
due to the acid-catalyzed reaction of the neutral amine with
the chloramine (Scheme 1) in a pH region where the amine is
mainly protonated and the increase in the fraction of reactive
amine with increasing pH is compensated for by the corre-
sponding decrease in [H3Oþ].
(kTauNH
(kTauNH
)
)
obsd/(Ka)TauNH þ, using the average value of
= 8.71 ꢀ 10-10 M for the
2
3
and (Ka)TauNH
þ
obsd
2
3
apparent acidity constant of protonated taurine.26
ðkRNH
Þ
¼ ðkRNH ÞH½H3OþꢁfRNH
ð3Þ
ð4Þ
2
2
2
obsd
ðkRNH
Þ
¼ ðkRNH Þ ðKaÞ
RNH3þ
2
2
obsd
H
Rate measurements in phosphate buffer solutions in D2O
at 25 ꢀC and I = 0.5 (NaClO4) provided second-order rate
At pH , (pKa)RNH þ, eq 3, derived for the forward reaction
3
(26) Antelo, J. M.; Arce, F.; Calvo, P.; Crugeiras, J.; Rıos, A. J. Chem.
Soc., Perkin Trans 2 2000, 2109–2114.
in Scheme 1, simplifies to eq 4, and a value of (kRNH )H=(1.87(
2
J. Org. Chem. Vol. 74, No. 15, 2009 5383

Calvo et al.
JOCArticle
TABLE 2. Rate and Equilibrium Constants for Reversible Chlorine Transfer from N-Chlorotaurine to Amines in Water at 25 ꢀC and I = 0.5 (NaClO4)
aRate constant for the forward reaction, determined as described in the text. bRate constant for the reverse reaction, determined as described in the
text. cEquilibrium constant for the reaction calculated as K = kf/kr.
FIGURE 2. (A) Dependence of (kR NH obsd
)
(M-1 s-1) for the reaction of N-chlorotaurine with dimethylamine on the concentration of the basic
(M-1 s-1) for the reaction of
2
form of phosphate buffer in H2O at 25 ꢀC and I = 0.5 (NaClO4). (B) Dependence of (kTauNH
N-chlorodimethylamine with taurine in the reverse direction on the concentration of the basic form of phosphate buffer in H2O at 25 ꢀC
and I = 0.5 (NaClO4). Key: (b) 20% free base, pH = 5.8; (9) 50% free base, pH = 6.4; (2) 80% free base, pH = 7.1.
)
obsd
2
constants (kRND
the reaction of N-chlorotaurine with benzylamine and
)
= (3.2 ( 0.3) ꢀ 10-2 M-1 s-1 for
shown) according to eq 1. The intercepts of these linear plots
give (kr)obsd (s-1, eq 1) for the reverse reaction and observed
obsd
2
(kTauND
)
obsd = (4.8 ( 1.0) ꢀ 10-2 M-1 s-1 for the reaction
second-order rate constants, (kTauNH
)
(M-1 s-1), for
obsd
2
2
of N-chlorobenzylamine with taurine. Third-order rate con-
stants (kRND )D=(3.3 ( 0.3) ꢀ 108 M-2 s-1 and (kTauND )D=
chlorine transfer from N-chlorodimethylamine to taurine
were determined as the slopes of linear plots of (kr)obsd
2
2
(1.9 ( 0.3) ꢀ 108 M-2 s-1 (Table 1) for the acid-catalyzed
chlorine transfer reactions in the forward and reverse direc-
tions (Scheme 1) were determined using eq 4 and a solvent
isotope effect on the acid ionization constant of the proto-
nated amines of (Ka)H O/(Ka)D O = 3.36.27
against [TauNH2]T or as (kTauNH
)
)
(eq 2). The values of (kR NH obsd
obsd=(kr)obsd/[TauNH2]T
increased linearly with
2
2
increasing phosphate buffer concentration up to 0.2 M
according to eq 5, where (k2)o (M-1 s-1) is the second-order
rate constant for solvent-catalyzed chlorine transfer at the
pH of the experiment and (k3)buffer (M-2 s-1) is the observed
third-order rate constant for the buffer-catalyzed reaction.
2
2
Chlorine Transfer to Dimethylamine. First-order rate con-
stants, kobsd (s-1), for the reaction of N-chlorotaurine with
dimethylamine in the presence of different fixed concentra-
tions of taurine at pH 5.8-7.1 (buffered by phosphate)
correspond to the approach to an equilibrium mixture of
N-chlorotaurine and N-chlorodimethylamine. Observed sec-
ðkR NHÞobsd ¼ ðk2Þo þ ðk3Þbuffer½bufferꢁT
ð5Þ
2
The buffer-independent rate constants, (k2)o, obtained by
extrapolation of the observed rate constants (kR NH obsd to
(M-1 s-1), for the
2
)
ond-order rate constants, (kR NH)obsd
reaction in the forward direction were determined as the
slopes of linear correlations of kobsd against [R2NH]T (not
2
zero buffer concentration, were found to be pH-independent
within experimental error in the pH range 5.8-7.1. The
increase in (k3)buffer with increasing the fraction of buffer base
is consistent with a general base catalysis rate law. Figure 2A
(27) Arrowsmith, C. H.; Guo, H. X.; Kresge, A. J. J. Am. Chem. Soc.
1994, 116, 8890–8894.
shows a plot of (kR NH)obsd against the concentration of the
2
5384 J. Org. Chem. Vol. 74, No. 15, 2009

Calvo et al.
JOCArticle
basic form of the phosphate buffer, according to eq 6. The
data obtained at different buffer ratios [HPO42-]/[H2PO4
SCHEME 2
-
]
fall on the same correlation line, which indicates that there is
no significant catalysis of this reaction by the acidic form of
the buffer. The slope of this plot gives the third-order rate
constant for catalysis of chlorine transfer from N-chlorotaur-
ine to dimethylamine by HPO42-, (kA-
)
obsd =(1.00 ( 0.03) ꢀ
10-1 M-2 s-1. A value of (k2)o=(1.21 ( 0.18) ꢀ 10-3 M-1 s-1
for the pH-independentrateconstantfor chlorine transfer was
determined as the intercept of the plot in Figure 2A.
SCHEME 3
ðkR NHÞobsd ¼ ðk2Þo þ ðkA Þobsd½A-ꢁ
ð6Þ
-
2
The values of (kTauNH
)
for chlorine transfer in the
obsd
2
reverse direction, determined at increasing concentrations of
phosphate buffer, were plotted against the total buffer
concentration. The slopes of the linear correlations observed
at different fixed ratios of the buffer acid and conjugate base
increased with increasing the fraction of the buffer present in
the basic form. The y-intercepts of these plots were found to
be pH-independent at pH values between 5.8 and 7.1.
(kTauNH )
AH =(3.91 ( 0.12) M-2 s-1 (Table 1) as the third-
order rate constants for chlorine transfer from N-chlorodi-
2
-
methylamine to taurine catalyzed by H3Oþ and H2PO4
respectively.
,
Figure 2B shows the dependence of (kTauNH
)
on the
obsd
Discussion
2
concentration of the basic form of the phosphate buffer. The
slope and intercept of this plot give (kA-
Chlorine transfer from N-chloramines to nucleophiles
occurs through an acid-catalyzed reaction pathway that
involves protonation of the leaving amine before or during
the rate-limiting step to avoid the formation of an extremely
unstable nitranion.16 We showed previously that the transfer
of a chlorine atom from N-chlorotaurine to iodide and less
reactive nucleophiles occurs through a stepwise mechanism
involving a protonated chloramine intermediate. We also
provided evidence for a change to a concerted mechanism
with increasing the reactivity of the nucleophile and sug-
gested that this is enforced by the absence of a significant
lifetime of N-protonated chlorotaurine in contact with the
nucleophile. We have now examined the reaction of
N-chlorotaurine with amines in order to determine whether
there is a similar change in mechanism with increasing amine
reactivity.
)obsd =(9.6 ( 0.3) ꢀ
10-3 M-2 s-1 and (k2)o = (9.5 ( 1.9) ꢀ 10-5 M-1 s-1 for
catalysis by HPO42- and uncatalyzed chlorine transfer from
N-chlorodimethylamine to taurine, respectively (eq 6).
At pH 5.8-7.1, dimethylamine and taurine exist mainly as
the N-protonated species and the fraction of amine present in
the reactive neutral form is given by fR NH = (Ka)R NH þ/
[H3Oþ], where (Ka)R NH
2
2
2
þ is the equilibrium constant for
2
2
dissociation of the conjugate acid of the amine. The experi-
mentally observed general base catalysis rate law for both the
forward and reverse reactions (eq 6) is therefore consistent
with catalysis by general acids of the reaction of the neutral
amine with the chloramine, as shown in Scheme 2.
At pH , (pKa)R NH þ, eq 7, derived for the forward reaction in
2
2
Scheme 2, simplifies to eq 8, where (Ka)AH is the acidity constant
of the general acid. Comparison of eqs 6 and 8 shows that (k2)o=
(kR NH)H(Ka)R NH þ, and a third-order rate constant (kR NH)H=
Reaction Mechanisms. The experimental data obtained in
this work show that there is no detectable general acid
catalysis of the reversible reaction of benzylamine with
N-chlorotaurine. This provides evidence that protonation
of the chloramine on nitrogen takes place in a rapid equilib-
rium step followed by rate-determining chlorine transfer to
the neutral amine (Scheme 3). Additional support for this
mechanism comes from the observed inverse solvent deuter-
ium isotope effects (kRNH )H/(kRND )D = (0.57 ( 0.05) and
2
2
2
2
(9.0 ( 1.3) ꢀ 107 M-2 s-1 (Table 1) for catalysis by H3Oþ of
chlorine transfer from N-chlorotaurine to dimethylamine
(Scheme 2) was calculated from the value of (k2)o given above
using (Ka)R NH þ = 1.35 ꢀ 10-11 M for protonated dimethyl-
2
2
amine. The rate constant (kA-
)
obsd=(1.00 (0.03) ꢀ 10-1 M-2 s-1
for catalysis by HPO42- of chlorine transfer to dimethylamine,
which in terms of eq 8 is equal to (kR NH AH[(Ka)R NH þ/
M
)
2
2 2
(Ka)AH], may be combined with (Ka)R NH þ =1.35 ꢀ 10-11
2
2
2
2
and (Ka)AH=3.55ꢀ 10-7 M togive (kR NH AH
)
=(2.63 ( 0.08) ꢀ
(kTauNH )H/(kTauND )D=(0.47 ( 0.07) on the acid-catalyzed
2
2
2
103 M-2 s-1 (Table 1) as the third-order rate constant for
catalysis by H2PO4- of chlorine transfer from N-chlorotaurine
to dimethylamine (Scheme 2).
forward and reverse reactions, respectively, which are typical
of preequilibrium substrate protonation mechanisms.28 The
introduction of a chlorine substituent at the nitrogen atom of
taurine (pKa=9.06) to give N-chlorotaurine brings down its
pKa by ca. 9 units.26 N-Chlorotaurine is therefore weakly
basic (pKa ≈ 0), so that it would be necessary to work in
concentrated acid solutions to observe a shift in the position
of the preequilibrium to the protonated chloramine species.
ðk
Þ
¼ ððk
Þ ½H3Oþꢁ þ ðk
Þ
½AHꢁÞf
R2NH
R2NH
R2NH
R2NH
obsd
H
AH
ð7Þ
ðkR NHÞobsd ¼ ðkR NHÞ ðKaÞ
þ
2
2
H
R2NH2
A second-order rate constant kRNH = (2.13 ( 0.13) ꢀ
2
108 M-1 s-1 for chlorine transfer from protonated N-chlor-
ðKaÞ
þ
R2NH2
þ ðkR NHÞAH
½A-ꢁ
ð8Þ
2
otaurine to neutral benzylamine was determined from the
ðKaÞAH
value of (kRNH
)
and (Ka)TauNH Clþ = 1.14 M26 using
H
2
2
A similar treatment of the data for the reverse reac-
H = (1.1 ( 0.2) ꢀ 105 M-2 s-1 and
tion gives (kTauNH
)
(28) Keeffe, J. R.; Kresge, A. J. Tech. Chem. (N. Y.) 1986, 6, 747–790.
J. Org. Chem. Vol. 74, No. 15, 2009 5385
2

Calvo et al.
JOCArticle
the relationship kRNH =(kRNH
)
H (Ka)TauNH Clþ (Scheme 3,
similar reactivity of these nucleophiles and there is no
experimental evidence to support the existence of the inter-
mediate shown in Scheme 4. We propose that chlorine
transfer from the protonated chloramine to the amine takes
place in a single step involving both breaking of the bond to
the leaving group and formation of a bond to the incoming
amine in the transition state.
2
2
2
pH . (pKa)TauNH Clþ). Similarly, the value of (kTauNH )H can
be combined with (Ka)RNH Clþ =0.149 M (see Experimental
2
2
2
Section) to give kTauNH =(1.32 ( 0.04) ꢀ 107 M-1 s-1 as the
2
second-order rate constant for the reaction of taurine with
protonated N-chlorobenzylamine in the reverse direction.
The overall equilibrium constant KCl = (16.1 ( 1.1) for the
reaction of protonated N-chlorotaurine with benzylamine to
form taurine and protonated N-chlorobenzylamine was
calculated as KCl =kRNH /kTauNH from the values of kRNH
We have shown that H2PO4- is an effective catalyst of the
reversible reaction of N-chlorotaurine with dimethylamine
in both directions. This is consistent with either of the
kinetically equivalent mechanisms shown in Schemes 5 and
6. The mechanism of Scheme 5 involves protonation of N-
chlorotaurine in a preequilibrium step, followed by slow
chlorine transfer assisted by removal of a proton from the
attacking amine by a general base. This corresponds to true
general acid catalysis of the reaction of N-chlorodimethyla-
mine with taurine in the reverse direction. The mechanism of
Scheme 6 involves proton donation from a general acid to the
nitrogen atom of N-chlorotaurine in the forward direction
and proton removal from the nitrogen atom of taurine by the
conjugate general base in the reverse direction. A choice
between these two mechanisms may be made from a com-
parison of the relative stabilities of the two N-protonated
chloramines in the presence of the incoming nucleophilic
2
2
2
and kTauNH reported above.
2
The kinetic behavior found in this work for the reaction of
N-chlorotaurine with benzylamine is similar to that observed
in earlier studies of the kinetics of chlorine transfer from
NH2Cl to nitrogen nucleophiles.13,20,21 However, Snyder
and Margerum13 suggested that the reaction between proto-
nated chloramine and methylamine occurs through a me-
chanism involving the formation of a hypervalent chlorine
species, as shown in Scheme 4. Their mechanistic proposal
was based on an analysis of the dependence of the second-
order rate constants for chlorine transfer from NH3Clþ to
nitrogen compounds on amine nitrogen basicity, which
showed a limiting value of ca. 2 ꢀ 108 M-1 s-1 for com-
pounds more basic than ammonia. The observed break in
this Brønsted-type correlation was attributed to a change in
rate-limiting step from nucleophilic attack of the amine at
chlorine (k1, Scheme 4) to N-Cl bond breaking (k2,
Scheme 4) with increasing amine reactivity. After extensive
studies on amine nucleophilicities in aqueous solution,29-32
it is now well-known that basicity is generally not a good
measure of the nucleophilicity of amines. In fact, the three
nitrogen compounds (glycine, β-alanine and methylamine)
that define the observed limiting region in the Brønsted-type
plot mentioned above react at similar rates with electrophiles
such as 1-methyl-4-vinylpyridinium cation,31 methyl 4-ni-
trobenzenesulfonate,30 and benzhydrylium ions29,33 despite
their different basicities. Therefore, the kinetic data reported
by Snyder and Margerum are consistent with the expected
amine. The reaction pathway shown in Scheme 5 avoids the
-
formation of the complex (CH3)2NHClþ NH2(CH2)2SO3
,
3
whereas that in Scheme 6 avoids the formation of the
kinetically and thermodynamically more unstable -O3S-
(CH2)2NH2Clþ NH(CH3)2 complex. Since the latter species
3
is more reactive than the former, it is more likely to be
avoided in a concerted mechanism, and it seems therefore
reasonable to conclude that the reaction of N-chlorotaurine
with dimethylamine follows the mechanism shown in
Scheme 6.
Scheme 6 shows that the observed acid-catalyzed forward
reaction corresponds to “true” general acid catalysis of
chlorine transfer from N-chlorotaurine to dimethylamine,
and third-order rate constants (kR NH)H and (kR NH)AH for
2
2
catalysis by H3Oþ and H2PO4-, respectively, were deter-
mined above (see Results). The acid-catalyzed reverse reac-
tion corresponds to preequilibrium protonation of N-
chlorodimethylamine followed by catalysis by general bases
of chlorine transfer from this protonated chloramine to
SCHEME 4
taurine. Rate constants (kTauNH )o =(2.2 ( 0.4) ꢀ 104 M-1 s-1
2
SCHEME 5
SCHEME 6
5386 J. Org. Chem. Vol. 74, No. 15, 2009

Calvo et al.
JOCArticle
and (kTauNH
)
=(2.20 ( 0.07) ꢀ 106 M-2 s-1 for catalysis
been neglected. An apparent intrinsic barrier of ΔG0q
=
A-
2
by H2O and HPO42-, respectively, can be calculated from
6.9 kcal/mol for chlorine transfer can be determined by
substituting the observed values of (ΔGq)obsd = 6.1 kcal/
mol and (ΔGꢀ)obsd = -1.7 kcal/mol for the reaction of N-
protonated chlorotaurine with benzylamine (Scheme 3) into
eq 9, using the assumption that the observed activation
barrier corresponds entirely to the chemical transformation
of the reactants to the transition state (wr = wp = 0).
However, a better estimate of the chemical intrinsic barrier
may be obtained if we are able to evaluate the significance of
the work terms for this reaction.
(Ka)(CH ) NHClþ =0.2 M34 and (Ka)AH=3.55 ꢀ 10-7 M using
3
2
the relationships (kTauNH )o=(kTauNH )H (Ka)(CH ) NHClþ and
2
2
3 2
A-
(kTauNH
for Scheme 6.
)
= (kTauNH
)
((Ka)(CH ) NHClþ/(Ka)AH) derived
AH
3 2
2
2
We have previously suggested that the acid-catalyzed
reaction of N-chlorotaurine with the highly reactive sulfur
nucleophiles HOCH2CH2S- and SO32- follows a concerted
mechanism, which is enforced by the absence of a significant
lifetime of the protonated chloramine in the presence of the
nucleophile.16 The N and n nucleophilicity scales, predict
The reactant and product pairs are strikingly similar, and
it is reasonable to assume that there is not a significant
difference in the work terms for formation of the reactant
and product complexes (wr =wp). The work term wr should
include the entropic cost of bringing the two reactants
together, the cost of the partial desolvation required to create
a complex in which the chlorine atom of the chloramine and
the nitrogen of the amine are in contact with the correct
orientation for the transfer of chlorine to take place, and
possible interactions between the two species in the encoun-
ter complex. The free energy change involved in the ap-
proach of the two reactants to form a complex may be
estimated following the work of Hine39 as 2.8 kcal/mol,
assuming that there is only one possible position for the
nucleophilic nitrogen atom in the complex and that there are
no interactions between the two reactants. There is evidence
in the literature that complete desolvation of amines, to free
the lone electron pair, must occur before nucleophilic attack
takes place.40-42 Berg and Jencks have provided estimates of
the equilibrium constants for dissociation of amine-water
complexes and have shown that desolvation becomes less
favorable as the amine becomes more basic.43 Interpolation
of their data to a pKa = 9.5 gives an energetic cost for
breaking the hydrogen bond between water and benzylamine
of 1.8 kcal/mol. Finally, it is necessary to consider the
existence of stabilizing interactions between the amine and
the protonated chloramine within the precursor complex. It
is well-known that halogenated organic molecules form
weak complexes with electron donor species, in which the
halogen atom acts as an electron acceptor site.44-46 This type
of intermolecular interaction has been named halogen bond-
ing to stress that many of its properties parallel those of the
analogous hydrogen bonds. It is difficult to quantify the
strength of an interaction between the nucleophilic nitrogen
of the amine and the electrophilic chlorine atom of the
protonated chloramine in the reactive complex. However,
the stabilizing energy associated with formation of a chlorine
bond has been estimated to be not much different from that
involved in formation of a similar hydrogen bond.47-49
þ
that dimethylamine (N = 7.95,31 n = 5.8330) will show a
þ
reactivity toward electrophiles similar to that of SO3
2-
(N = 8.01,35 n = 5.6736). It is therefore likely that the
þ
barrier for collapse of an encounter complex between N-
protonated chlorotaurine and dimethylamine is insignifi-
cant, which forces chlorine transfer to occur through a
mechanism in which proton transfer to the nitrogen atom
of the chloramine and chlorine transfer merge into a single
step.
Intrinsic Barriers. The reversibility of the reaction between
N-chlorotaurine and benzylamine allowed the determination
of the corresponding rate and equilibrium constants for this
process. This set of data may now be analyzed in the context
of Marcus theory,37,38 which provides a relationship (eq 9)
between the activation barrier, ΔGq, and the thermodynamic
driving force for a reaction, ΔGꢀ, in terms of what is
commonly called the intrinsic activation barrier, ΔGq0, de-
fined as the kinetic barrier for the hypothetical thermoneu-
tral process (ΔGꢀ = 0). The Marcus eq 9 applies to the
chemical step of the reaction and, therefore, the observed
activation and thermodynamic barriers, (ΔGq)obsd and
(ΔGꢀ)obsd, should be corrected for the free energy changes
associated to formation of a reactive complex (wr) and
separation of the product complex to give free products
(wp) according to eqs 10 and 11.
!
2
ΔG0
4ΔGq0
ΔGq ¼ ΔGq0 1 þ
ð9Þ
ΔGq ¼ ðΔGqÞobsd - wr
ð10Þ
ð11Þ
ΔG0 ¼ ðΔG0Þobsd - wr þ wp
It is generally difficult to identify the different processes
involved in forming a reactive complex and to estimate their
energetic contributions to the observed reaction barrier. For
this reason, in most of the cases where the Marcus formalism
has been applied to organic reactions the work terms have
(29) Brotzel, F.; Chu, Y. C.; Mayr, H. J. Org. Chem. 2007, 72, 3679–3688.
(30) Bunting, J. W.; Mason, J. M.; Heo, C. K. M. J. Chem. Soc., Perkin
Trans. 2 1994, 2291–2300.
(39) Hine, J. J. Am. Chem. Soc. 1971, 93, 3701–3708.
(40) Jencks, W. P.; Haber, M. T.; Herschlag, D.; Nazaretian, K. L. J. Am.
Chem. Soc. 1986, 108, 479–483.
(31) Heo, C. K. M.; Bunting, J. W. J. Chem. Soc., Perkin Trans. 2 1994,
2279–2290.
(32) Garcia-Rio, L.; Iglesias, E.; Leis, J. R.; Pena, M. E.; Rios, A. J.
Chem. Soc., Perkin Trans. 2 1993, 29–37.
(33) Brotzel, F.; Mayr, H. Org. Biomol. Chem. 2007, 5, 3814–3820.
(34) Antelo, J. M.; Arce, F.; Franco, J.; Sanchez, M.; Varela, A. Bull. Soc.
Chim. Belg. 1989, 98, 85–89.
(41) Richard, J. P. J. Chem. Soc., Chem. Commun. 1987, 1768–1769.
(42) McClelland, R. A.; Kanagasabapathy, V. M.; Banait, N. S.; Steenken,
S. J. Am. Chem. Soc. 1992, 114, 1816–1823.
(43) Berg, U.; Jencks, W. P. J. Am. Chem. Soc. 1991, 113, 6997–7002.
(44) Legon, A. C. Angew. Chem., Int. Ed. 1999, 38, 2687–2714.
(45) Metrangolo, P.; Neukirch, H.; Pilati, T.; Resnati, G. Acc. Chem. Res.
2005, 38, 386–395.
(35) Ritchie, C. D. Can. J. Chem. 1986, 64, 2239–2250.
(36) Koskikallio, J. Acta Chem. Scand. 1969, 23, 1477–1489.
(37) Cohen, A. O.; Marcus, R. A. J. Phys. Chem. 1968, 72, 4249–4256.
(38) Marcus, R. A. J. Am. Chem. Soc. 1969, 91, 7224–7225.
(46) Metrangolo, P.; Meyer, F.; Pilati, T.; Resnati, G.; Terraneo, G.
Angew. Chem., Int. Ed. 2008, 47, 6114–6127.
(47) Auffinger, P.; Hays, F. A.; Westhof, E.; Ho, P. S. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 16789–16794.
J. Org. Chem. Vol. 74, No. 15, 2009 5387

Calvo et al.
JOCArticle
SCHEME 7
HOBr > HOCl) and N-halosuccinimides59,60 (NBS > NCS)
with nucleophiles. These reactivity trends are consistent with
an easier transfer of bromine than of chlorine between the
same nucleophilic centers, and therefore we expect the
intrinsic barriers to chlorine transfer between carbanions
to be larger than the 10.9 and 16.3 kcal/mol reported for the
analogous bromine transfer between cyano- and nitro-acti-
vated carbanions, respectively.25
Therefore, the energetic cost of breaking the hydrogen bond
to a water molecule in the solvated amine is expected to be
compensated for, to a large extent, by the stabilization
energy associated to formation of a halogen bond to the
protonated chloramine. If this is so, the value of wr should be
close to the 2.8 kcal/mol needed to bring the reactants
together, giving ΔGq0 = 4.1 kcal/mol as the intrinsic barrier
for the chemical step.
A comparison of the intrinsic barrier reported here for
chlorine transfer between amines with that expected for the
corresponding transfer between carbanions shows that the
reaction at carbon is intrinsically slower than that between
nitrogen atoms, and therefore, halogen transfer reactions
seem to share this exceptional feature with proton transfer
reactions. Moreover, it has been shown that the nitro
anomaly, typical of proton transfer reactions, is also a
peculiarity of halogen transfer.25,61 The anomalous beha-
vior of carbanions in protonation and halogenation reac-
tions contrasts with their behavior in nitrosation reactions,
in which they have been found to react at rates similar to
those of secondary amines of similar basicity.62 Further-
more, the difference in reactivity between nitronate and
enolate ions of similar pKa toward the NO group is abnor-
mally low compared to that observed in other chemical
reactions. This nonanomalous behavior of carbanions in
nitrosation reactions was attributed to the high intrinsic
barriers to NO transfer, with bond formation and cleavage
providing the dominant energetic contribution to these
barriers. This raises the question of whether the observed
similarities between proton and halogen transfer reactions
are due to bonding changes making only a minor contribu-
tion to the intrinsic barriers for halogen transfer as it is
believed to occur for proton transfer reactions.
Kresge explored the possibility that delocalization of the
lone pair on nitrogen would make protonation of this atom
slow and found that the extensive delocalization of the
nitrogen electron pair in an amide does not cause a big
decrease in the rate of protonation.63 The apparent intrinsic
barrier for the reversible transfer of a chlorine atom from
N-chlorosuccinimide to dimethylamine, ΔGq0 = 7.6 kcal/
mol, estimated from reported rate and equilibrium data on
this reaction,64 is similar to the apparent intrinsic barrier
ΔGq0 = 6.9 kcal/mol reported here for chlorine transfer
between amines. It seems therefore that as has been shown
to occur for proton transfer, delocalization of charge into
the carbonyl groups of succinimide does not lead to a
significant increase in the intrinsic barrier for chlorine
transfer.
Literature reports on the calculation of intrinsic barriers
for organic reactions are scarce,50-54 and to the best of our
knowledge there have been no previous determinations of
these barriers for chlorine transfer. Our results show that
chlorine transfer between amines is intrinsically slower than
the apparently similar direct transfer of a proton between
nitrogen atoms, for which an intrinsic barrier of 1 kcal/mol
was estimated.24 Proton transfer between nitrogen atoms
along a preformed hydrogen bond is a very fast process
because it occurs through a symmetrical transition state in
which hydrogen is involved in a stable three-centered inter-
action with the electronegative atoms (Scheme 7A). There is
strong experimental evidence for the formation of stable bis
(amine)-iodine and bromine complexes.55-57 However, to
the best of our knowledge, similar stable hypervalent chlor-
ine compounds have not been described. The intrinsic barrier
of ca. 4 kcal/mol determined here for chlorine transfer
between amines provides evidence that the hypervalent
chlorine species (Scheme 7B) is ca. 4 kcal/mol higher in
energy than the pre-reactive protonated chloramine-amine
complexes.
It has been shown that bromine transfer between carba-
nions is faster than the corresponding proton transfer be-
tween the same species.25 This reactivity order was
tentatively attributed to the fact that bromine can expand
its valence shell better than hydrogen. The increasing ability
of halogens to expand the valence shell on going from
fluorine to iodine provides a successful explanation for the
observed reactivity order of hypohalous acids58 (HOI >
(48) Corradi, E.; Meille, S. V.; Messina, M. T.; Metrangolo, P.; Resnati,
G. Angew. Chem., Int. Ed. 2000, 39, 1782–1786.
(49) Alkorta, I.; Blanco, F.; Solimannejad, M.; Elguero, J. J. Phys. Chem.
A 2008, 112, 10856–10863.
(50) Bernasconi, C. F. Acc. Chem. Res. 1987, 20, 301–308.
(51) Richard, J. P.; Amyes, T. L.; Toteva, M. M. Acc. Chem. Res. 2001,
34, 981–988.
(52) Guthrie, J. P. J. Am. Chem. Soc. 2000, 122, 5529–5538.
(53) Guthrie, J. P.; Pitchko, V. J. Am. Chem. Soc. 2000, 122, 5520–5528.
(54) Guthrie, J. P.; Pitchko, V. J. Phys. Org. Chem. 2004, 17, 548–559.
(55) Brock, C. P.; Fu, Y.; Blair, L. K.; Chen, P.; Lovell, M. Acta
Crystallogr., Sect. C: Cryst. Struct. Commun. 1988, C44, 1582–1585.
(56) Blair, L. K.; Parris, K. D.; Hii, P. S.; Brock, C. P. J. Am. Chem. Soc.
1983, 105, 3649–3653.
To summarize, halogen transfer reactions seem to share
some of the unique features of proton transfer: (1) There is
only a small intrinsic barrier to chlorine transfer between
amines in aqueous solution, and we would expect this barrier
to be lower for the analogous bromine transfer reaction. (2)
Intrinsic barriers for halogen transfer at carbon are larger
than for the corresponding transfer between electronegative
atoms. (3) The well-known nitro anomaly is also present in
halogen transfer reactions.
(57) Elding, M.; Albertsson, J.; Svensson, G.; Eberson, L. Acta Chem.
Scand. 1990, 44, 135–138.
(58) Kumar, K.; Margerum, D. W. Inorg. Chem. 1987, 26, 2706–2711.
(59) Antelo, J. M.; Arce, F.; Crugeiras, J. J. Chem. Soc., Perkin Trans. 2
1995, 2275–2279.
(61) Eliad, L.; Hoz, S. J. Phys. Org. Chem. 2002, 15, 540–543.
(62) Leis, J. R.; Pena, M. E.; Rios, A. J. Chem. Soc., Perkin Trans. 2 1993,
1233–1240.
(60) Antelo, J. M.; Arce, F.; Crugeiras, J.; Parajo, M. J. Phys. Org. Chem.
1997, 10, 631–636.
(63) Kresge, A. J. Acc. Chem. Res. 1975, 8, 354–360.
(64) Higuchi, T.; Hasegawa, J. J. Phys. Chem. 1965, 69, 796–799.
5388 J. Org. Chem. Vol. 74, No. 15, 2009

Calvo et al.
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SCHEME 8
Experimental Section
a solution of perchloric acid (0.01-0.5 M) to give a reaction
mixture containing 0.3 mM substrate. The reactions were
monitored by following the increase in absorbance at 245 nm
using a conventional UV spectrophotometer. Second-order rate
constants, (k2)obsd (M-1 s-1), were calculated from the non-
linear least-squares fit of the data to the integrated second-order
rate equation, eq 12.
Materials. The sodium salt of N-chlorotaurine was prepared
by reaction of taurine with chloramine-T in ethanol. Deuterium
oxide and deuterium chloride (35% w/w) were 99.9% D and
99.5% D, respectively. Inorganic salts and organic chemicals
were reagent grade from commercial sources and were used
without further purification.
General Methods. Phosphate buffers were prepared by mixing
stock solutions of NaH2PO4 and Na2HPO4 in H2O at I = 0.5
(NaClO4) to give the desired acid/base ratio. Solution pH was
maintained by use of 0.03-0.15 M phosphate buffer (pH 5.8-
7.1). Measurements of pH at 25 ꢀC were obtained using a
radiometer PHM82 pH-meter equipped with a GK3401C com-
bined glass electrode. Values of pD were calculated by adding
0.4 to the observed reading of the pH meter. An apparent pKa of
pKBH=9.48 ( 0.04 for benzylamine in H2O at 25 ꢀC and I=0.5
(NaClO4) was determined by potentiometric titration of a
10 mM solution of the amine with HClO4.
Kinetic Studies. All kinetic studies were carried out in H2O at
25 ꢀC with the ionic strength maintained at I = 0.5 (NaClO4).
Kinetic experiments always employed at least a 10-fold molar
excess of both taurine and amine over N-chlorotaurine to ensure
pseudo-first-order conditions for both the forward and the
reverse reactions. Reactions were initiated by making a 100-fold
dilution of an aqueous solution of chloramine into the reaction
mixture to give a final substrate concentration of 0.3-3 mM.
The chlorine transfer from N-chlorotaurine to amines was
followed by conventional UV spectrometry by monitoring the
change in absorbance at the following wavelengths: benzyl-
amine, 230 nm; dimethylamine, 280 nm. Observed first-order
rate constants, kobsd (s-1), were determined from the fit of the
absorbance-time data to a single exponential function and were
reproducible to ( 5%.
ðA¥ - A0Þ
A ¼ A¥
-
ð12Þ
1 þ 2½BzNHClꢁ0ðk2Þobsdt
Figure S1 of Supporting Information shows the dependence
of (k2)obsd for the disproportionation of N-chlorobenzylamine
in water at 25 ꢀC and I=0.5 (NaClO4) on the concentration of
hydronium ion. The observed nonlinear dependence is consis-
tent with the mechanism proposed in previous work for the
disproportionation of N-chlorotaurine (Scheme 8), which in-
volves the transfer of a chlorine atom from a protonated to a
neutral chloramine molecule to form the dichloramine.
The solid line in Figure S1 shows the nonlinear least-squares
fit of the experimental data to eq 13, derived for Scheme 8, which
gave k2=47.8 ( 0.5 M-1 s-1 for the second-order rate constant
for disproportionation of N-chlorobenzylamine and Ka=0.149 (
0.004 M for the acidity constant of the conjugate acid of this
chloramine.
k2Ka½H3Oþꢁ
ðk2Þobsd
¼
ð13Þ
2
ðKa þ ½H3OþꢁÞ
Acknowledgment. We thank Prof. John P. Richard for
helpful discussions of this work and Prof. J. Peter Guthrie for
valuable suggestions on the calculation of intrinsic barriers.
This research was supported by a grant from the Ministerio
de Ciencia y Tecnologıa (BQU2001-2912).
pKa of Protonated N-Chlorobenzylamine. The pKa of the
conjugate acid of N-chlorobenzylamine at 25 ꢀC and I = 0.5
(NaClO4) was determined from a kinetic study of the dispro-
portionation of this N-chloramine carried out following proce-
Supporting Information Available: Table S1 of the observed
second-order rate constants for the reversible reaction of N-
chlorotaurine with benzylamine in aqueous solution at pH 5.8-
7.1 (buffered by phosphate) at 25 ꢀC and I = 0.5 (NaClO4).
Figure S1 showing the dependence of the observed second-order
rate constants (k2)obsd for disproportionation of N-chloroben-
zylamine on the concentration of hydronium ion. This material
is available free of charge via the Internet at http://pubs.acs.org.
dures described previously.26
A 5 mM solution of N-
chlorobenzylamine was prepared by adding the appropriate
amount of 0.027 M NaOCl to a 7.5 mM solution of the amine
at pH 8-9. The kinetics of disproportionation of N-chloroben-
zylamine to give N,N-dichlorobenzylamine were initiated by
adding a volume of the basic solution of N-chloro compound to
J. Org. Chem. Vol. 74, No. 15, 2009 5389