Halogenation of enol tautomers of 2-cyanoacetamide and malonamic acid

Article abstract of DOI:10.1039/b202542f

Reactions of 2-cyanoacetamide (CA) with both bromine and iodine at low halogen concentration in aqueous acid solution were first order in halogen and CA, consistent with an interpretation involving rate-limiting halogenation of the enol tautomer. There was no acid dependence in the range 0.1-0.5 mol dm^-3. The observed rate constants for bromination and iodination were very similar, indicating that both probably occurred at the encounter limit. This enabled a value for K_E, the equilibrium constant for enolisation, to be determined as 6 × 10^-10. There was strong evidence that at low acidities (pH ～ 4) enolisation is rate-limiting, but we were unable to achieve a fully zero-order kinetic dependence upon halogen. However we did obtain a value for the acid-catalysed enolisation rate constant k_e of 2.7 × 10^-3 dm³ mol^-1 s^-1 from measurements of rates of deuterium exchange with the solvent. The bromination of malonamic acid (ML) in dilute acid solution at low [Br₂] was zero-order in [Br₂] and we obtained a value of 1.3 × 10^-2 dm³ mol^-1 s^-1 for the acid catalysed enolisation rate constant. There is some evidence which suggests that enolisation of ML takes place via the amide group rather than the carboxylic acid group. The results are compared with earlier studies.

Full text of DOI:10.1039/b202542f

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Halogenation of enol tautomers of 2-cyanoacetamide and
malonamic acid
Alex Eberlin and D. Lyn H. Williams*
2
Chemistry Department, University of Durham, South Road, Durham, UK DH1 3LE.
E-mail: D.L.H.Williams@durham.ac.uk
Received (in Cambridge, UK) 12th March 2002, Accepted 13th May 2002
First published as an Advance Article on the web 29th May 2002
Reactions of 2-cyanoacetamide (CA) with both bromine and iodine at low halogen concentration in aqueous acid
solution were first order in halogen and CA, consistent with an interpretation involving rate-limiting halogenation
Ϫ3
of the enol tautomer. There was no acid dependence in the range 0.1–0.5 mol dm . The observed rate constants for
bromination and iodination were very similar, indicating that both probably occurred at the encounter limit. This
Ϫ10
enabled a value for K , the equilibrium constant for enolisation, to be determined as 6 × 10 . There was strong
E
evidence that at low acidities (pH ∼ 4) enolisation is rate-limiting, but we were unable to achieve a fully zero-order
kinetic dependence upon halogen. However we did obtain a value for the acid-catalysed enolisation rate constant k
e
Ϫ3
3
Ϫ1 Ϫ1
of 2.7 × 10 dm mol
s
from measurements of rates of deuterium exchange with the solvent. The bromination of
Ϫ2
malonamic acid (ML) in dilute acid solution at low [Br ] was zero-order in [Br ] and we obtained a value of 1.3 × 10
2
2
3
Ϫ1 Ϫ1
dm mol
s
for the acid catalysed enolisation rate constant. There is some evidence which suggests that enolisation
of ML takes place via the amide group rather than the carboxylic acid group. The results are compared with earlier
studies.
In recent years there has been a growing interest in the char-
acterisation of enol tautomers of carbonyl compounds other
than those from ketones, in particular from carboxylic acids,
esters and amides. In general these compounds exist over-
whelmingly in their keto forms and the enol tautomers are
generated the enol form of dicyanoacetamide. More recently
11
a systematic search for the existence of enols derived from
amides was conducted using powerful electron-withdrawing
substituents in the amides in an attempt to stabilise the enol
tautomer and a number were identified. Until recently the only
kinetic investigation was that of the halogenation and nitros-
1
extremely difficult to observe directly. Theoretical calculations
2
12
support this view, which has been rationalised in terms of
ation of malonamide. Under appropriate conditions it was
strong stabilisation of the keto forms by electron donation from
the heteroatom (oxygen or nitrogen in the case of carboxylic
acids, esters and amides) attached to the carbonyl group.
However there is strong kinetic evidence that enols are reactive
intermediates in, for example, halogenation (and other electro-
philic) reactions of, for example, malonic acid and some of
possible to obtain both limiting cases—where reactions were
respectively (a) zero-order and (b) first-order in electrophile.
Enolisation here is subject to acid-catalysis. The results enabled
values of both K (the equilibrium constant for enolisation) and
E
ke (the rate constant for acid catalysed enolisation) to be
obtained. In order to establish the generality of the enolisation
of simple amides, we have now extended these kinetic studies to
3,4
its derivatives. Under certain experimental conditions such
reactions are kinetically zero-order in halogen, and the obvious
conclusion is that rate determining enolisation is being
observed. There is also compelling evidence that the enolisation
in malonic acid derivatives involves intramolecular proton
transfer. In some cases it has been possible to obtain some such
the reactions of 2-cyanoacetamide, CH (CN)CONH2 (CA),
2
and of malonamic acid CH (CO H)CONH (MA), and present
2
2
2
13
the results in this paper. It is known that, as expected,
bromination yields the 2-bromo product (and the dibromo
at high bromine concentrations), and nitrosation the corre-
5
14
enols in the pure state using the Fuson technique (employed
sponding 2-oxime.
15
originally for ketones), whereby there are present in the
molecule large bulky groups which destabilise the keto form by
In a recent publication, the Kresge group has measured
the enolisation rate constant for 2-cyano-2-hydroxy-N-methyl-
acetamide by hydrogen exchange and also the ketonisation of
6
inhibition of solvation. Hegarty and O’Neill obtained enols
from carboxylic acids using bis(mesityl) and bis(pentamethyl-
phenyl) groups, which were sufficiently stable in solution to
allow successful structural determination. Similarly Frey and
the enol (generated by flash photolysis of a diazo precursor).
Ϫ13
They find a value of 8.4 × 10 for K , and by use of known
E
substituent effects upon K have obtained an estimate of
E
7
Ϫ22
Rappoport obtained the enol of ditipylacetic acid (tipyl =
2 × 10 for the K of the parent N-methylacetamide for the
E
2
,4,6-triisopropylphenyl), again in solution, but which had a
first time.
8
greater kinetic stability. Kresge and co-workers generated
enols of simpler ketones by flash photolysis methods to
generate a ketene which underwent hydration to give the enol.
In this way the enols of mandelic acid and other species were
identified spectrally as short lived species, and the rate of their
ketonisation measured. More recently poly(methoxycarbonyl)-
Results
(
a) Reactions of 2-cyanoacetamide CA
Ϫ4
Ϫ3
Reactions of both bromine (2.5 × 10 mol dm ) and iodine
9
Ϫ5
Ϫ3
cyclopentadiene structures have been synthesised which have
(7 × 10 mol dm ) with CA in at least a 20-fold excess in
Ϫ3
been shown to be enolic in the solid state and in solution.
Much less is known regarding the enols of amides.
0.1 mol dm aqueous acid solution were quite rapid and gave
excellent first-order kinetic behaviour. In all cases reactions
were followed in a stopped-flow spectrophotometer, by noting
10
Trofimenko claimed that the hydration of dicyanoketenimine
1
316
J. Chem. Soc., Perkin Trans. 2, 2002, 1316–1319
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b202542f

View Article Online
Ϫ4
Table 1 Values of k for the bromination of CA with [Br ] 2.5 × 10
Table 3 Values of k K for iodination and bromination of CA
2 E
1
2
Ϫ3
mol dm
3
Ϫ1 Ϫ1
Reaction
Method
k K /dm mol
s
2
E
Ϫ3
ϩ
Ϫ3
Ϫ1
[CA]/mol dm
[H ]/mol dm
k1/s
ϩ
Iodination
Iodination
Bromination
Bromination
Constant [CA], varying [H ]
2.54 ± 0.01
2.50 ± 0.08
1.61 ± 0.07
1.24 ± 0.06
ϩ
0
0
0
0
0
0
0
0
0
0
.025
.050
.100
.125
.150
050
.050
.050
.050
.050
0.500
0.500
0.500
0.500
0.500
0.500
0.625
0.750
0.875
1.000
0.066
0.103
0.173
0.196
0.220
0.074
0.077
0.075
0.082
0.093
Constant [H ], varying [CA]
ϩ
Constant [CA], varying [H ]
ϩ
Constant [H ], varying [CA]
Table 4 Approximate values of the zero-order rate constants k in the
0
Ϫ3
Ϫ3
bromination ([Br ] ∼ 2 × 10 mol dm ) of CA at low acidity using
2
acetic acid–acetate buffers
Ϫ3
Ϫ4
Ϫ3 Ϫ1
pH
[CA]/mol dm
k0/10 mol dm
s
4
4.12
4.12
4
4.46
4
4
4
5
5
5
5
.12
0.050
0.075
0.100
0.125
0.050
0.075
0.100
0.125
0.050
0.075
0.100
0.125
3.34
4.31
5.49
6.71
5.05
7.86
9.32
12.6
11.9
14.5
19.2
22.9
Ϫ5
Table 2 Values of k for the iodination of CA with [I ] 7.0 × 10 mol
1
2
Ϫ3
dm
.12
Ϫ3
ϩ
Ϫ3
Ϫ1
[CA]/mol dm
[H ]/mol dm
k1/s
.46
.46
.46
.27
.27
.27
.27
0
0
0
0
0
0
0
0
0
.025
.050
.124
.149
.198
.150
.150
.150
.150
0.250
0.250
0.250
0.250
0.250
0.063
0.125
0.375
0.500
0.083
0.143
0.308
0.389
0.522
0.264
0.325
0.379
0.378
by working at low acidities, since we were limited in our ability
to increase [halogen] significantly. We found that at around
pH 4 in acetic acid–acetate buffers, reactions initially were
zero-order in [halogen], but this was only maintained for
the disappearance of the halogen absorbance at the appropriate
wavelength. Reactions were also found to be first order
in CA and independent of [H ] above about 0.1 mol dm . The
experimental values of k , the measured first-order rate
constants, are given in Tables 1 and 2 for bromination and
iodination respectively.
2
0–30% reaction when linearity of the absorbance–time plot
ϩ
Ϫ3
gave way to a degree of curvature. It was clear that under these
conditions enolisation was partly rate-limiting, but that we had
not fully achieved the appropriate limiting condition. Never-
1
theless we measured zero-order rate constants k from the first
0
part of the reaction, which we recognise are subject to possible
significant error. These results (shown in Table 4) however are
sufficiently clear to demonstrate that reactions are under these
conditions, first-order in CA and also show strong base-
catalysis by acetate ion. Because of the inability to achieve fully
zero-order kinetics and the complication due to base catalysis,
we sought to obtain the enolisation rate constant by way of
The results indicate that we are looking at rate-limiting
reaction of the halogen with the enol tautomer of CA [eqn. (1)],
KETO
ENOL ϩ Halogen
Product
(1)
i.e. when the rate of ketonisation is much greater than the rate
ϩ
deuterium exchange experiments using D SO . This procedure
2 4
16
of enol halogenation (k [H ] ӷ k [halogen], where k is the rate
k
2
k
was used successfully by Hansen and Ruoff for the enolisation
of malonic acid, where the results were in reasonable agreement
with those derived from halogenation experiments. We have
also used the same procedure successfully earlier in the case of
constant for ketonisation of the enol and k the rate constant
2
for halogenation of the enol, assuming for the moment that
ketonisation and enolisation are acid-catalysed processes). We
obtain values for k KE (KE is the enolisation equilibrium
2
17
enolisation of ethyl cyanoacetate.
constant) for both halogenation reactions, (a) from the [CA]
dependence and (b) from the experiments at different acidities,
which are given in Table 3.
A product analysis was carried for the bromination of CA,
adding bromine slowly to a ten-fold excess of CA in dilute acid
solution. The product was analysed by proton NMR and
showed clearly that under these conditions a mixture of the
mono- and di-brominated product was formed. The singlet at
During exchange with D SO –D O the singlet peak in
2
4
2
the proton NMR spectrum from the methylene protons (at
.6 ppm) was replaced by triplet arising from the
3
a
mono-deuterated species B (due to coupling with the deuterium
atom). Over a longer time period there was evidence of con-
version to the di-deuterated species C. Reaction was monitored
by the decreasing singlet peak integral due to A.
3
.6 ppm due to the methylene protons in CA disappeared as
expected in the dibromo product and was shifted to 5.6 ppm in
the monobromo product. The protons of the amide group were
split into a doublet (probably due to restricted rotation around
the C–N bond) and were shifted from 7.6 and 7.4 in CA to 8.0
and 7.8 in the monobromo product and 8.5 and 8.3 in the
dibromo product. The integration gave ratios of 1 : 1 for the
amide protons : methylene protons in CA and 2 : 1 for the same
ratio in the monobromo product. When the experiment was
repeated at equal concentrations of CA and bromine, only the
dibromo compound was formed. A similar experiment using
iodine gave evidence of the monoiodo product by a (smaller)
shift of the methylene proton signal to 3.8 ppm.
(
2)
Unfortunately it was not possible (as was the case with ethyl
cyanoacetate) to obtain reliable values for the concentration of
B because of the broad peaks encountered. We could only then
get the rate constant for the conversion of A into B. Three runs
were carried out in the acid range 0.1–0.3 mol dm . Good
first-order plots were obtained in each case, following the
Ϫ3
disappearance of A. The first-order rate constants k are given
in Table 5. Clearly the reaction is acid-catalysed and there is an
1
We also attempted to identify the other limiting condition
excellent straight line plot between k1 and [D SO ], which
passes through the origin and the slope gives the acid-catalysed
2
4
ϩ
when enolisation is rate limiting i.e. when k [H ] Ӷ k [halogen]
k
2
J. Chem. Soc., Perkin Trans. 2, 2002, 1316–1319 1317

View Article Online
Table 5 The first-order rate constants k for proton exchange in CA
There was a small positive intercept for the plots of the
measured first-order rate constants vs. [CA], which is readily
explicable for iodination by the likelihood of a small degree of
reversibility, which is well-known in iodination. Generally this
is not a problem with bromination in water, so the result is a
little puzzling. However, from the slopes of these plots, and the
results from the acidity variation, we obtain consistent results
for the product k K (see Table 3). In addition there is a
1
2
with D SO4
Ϫ3
Ϫ4 Ϫ1
[
D SO ]/mol dm
k1/10
s
2
4
0
0
0
.05
.10
.20
1.76 ± 0.34
3.53 ± 0.15
5.87 ± 0.43
2
E
reasonably close correspondence between the bromination and
iodination results, when normally bromination in water is
orders of magnitude more rapid than is iodination. The only
sensible rationalisation is that both reactions are taking place
at, or close to, the encounter-controlled limit. This has
previously been noted on many previous occasions, e.g. in the
Table 6 Zero-order rate constants k for the bromination ([Br ] =
0
2
Ϫ3
Ϫ3
1
.5 × 10 mol dm ) of ML
Ϫ3
ϩ
Ϫ3
Ϫ4
Ϫ3 Ϫ1
[ML]/mol dm
[H ]/mol dm
k0/10 mol dm
s
0
0
0
0
0
0
0
0
0
0
0
0
0
.037
.048
.100
.147
.196
.032
.032
.032
.032
.032
.032
.032
.032
0.80
0.80
0.80
0.80
0.80
0.05
0.10
0.20
0.30
0.40
0.50
0.60
0.80
3.38
4.30
9.10
14.2
18.5
0.30
0.41
0.78
1.39
1.86
2.10
2.66
3.58
19
halogenation of ketones at low [halogen]. Workers have
9
3
Ϫ1 Ϫ1
usually used a value of 5 × 10 dm mol
s
for the encounter-
controlled process. This is slightly lower than the value
20
predicted by the theory. However, it has been argued (on the
basis of an extended study of the bromination of enols derived
21
from ketones) that these reactions are not fully diffusion-
controlled, and that a more appropriate average value to take
9
3
Ϫ1 Ϫ1
for the second-order rate constant is 3.4 × 10 dm mol s .
3
Ϫ1 Ϫ1
Using this value and an average value of 2 dm mol
product k
s
for the
Ϫ10
Ϫ10
K
from Table 3, we obtain a value of 6 × 10 for K
2
E
E
for CA. This compares with a similar value of 8 × 10 for the
Ϫ3
3
Ϫ1 Ϫ1
enolisation of malonamide (using the more recent appropriate
enolisation rate constant as 2.7 ± 0.3 × 10 dm mol s . At
value for k ). These numbers are the same within the experi-
2
these acidities we have taken D SO to be a monobasic acid.
2
4
mental error in their determination. Similarly the deuterium
isotope exchange measurements gave a value of k , the acid-
e
3
(
b) Reactions of malonamic acid ML
Ϫ3
Ϫ1 Ϫ1
catalysed enolisation rate constant, of 2.7 × 10 dm mol s ,
12
Malonamic acid proved rather difficult to synthesise in a pure
state and so we were rather limited in our ability to carry out
rate measurements. Spontaneous loss of carbon dioxide occurs,
generating acetamide. It was possible to obtain reasonably good
kinetic data for bromination of ML when [Br ] was ∼1 × 10
mol dm in the acid range 0.05–0.8 mol dm always with [ML]
in at least a 20-fold excess. Most runs showed good zero-order
behaviour, but there was a tendency for there to be a small rapid
decrease of absorbance preceding the linear drop, particularly
at the higher [ML]. This suggests that there is some impurity
present, which reacts more rapidly with bromine. We have
ignored these small discrepancies and report zero-order rate
constants in Table 6. It is quite clear that reaction is fully
first-order in ML and also in H , since both appropriate plots
gave excellent straight lines which passed through the origin.
This enabled us to generate from the two sets of experiments
two values of k , the rate constant for acid-catalysed enolisa-
tion, as 1.20 ± 0.10 and 1.37 ± 0.03 × 10 dm mol
respectively, which represents an excellent level of agreement.
We take the average value for k to be 1.3 ± 0.1 × 10 dm
mol s . We were unable experimentally to achieve the other
possible limiting case when reaction of the enol is rate-limiting.
which compares favourably with the literature value of 3.3 ×
Ϫ3
10 for the corresponding reaction of malonamide. It appears
that substitution of –CONH2 by the more electron-
withdrawing –CN group makes little difference. This finding
is consistent with the accepted mechanism for acid-catalysed
Ϫ3
2
Ϫ3
Ϫ3
22
enolisation [eqn. (3)]
ϩ
Ϫ
–
CH –CO– ϩ HA
–CH –C(OH )– ϩ A
2
2
–
CH᎐C(OH)– ϩ HA (3)
᎐
which involves rapid proton transfer from a general acid to
the carbonyl oxygen atom, followed by rate limiting proton
Ϫ
abstraction by A (water in our case). Substituent effects on the
ϩ
rate of such enolisations (of ketones) are small and follow no
pattern, since the effect on the oxygen basicity (first step) is
offset by the effect on the α-hydrogen atom acidity. Much the
e
same occurs in the acid-catalysed hydrolysis of esters.
Ϫ2
3
Ϫ1 Ϫ1
s
15
We can, using the Kresge approach, use our pK value of
E
9
.2 for CA to estimate the pK of the parent amide acetamide,
Ϫ2
3
E
e
making use of the approximate substituent effects upon pKE
Ϫ1 Ϫ1
values, notably the ∆pK for the CN group of 9.4. This yields a
E
pKE for acetamide of ∼ 18.6, which unfortunately is not in
particularly good agreement with a similar estimate of 21.7 for
15
N-methylacetamide.
Discussion
The product analysis with the bromine reaction confirmed
that the monobromo and possibly some dibromo products were
formed. Our product work was necessarily carried out at
somewhat higher concentration than were the kinetic experi-
ments, which may exaggerate the % dibromo product. In any
case the kinetic curves were all smooth and consistent with
rate limiting monobromination of the enol. Any subsequent
reaction is likely to be fast (and post-rate limiting), given the
(
a) Reactions of CA
At halogen concentrations convenient for spectrophotometric
analysis (Br ∼ 2 × 10 mol dm and I ∼ 7 × 10 mol dm )
Ϫ4
Ϫ3
Ϫ4
Ϫ3
2
2
Ϫ3
and at acidities > ∼ 0.1 mol dm , reaction with CA (always in
large excess) is first-order in halogen and CA and independent
of acidity. There is thus no kinetic evidence for involvement of
the enolate (carbanion) as is expected from the published pKa
value for CA of 13.45. Our results are consistent with rate
limiting halogenation, of the enol form of CA. There was
strong evidence that the enol (D) is involved, from the change
towards a zero-order dependence on halogen at very low
acidities.
18
expected much higher K for the monobromo compound. This
E
is a familiar situation in the halogenation of enols from simple
ketones.
(b) Reactions of ML
We were limited by purification difficulties in our attempt to get
kinetic data for the halogenation of ML. However it was
1
318
J. Chem. Soc., Perkin Trans. 2, 2002, 1316–1319

View Article Online
possible to carry out some bromination experiments over a
wide acidity range. Reactions were zero-order throughout (with
Bromine (1 g) in water was added slowly to a solution of CA
(5 g) in water (300 cm ). The product was extracted with ether,
3
[
ML] ӷ [Br ]), apart from a small initial deviation which we
dried, the solvent removed and the prooton NMR spectrum run
on a 200 mHz spectrometer.
2
attribute to the presence of an impurity. Reactions were first
order in ML and H indicating rate-limiting acid-catalysed
ϩ
enolisation. We find no evidence of intramolecular proton
Acknowledgements
transfer as is the case with malonic acid and its derivatives,
Ϫ3
at least over the acid range covered, 0.05–0.80 mol dm .
We thank the EPSRC for a research studentship to ARE
and David Parkin for help with some of the NMR
experiments.
There are of course two possible modes of enolisation in ML,
involving the amide function (E) or the carboxylic function (F),
and it is not easy to distinguish between these possibilities.
References
1
A. F. Hegarty and P. O’Neill, in The Chemistry of Enols, ed.
Z. Rappoport, Wiley-Interscience, Chichester, 1990, Chapter 10.
Y. Chiang, E. A. Jefferson, A. J. Kresge, V. V. Popik and R.-Q. Xie,
J. Phys. Org. Chem., 1998, 11, 610; B. D. Wagner, B. R. Arnold,
G. S. Brown and J. Lusztyk, J. Am. Chem. Soc., 1998, 120, 1827 and
earlier references.
2
Acid-catalysis of enolisation generally disappears when the
carbon acidity of the α-proton is increased (when there are
powerful electron-attracting 2-substituents e.g. as in 1,3-
dichloroacetone and other examples). This does not seem to
be the case with malonamide, cyanoacetamide and malonamic
acid. This probably arises because of the increased basicity (for
23
3 V. M. Bahle, S. L. Bafna and W. V. Bhagwat, Z. Phys. Chem., 1957,
2, 298.
A. R. Eberlin and D. L. H. Williams, J. Chem. Soc., Perkin Trans. 2,
996, 883.
5 R. C. Fuson, R. E. Foster, W. J. Shenk, Jr. and E. W. Maynert, J. Am.
Chem. Soc., 1945, 67, 1937.
6 P. O’Neill and A. F. Hegarty, J. Chem. Soc., Chem. Commun., 1987,
1
4
1
oxygen protonation) of amides (typical pK Ϫ0.7) compared
a
with carboxylic acids and esters (typical pK Ϫ6 to Ϫ8). This
a
can be taken to be an argument in favour of the suggestion that
enolisation of malonamic acid occurs in the amide group
following oxygen protonation. The enolisation of 2-hydroxy-2-
cyano-N-methylacetamide is also an acid-catalysed process in
744.
7
J. Frey and Z. Rappoport, J. Am. Chem. Soc., 1996, 118,
5
128.
8
9
A. J. Kresge, Chem. Soc. Rev., 1996, 25, 275.
15
this acid region.
Y. X. Lei, G. Cerioni and Z. Rappoport, J. Org. Chem., 2000, 65,
4
028.
1
1
1
0 S. Trofimenko, T. H. Little and H. F. Mower, J. Org. Chem., 1962, 27,
33.
1 J. K. Mukhopadhyaya, S. Sklenak and Z. Rappoport, J. Org. Chem.,
000, 65, 6856.
2 D. L. H. Williams and L. Xia, J. Chem. Soc., Perkin Trans. 2, 1993,
429.
Experimental
4
Malonamic acid was prepared by the method of Jeffery and
2
24
Vogel from ethyl hydrogen malonate and aqueous ammonia.
Repeated recrystallisation from pentan-3-one gave significant
amounts of acetamide impurity (as detected by H NMR
1
1
13 J. Suzuki, K. Suzuki and M. Sekiya, Chem. Pharm. Bull., 1974, 22,
measurements). This was reduced by washing with pentan-3-
one and allowing the product to dry slowly on the top of an
oven. This gave a sample with mp 116 ЊC (lit. 121 ЊC). Repeated
purification attempts did not yield a product with a higher
melting point. All other materials were commercial samples of
the highest purity grade available. Kinetic halogenation
measurements were carried out in a stopped-flow UV–visible
spectrophotometer interfaced with the appropriate software.
All reactions were carried out in water at 25 ЊC, with the
reactants CA or ML in at least a 25-fold excess over the
halogen. Reactions were followed by noting the disappearance
of the halogen absorbance (at 390 nm for bromine and 460 nm
for iodine). First-order and zero-order plots were analysed in
the conventional manner. The deuterium exchange experiments
for CA were carried out using D SO –D O measuring the
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