Kinetics and mechanism of acid-catalyzed hydrolysis of cyclohexyl isocyanide and pKa determination of N-cyclohexylnitrilium ion

Article abstract of DOI:10.1016/S0040-4039(01)00863-2

A novel mechanism for acid-catalyzed hydrolysis of cyclohexyl isocyanide is proposed. It is specific acid/general base catalysis, involving a fast, pre-equilibrium C-protonation of the isocyanide, followed by a rate-determining attack of water on the electron-deficient carbon of the protonated isocyanide. The pK_a of N-cyclohexylnitrilium ion was determined to be 0.86±0.05.

Full text of DOI:10.1016/S0040-4039(01)00863-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4845–4848
Kinetics and mechanism of acid-catalyzed hydrolysis of
cyclohexyl isocyanide and pK determination of
a
N-cyclohexylnitrilium ion
Kuangsen Sung* and Chao-Chih Chen
Department of Chemistry, National Cheng Kung University, Tainan, Taiwan, ROC
Received 27 March 2001; accepted 18 May 2001
Abstract—A novel mechanism for acid-catalyzed hydrolysis of cyclohexyl isocyanide is proposed. It is specific acid/general base
catalysis, involving a fast, pre-equilibrium C-protonation of the isocyanide, followed by a rate-determining attack of water on the
electron-deficient carbon of the protonated isocyanide. The pK of N-cyclohexylnitrilium ion was determined to be 0.86±0.05.
a
©
2001 Elsevier Science Ltd. All rights reserved.
A correct structure 1a for isocyanides was first pro-
ments on the issue, we reach a different conclusion for
the mechanism.
1
posed by Lindemann and Wiegrebe in 1930. Based on
microwave and IR studies, 1a resonance structure gives
2
more contribution than 1b resonance structure. The
The isocyano carbon was confirmed to form hydrogen
5
resonance structure 1a has a nucleophilic carbon carry-
ing a negative charge and a lone pair of electrons, while
the resonance structure 1b has an electron-deficient
bonding with water or alcohols, but both water and
alcohols hardly react with isocyanides without any cat-
3
alyst. It turns out that the hydrogen-bonding com-
3
carbon, which behaves as an electrophile. Whether the
plexes don’t activate the isocyanide functional group
enough for further nucleophilic attack by a nucleophile.
Furthermore, the hydrogen-bonding complex of isocya-
nide with an acid molecule is unlikely to form in a
isocyano carbon behaves as a nucleophile or an elec-
trophile depends on reaction conditions, reagents, and
3
its substituents.
6
polar protic solvent like water. Therefore, it seems
unlikely that the mechanism of Scheme 1 is correct.
To understand a mechanism for the isocyano carbon to
behave as an electrophile, alkaline hydrolysis of aro-
4a,b
matic isocyanides has been studied.
To understand a
mechanism for the isocyano carbon to behave as a
nucleophile, acid-catalyzed hydrolysis of isocyanides
has been studied and it was reported that acid-catalyzed
hydrolysis of methyl isocyanide forming methyl for-
mamide is a general-acid catalyzed process, in which
there is a reversible hydrogen bonding between a gen-
eral acid and the isocyano carbon, followed by a rate
determining nucleophilic attack at the same carbon by
Scheme 1.
4
c
water. (Scheme 1) However, after doing more experi-
Keywords: isocyanide; mechanism; hydrolysis; specific acid catalysis;
nitrilium ion.
*
Corresponding author. Fax: 886-6-2740552; e-mail: kssung
mail.ncku.edu.tw
@
Scheme 2.
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00863-2

4
846
K. Sung, C.-C. Chen / Tetrahedron Letters 42 (2001) 4845–4848
−
2
−1 −1
−2
−1 −1
Acid-catalyzed reactions can be divided into two main
classes (eq 1, 2a, and 2b) involving the proton transfer
occurring before or during the rate-determining step of
10
M
S , i.e. k +=7.77×10
M
S . Similarly,
H
+
the reaction was also catalyzed by D O , and k +=
1.77×10
inverse solvent isotope effect indicates the reaction is
specific-acid catalyzed and involves a fast, pre-equi-
librium protonation before a rate-determining step.
3
D
−
1
−1
−1
M
S . The ratio k +/k + is 2.28. The
D H
7
the reaction (Scheme 2). Eq 1 involves a slow, rate-
determining proton transfer, which is more likely to
transfer to substrates containing carbon atoms as the
basic center. The type of reactions is supposed to be
general-acid catalyzed and they show normal solvent
Normally, in the case of specific hydronium-ion cata-
lyzed reactions, the reaction rate does not depend on
the concentration of any acid other than hydronium
ion. However, as shown in Table 2, hydrolysis of the
isocyanide at the CH CO H/CH CO Na buffer systems
was catalyzed by undissociated acetic acid (kAcOH=
2.94×10
standard deviation, it is statistically insignificant. It is
known that general acid catalysis can not be kinetically
distinguished from specific acid followed by general
7
isotope effect (k +/k +>1). Both eq 2a and 2b, includ-
H
D
ing a fast, pre-equilibrium protonation before a rate-
determining step, are expected to apply to substrates
containing oxygen or nitrogen atoms as the basic cen-
ter. Eq 2a involves an A1 mechanism and eq 2b belongs
to an A2 mechanism. Both eq 2a and eq 2b are
expected to be specific-acid catalyzed and they show
7
3
2
3
2
−
3
−1
−1
M
S ) Since k
is smaller than a
AcONa
7
inverse solvent isotope effect (k +/k +>1).
D
H
7
Acid-catalyzed hydrolysis of cyclohexyl isocyanide was
measured by time-scan of UV at 210 nm, where there is
no absorption change for acid-catalyzed hydrolysis of
cyclohexyl formamide. As shown in Table 1, hydrolysis
of the isocyanide was catalyzed by hydronium ion,
base catalysis. Therefore, the reaction may involve fast
pre-equilibrium hydronium-ion catalysis (specific acid
catalysis) followed by slow hydration catalyzed by
CH CO Na (general base catalysis) (Scheme 3).
3
2
+
+
H O . At [H O ]=0.06ꢀ0.002 M, the pseudo-first-
After pre-equilibrium protonation of the isocyanide,
there are three possible species (chloride, AcOH/AcO ,
3
3
−
order rate constants were linearly proportional to the
concentration of hydronium ion with a slope of 7.77×
and water) involving their rate-determining attack on
a
Table 1. Rate constants for acid-catalyzed hydrolysis of cyclohexyl isocyanide in HCl/H O or DCl/D O solutions
2
2
+
kobs (s−1
+
kobs (s−1
)
[
H
] (M)
T (°C)
)
[D ] (M)
T (°C)
−
−
−
−
−
−
−
−
−
−
−
3
2
2
2
3
3
4
4
4
4
4
1.05×10−2
0
0
0
0
0
0
0
0
0
0
0
.06
.06
.06
.06
.04
.02
.01
.008
.006
.004
.002
26
35
45
50
26
26
26
26
26
26
26
4.73×10
1.01×10
1.74×10
2.35×10
3.15×10
1.70×10
8.35×10
7.27×10
5.61×10
3.56×10
1.72×10
0.06
26
0.02
26
3.38×10−3
9.09×10−4
0.006
0.002
26
26
2.74×10−4
a
v (ionic strength)=0.06 (NaCl); kH+=7.77×10−2±8.45×10−4 M−1 S−1; kD+=1.77×10−1±2.94×10−3 M−1 S−1; kD+/kH+=2.28; DH =12.0±0.8
‡
‡
‡
+
kcal/mol, DS =−29.0±2.5 cal/mol K, DG =21.0±1.6 kcal/mol at [H ]=0.06 M, T=26–50°C. All rate constants are measured at least in
duplicate with maximum deviations of ±5%.
Table 2. Rate constants for acid-catalyzed hydrolysis of cyclohexyl isocyanide in CH CO H/CH CO Na aqueous buffer
3
2
3
2
a
solutions
hHa
[CH CO H] (M)
[CH CO Na] (M)
[CH CO H]+[CH CO Na] (M)
kobs (s−1)
3
2
3
2
3
2
3
2
−
5
5
5
4
5
5
5
5
5
5
5
5
0
0
0
.8
0.008
0.002
0.004
0.006
0.008
0.005
0.010
0.015
0.020
0.010
0.015
0.020
0.025
0.01
0.02
0.03
0.04
0.01
0.02
0.03
0.04
0.016
0.024
0.032
0.040
5.81×10
7.93×10
9.86×10
1.30×10
1.80×10
2.76×10
4.50×10
6.16×10
1.35×10
2.52×10
3.31×10
4.01×10
−
−
−
−
−
−
−
−
−
−
−
0
0
0
.016
.024
.032
.5
0.005
0.010
0.015
0.020
.375
0.006
0
0
0
.009
.012
.015
a
−
=2.94×10−3±4.69×10−5 M−1 S−1; kAcONa=5.20×10−8±2.75×10−5 M−1
AcOH
hHA=[HA]/([HA])+[A ]); v (ionic strength)=0.6 (NaCl); T=26°C; k
S− . All rate constants were measured at least in duplicate with maximum deviations of ±5%.
1

K. Sung, C.-C. Chen / Tetrahedron Letters 42 (2001) 4845–4848
4847
Scheme 3.
‡
the protonated isocyanide. Hydrolysis of the isocyanide
in a series of buffer solutions with fixed buffer ratio and
buffer concentration was carried out in a fixed ionic
strength, which was made with varied ratio of NaCl
range of 25–50°C, entropy of activation (DS ) of acid-
catalyzed hydrolysis of the isocyanide is −29.0 cal/mol
K. Since the A1 and A2 mechanisms are specific-acid
catalyzed reactions and protonation on the isocyano
carbon is not the rate-determining step, presumably
hydronium ion concentration has limited influence on
and NaClO . The hydrolysis rate did not change as the
4
salt was switched from NaCl to NaClO . Therefore, it
4
7b
turns out that chloride does not join the rate-determin-
ing attack. In addition, hydrolysis of the isocyanide in
activation entropy of the reaction. Besides, the highly
negative activation entropy indicates the reaction
involves an A-2 mechanism instead of an A-1 mecha-
nism, and the result is consistent with the mechanism
we propose in Scheme 3.
−
the presence of AcOH/AcO and a little bit water in
CDCl was monitored by proton NMR spectrometer,
3
and it was found that no reaction occurred at room
temperature. When the deuteriated solvent was
switched from CDCl3 to CD CN, the reaction did
The acid-catalyzed hydrolysis of the isocyanide was
also carried out in high concentration of HCl aqueous
solutions (Table 3). The pH-rate profile (Fig. 1) of the
hydrolysis shows a downward bend, which involves
gain of a proton by the isocyanide in a rapid equi-
3
occur at room temperature, and one can see that, as the
reaction progressed, the amount of water was getting
decreased and the amount of the product (cyclohexyl
formamide) was getting increased. However, there is no
−
9
evidence that AcOH/AcO join the rate-determining
librium prior to a rate-determining step. Clearly it
attack because compound 3 can not be detected at all
as a product of the reaction by means of proton NMR
and mass spectrometer. It is known that 2 can undergo
intramolecular isomerization to 3 very fast at room
involves titration of the isocyanide and the curve in Fig.
9
1 should fit eq 3. Rearrangement of eq 3 into eq 4
+
allows us to make a plot of (1/kobs) versus 1/[H ] and to
get K =0.138±0.016 (pK =0.86±0.05) for N-cyclo-
a a
8
temperature. Presumably, it is faster than bimolecular
intermolecular hydrolysis of 2. We also did a similar
Table 3. Rate constants for acid-catalyzed hydrolysis of
cyclohexyl isocyanide in high concentration of HCl
reaction of ketenimine 4 with acetic acid in CD CN and
3
a
aqueous solutions
monitored it by proton NMR at room temperature.
The reaction lasted for a few minutes but intermediate
+
kobs (s−1
)
[
H
] (M)
T (°C)
5
could not be detected during the whole process. It
turns out that the isomerization rate of 5 to 6 is much
faster than that of the first step. Therefore, it is clear
that water is the only nucleophile to attack the proto-
nated isocyanide at the rate-determining step.
−2
−2
3
2
1.50
1.00
.00
.00
26
26
26
26
26
26
26
26
26
26
4.02×10
3.83×10
3.27×10
3.89×10
3.19×10
2.24×10
1.25×10
6.99×10
2.58×10
1.68×10
−
−
−
−
−
−
−
2
2
2
2
2
3
3
0.60
0.15
0.06
Solvent isotope effect is a good criterion to distinguish
between specific-acid and general-acid catalysis, but it is
7
0.03
not sensitive enough to tell A-2 from A-1 mechanism.
0
0
.01
.006
Therefore, entropy of activation was measured for the
purpose. It was reported that A-1 mechanism gives
−3
‡
DS $0 to 10 eu, whereas the A-2 mechanism gives
a
v (ionic strength)=3.0 (NaCl); UV wavelength for monitoring the
reaction=210 nm. All rate constants were measured at least in
duplicate with maximum deviations of ±5%.
‡
+ 6
DS $−15 to −30 eu in systems of 1 M of [H O ]. As
3
+
shown in Table 1, at [H O ]=0.06 M and temperature
3

4
848
K. Sung, C.-C. Chen / Tetrahedron Letters 42 (2001) 4845–4848
protonated isocyano carbon. However, acid-catalyzed
hydration of ketenes, which have electron-rich C and
b
O and electron-deficient C , involves slow, rate-deter-
a
10b
mining C -protonation.
b
Acknowledgements
Financial support from the National Science Council of
Taiwan, ROC (NSC 89-2113-M-006-020) is gratefully
acknowledged.
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2
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1964, 20, 1197.
3
4
. Ugi, I. Isocyanide Chemistry; Academic Press: NY, 1971.
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Figure 1. PH-rate profile for acid-catalyzed hydrolysis of
cyclohexyl isocyanide in high concentration of HCl aqueous
solutions (v=3.0 (NaCl)).
5
. (a) Meot-Ner, M.; Sieck, L. W.; Koretke, K. K.;
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plot. The very low pK value indicates the nitrilium ion
a
is a strong acid, which is caused by both sp-hybridized
carbon and positive charge on nitrium nitrogen.
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It is interesting to compare mechanisms of acid-cata-
lyzed hydrolysis of nitriles, isocyanides, and ketenes.
Benzonitrile was reported to involve fast pre-equi-
librium N-protonation, followed by rate-determining
attack of water on cyano carbon. Cyclohexyl isocya-
nide, however, involves fast pre-equilibrium C-protona-
tion, followed by rate-determining attack of water on
9. (a) Kresge, A. J. Chemtech 1986, 250; (b) Ruane, P. H.;
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10a
.