Evidence for proton transfer from carbon to chloride ion in solution

Article abstract of DOI:10.1016/j.tetlet.2005.11.005

Unambiguous evidence for proton transfer from carbon to chloride ion in solution has been obtained for the first time, in the formation of hydroxamic acids from aldehydes and nitrosobenzenes in acetonitrile.

Full text of DOI:10.1016/j.tetlet.2005.11.005

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 371–375
Evidence for proton transfer from carbon to chloride ion in solution
a
a
b
Viktor Pilepic, Cvijeta Jakobusic, Drazˇen Vikic-Topic and Stanko Ursic
ˇ ´a,*
ˇ ´
´
´
´
aFaculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovacˇic´a 1., 10000 Zagreb, Croatia
bNMR Center, Institute Rugjer Bosˇkovic´, Bijenicˇka 54, 10 000 Zagreb, Croatia
Received 25 August 2005; revised 27 October 2005; accepted 2 November 2005
Available online 18 November 2005
Abstract—Unambiguous evidence for proton transfer from carbon to chloride ion in solution has been obtained for the first time, in
the formation of hydroxamic acids from aldehydes and nitrosobenzenes in acetonitrile.
Ó 2005 Elsevier Ltd. All rights reserved.
Proton transfers are fundamental processes of central
importance in many fields of chemistry and biochemis-
try.1–12 A very broad range of phenomena has been
studied, including proton transfers in DNA and related
systems,2–4 proton coupled electron transfer pro-
cesses,5–7 multiple proton transfers8 and proton transfers
involving phosphorus, sulfur and other atoms.9,10
Proton transfers which involve carbon,11,12 are of consid-
erable interest. Thus, for example proton transfer from
carbon to Brønsted bases constitutes an important step
in many complex biochemical processes.13 However,
the possible involvement of halide ions in proton trans-
fers from carbon has been considered only occasionally.
Recently, two reports14,15 appeared dealing with the
question of the possible involvement of chloride ion in
proton transfer from carbon. Meng and Thibblin14 pro-
posed that the leaving chloride in certain elimination
reactions at tertiary carbon abstracts the proton from
the b-C–H bond within the carbocation–chloride contact
ion pair in acetonitrile-water solvent. In the paper by
Moss, Sauers and co-workers,16 which appeared two
years later, essentially the same question was addressed
though within a different context, that is, the investiga-
tion of the fragmentation of 2-norbornyloxychlorocarb-
enes in MeCN. We have reported15 the observation of
unusual interconnected salt effects and kinetic isotope
effects in the acid catalysed reactions of aldehydes with
C-nitroso compounds in mixed solvents in the presence
of halide ions, which could suggest the involvement of
chloride ion in the proton transfer from carbon. There
are also other reports17,18 where the promoting influence
of the added chloride on the elimination was considered.
However, the evidence reported so far does not seem to
be conclusive.19 Now, we have obtained unambiguous
evidence for proton transfer from carbon to chloride
ion in the formation of hydroxamic acids from aldehydes
and nitrosobenzenes in 99.9% acetonitrile solution. The
overall reactionꢀ is the same as in water20–22 or in some
mixed solvents15 but the process is complex in all cases
involving several steps prior to final formation of the
hydroxamic acid. Taking into regard the mechanism of
the reaction proposed earlier20–23 for the reaction in
water and in mixed solvents, and the results obtained
in 99.9% acetonitrile, the key features of the mechanism
in acetonitrile can be described by Scheme 1.
The reaction is acid catalysed. The products of the reac-
tion are undetectable after several hours in the absence
of a catalyst.ꢁ As expected, the addition of acid to a
solution of aldehyde in 99.9% acetonitrile leads to an in-
crease in the rates of both acid-catalysed hydration of
the aldehyde and acid-catalysed dehydration of the alde-
hyde hydrate. Thus, broadening of the 1H NMR
absorption signal of the proton attached to the carbonyl
group on addition of HCl to a solution of formaldehyde
in 99.9% acetonitrile was observed (Fig. 2B). A com-
pletely analogous broadening was obtained by adding
ꢀ The overall reaction is: RCHO + Ph–NO ! RC(O)N(Ph)OH, the
reaction goes to completion under the conditions employed and the
corresponding N-phenylformylhydroxamic or N-phenylacetohydrox-
amic acids in the case of acetaldehyde are the products, as confirmed
by methods reported elsewhere.20–22,24,25
ꢁ One could doubt that traces of acidic impurities may cause the very
slow process.
Keywords: Proton transfer; Kinetics; Isotope effects; Chloride;
Hydroxamic acids.
*
Corresponding author. Tel.: +385 1 4818 306; fax: +385 1 4856
201; e-mail: stu@pharma.hr
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.005

372
V. Pilepic´ et al. / Tetrahedron Letters 47 (2006) 371–375
O
N
OH
C
-
O
O
HO
OH
H
+
O
O
–
+
N
- H+,Cl
N
H
Cl–
HCHO . H+Cl–
H+Cl-
C
N C
+
H
H
H
H
1
2
3
Scheme 1.
of HClO4 to the aldehyde solution in 99.9% acetonitrile.
The addition of excess HClO4 did not alter the estab-
lished aldehyde/aldehyde hydrate equilibrium notice-
ably, as shown by the UV evidence (see also below).
5
4
3
2
1
0
4
3
2
1
0
The proton transfer to the aldehyde oxygen atom is
probably the cause of the catalysis. Dipolar addition spe-
cies probably do not exist as discrete intermediates in the
general acid catalysed reactions of formaldehyde with
water and alcohols. These reactions proceed by a con-
certed class e mechanism.26 An attractive possibility here
would be a concerted mechanism involving a nitroso
compound as the addition species and the formation of
a nitrosocarbinolic cation as the resulting intermediate
in the reaction. An assessment of the precise timing of
the proton transfer or the corresponding transition states
or intermediates in the process, is a very subtle task.
However, these limitations do not bring into question
the main conclusions arising from this investigation.
0.000
0.001
c (HCl) / mol dm-3
0.002
0.00
0.01
0.02
0.03
c (HCHO) / mol dm-3
Figure 1. The dependence of the observed rate constants for the
formation of N-phenylformylhydroxamic acid in 99.9% MeCN on the
aldehyde concentration, in excess. [HCl] = 0.00025 M, [nitrosobenz-
ene] = 0.00002 M, throughout. The pseudo-first order rate constants
were determined spectrophotometrically, using the method
reported.19–21 Inset: the corresponding dependence of the observed
rate constants on the concentration of HCl. [HCHO] = 0.0057 M,
throughout, at 25 °C.
The observed q Hammett parameter is negative suggest-
ing a nucleophilic20–23 role for the nitroso compound
and in the presence of HClO4 as the catalyst, the ob-
served primary deuterium kinetic isotope effect (PKIE)
between formaldehyde and d2-formaldehyde in the reac-
tion suggests that proton transfer from the CH2 carbon
of the nitrosocarbinolic intermediate to a molecule of
water should be the rate controlling step. The evidence
in support of the mechanism and the proton transfer
from carbon to chloride ion in the reaction comprises
of the following:
between the aldehyde and the solvated hydronium
ion in the presence of HClO4 catalyst, or the analo-
gous complex involving the ion pair H+Clꢀ when
hydrochloric acid is used (see below).
(2) When aldehyde concentration was kept constant
and in a sufficiently large excess over the HCl con-
centration (or vice versa) a strong linear depen-
dence of the observed rate constants on the HCl
concentration in the reaction was obtained (see
Fig. 1, inset). The slopes of the linear dependencies
are essentially the same for the same concentrations
of reactant in a large and constant excess. Further
increase of the concentration of the minor reaction
component leads to departure from linearity in the
dependence observed. This observation corrobo-
rates the involvement proposed above of a complex
between the aldehyde and the catalyst. The
observed concentration dependence shows that the
H+Clꢀ ion pair must be involved in the complex.§,–
(3) The spectroscopic evidence obtained seems to be in
support of the presence of chloride ions in the
kinetically observed association complex in the pro-
(1) A levelling-off was observed in the dependence of the
rate constants observed for the formation of the N-
phenylformohydroxamic acids in the reaction of
formaldehyde with substituted nitrosobenzenes on
the aldehyde concentration, at small and constant
concentrations of HCl or HClO4 as the catalysts,
in 99.9% acetonitrile (Fig. 1). This observation is
consistent with the involvement of a complex§
§ An estimate from the kinetic measurements of the concentration
quotient for the formation of the complex with HCl, tentatively
assuming the process: HCHO + H+Clꢀ ¢ HCHOÆH+Clꢀ gave a
value of ca. 104 Mꢀ1. At present, more information on the nature
of this complex, solvation of the species that constitutes the
association, etc. are not easily accessible. Recall that HClO4 is fully
dissociated in MeCN, while the association constant for HCl is of the
order of 108 Mꢀ1 in the same medium.27 Similar levelling-off in the
dependence of the observed rate constants for the reaction on the
aldehyde concentration in excess was obtained for the reaction of
nitrosobenzene with acetaldehyde but at substantially greater con-
centrations of the aldehyde.
– Obviously, nonlinear dependence should be obtained if the complex
involved the solvated hydronium ion only (arising from the dissoci-
ation of HCl).

V. Pilepic´ et al. / Tetrahedron Letters 47 (2006) 371–375
373
0.06
A
(A)
(B)
0.04
0.02
0.00
d
c
b
a
9.9 9.8 9.7 9.6 9.5 9.4
ppm
250
300
350
λ (nm)
Figure 2. (A) Change in the UV spectra of 0.01 M formaldehyde in 99.9% acetonitrile solution on addition of (downward): 0.001 M HCl, 0.005 M
HCl, 0.01 M HCl, 0.02 M HCl, 0.03 M HCl and 0.05 M HCl. The spectra of HCl were subtracted since HCl absorbs slightly in the range, at 25.0 °C.
(B) Change in the 1H NMR signal of carbonyl protons of 0.01 M HCHO in 99.9% acetonitrile-d3 on addition of (a) 0.001 M HCl, (b) 0.005 M HCl,
(c) 0.01 M HCl and (d) 0.02 M HCl, at 25 °C.
Table 1. Kinetic isotope effects in the reaction of formaldehyde and
cess. The aldehyde carbonyl absorption band in the
nitrosobenzene in 99.9% acetonitrilea
UV spectrum of formaldehyde in 99.9% acetonitrile
disappears in partk on the addition of HCl to the
solution (Fig. 2A).
Catalyst
103 kH/sꢀ1
103 kD/sꢀ1
PKIE
HClO4
HCl
1.57 (0.05)
2.25 (0.06)
0.34 (0.01)
2.26 (0.07)
4.68 (0.23)
1.00 (0.04)
The change is reversible. The spectrum of the alde-
hyde was instantaneously and quantitatively regen-
erated on addition of an equivalent of a base (e.g.,
triethylamine), but no change in the carbonyl peak
in the spectrum was observed on the addition of
the same amount of HClO4 to the aldehyde solution
in 99.9% acetonitrile. This observation suggests that
the absorbance of the carbonyl group is not strongly
influenced by the solvated hydronium ion in the
complex which is indicated by the kinetic experi-
ments. In contrast, the influence of HCl is obvious
from the UV spectra (Fig. 2A) and could be a
consequence of dipole–dipole interactions of the
carbonyl group and the H+Clꢀ ion pair in the
association.
a [HCHO] = [DCDO] = 0.0022 M, throughout. [HClO4] = 0.0003 M,
[HCl] = 0.0003 M. At 298 K.
0.5
p
-CH3
0
-0.5
-1
H
p
-F
p
-Cl
(4) The observed primary deuterium kinetic isotope
effect kH/kD between formaldehyde and d2-formal-
dehyde is 4.7 when HClO4 is used in the reaction
p
-Br
m
-Cl
k The appearance of the carbonyl absorption band in the UV spectrum
is very slow after the addition of small amounts of formaldehyde
hydrate (ca. 14 M solution) to 99.9% acetonitrile, but the new
aldehyde/hydrate equilibrium is established within a minute or less
(within seconds in the case of HClO4) and is stable for hours on
addition of 10ꢀ4 to 10ꢀ3 M HCl. With regard to the proposed
complex, comparison with the kinetic observations shows that the
disappearance of the absorbance of the carbonyl peak on the further
addition of HCl is not complete even at several times excess of the
acid. In our opinion, this is not surprising since there is no covalent,
but only dipole–dipole, interactions between the carbonyl group and
the H+Clꢀ ion pair in the complex, which changes the carbonyl group
absorption coefficient only marginally. At present, we do not have
information about the molar absorption coefficients of the aldehyde
and the complex in the medium. Finally, there is no obvious reason
for the absence of aggregates containing more than one HCl per one
carbonyl group at higher acid concentrations. The further addition
(in excess of 0.001 M) of HClO4 did not influence the carbonyl
absorbance noticeably though the kinetic results suggested the
occurrence of association in the process.
-1.5
-0.2
0
0.2
0.4
σ
Figure 3. The plot of logkR/kH versus Hammett r parameters for the
reaction of the substituted nitrosobenzenes with formaldehyde in 99.9%
acetonitrile containing hydrochloric acid catalyst. [HCHO] =
0.005 mol dmꢀ3, [HCl] = 0.0015 mol dmꢀ3 and [R-C6H4–NO] = 0.0001
mol dmꢀ3, at 25.0 0.1 °C. q = ꢀ3.18 (r = 0.995).
(Table 1). This PKIE is consistent with a rate-con-
trolling proton transfer from carbon27,28 of the CH2
moiety in the nitrosocarbinolic intermediate 2 to a
molecule of water.** This PKIE can be compared
with the values of ca. 7 obtained for the reaction
**
The reaction solution contained ca. 0.022 M of water. The HPLC
grade MeCN used contains 0.017 M of water.

374
V. Pilepic´ et al. / Tetrahedron Letters 47 (2006) 371–375
+
O
O
OH2
H
HO
H
HO
H
Cl
H
+
OH3
+
HCl
+
H
H
H
H
N
O
O
O
O
OH
OH
H
+
+
+
OH2
HO
H
:
N
:
HO
Cl
H
N
RLS
N
–
OH2
Cl
+
+
+
+
+
H
H
H
H
H
O
OH
O
HO
OH
OH
H
HO
+
OH
H
+
RLS
+
N
+
+
N
–
N
OH2
+
OH3
Cl
N
+
HCl
+
H
H
H
H
I+
I+
Scheme 2.
in water20 and in some mixed solvents.15 The corre-
sponding PKIE observed when HCl was used is 1.0.
The observed absence of a PKIE could be the con-
sequence either of a change in the rate controlling
step in the reaction or a change in the transition
state for the proton transferꢀꢀ (or possibly both of
these). In order for a change to occur in the rate-
controlling step, to cancel the observed PKIE of
4.7, the proton transfer step must become corre-
spondingly faster, or one of the preceding reaction
steps must become correspondingly slower than
the proton transfer step. The reaction systems
in the two experiments differed only with regard
to the presence of the catalytic acid. The existence
of the proposed complex of HCl and aldehyde in
the process is also consistent with the result, since
the chloride ion is already present in the encounter
complex at the time when the nitroso compound
enters the process and the C–N bond is formed.
Therefore, it seems reasonable to conclude that
chloride ion is involved in the proton transfer from
the CH2 moiety in the process.ꢀꢀ
not correspondꢁꢁ to the association constant of the
kinetically observed complex (see Fig. 1); (ii) the broad-
1
ening of the H NMR absorption line of the proton at-
tached to the carbonyl group was observed on addition
of HCl as well as on addition of HClO4; (iii) a levelling-
off was observed in the dependence of the rate constants
observed for the formation of the N-phenylformylhydr-
oxamic acids in the reaction of formaldehyde with
substituted nitrosobenzenes on the aldehyde concentra-
tion, at small and constant concentrations of HCl as
well as HClO4, in 99.9% acetonitrile. Therefore, the for-
mation of the nitrosocarbinolic cationic intermediate, by
a concerted mechanism involving the nitroso com-
pound, the aldehyde and the catalyst is perhaps a more
attractive possibility at present, as already noted above.
In conclusion, the evidence obtained suggests that a
proton transfer takes place from the carbon of the
CH2 moiety to the chloride in the formation of
hydroxamic acids from aldehydes and nitrosobenzene.
This observation could be of use for understanding
the role of chloride in certain elimination reactions in
nonaqueous solvents and the potential role of the ion
in processes in related biological environments. It is
noteworthy that the rate constant of formation of
hydroxamic acid in the reaction in 99.9% acetonitrile
is 103 times greater than the corresponding rate constant
in water. This observation could be of value for the
preparation/synthesis of hydroxamic acids since the
biochemical/biomedicinal significance of this class of
compounds is well known.32,33
(5) The observed q Hammett parameter in the reaction
is ꢀ3.18 (Fig. 3) when HCl was used as the catalyst.
The corresponding value observed under the same
reaction conditions in the presence of HClO4 as
the catalyst was ꢀ1.69. The change of the q para-
meter is consistent with a change in the rate-
controlling step which becomes a proton transfer
from the CH2 in the presence of HClO4, as indi-
cated by the observed PKIE in this case.
A referee has suggested a different reaction pathway
(Scheme 2) to the nitrosocarbinolic cation intermediate
I+. The key feature of the mechanism suggested is the
formation of chloromethanol in the case of HCl cataly-
sis. However, we believe that the observed changes in the
UV and NMR spectra are not unambiguously in sup-
port of the formation of chloromethanol in the system.
Thus, (i) the disappearance of the absorbance of the
aldehyde carbonyl band at 300 nm in Figure 2A does
Acknowledgements
We thank the Ministry of Science and Education of the
Republic of Croatia, for financial support (project 0006-
431).
ꢁꢁ Chloromethanol has never been detected in a solution but was
studied in argon matrices30 and in the gas phase31 as the product of
certain photochemical processes and the lifetime of the compound is
measured in seconds. Chloroform and dichloromethane have a
negligible absorbance at 300 nm; therefore the same should be the
case with chloromethanol. From the kinetic measurements, the
association constant of the complex is ꢁ104 Mꢀ1, and at 0.01 M of
both HCl (dry HCl was used) and aldehyde, there would be more
than 90% of chloromethanol formed. This is inconsistent with the
experiment (Fig. 2A) where the absorbance at 300 nm is more than a
half that of the initial one.
ꢀꢀ The PKIE could also be substantially reduced if there were a highly
ꢂasymmetricꢃ transition state for the proton transfer.28,29 We have
1
also performed the appropriate control H NMR experiments using
solutions containing formaldehyde, d2-formaldehyde and HCl in
various proportions in CD3CN. No H/D exchange was detected over
a period of several hours.

V. Pilepic´ et al. / Tetrahedron Letters 47 (2006) 371–375
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