Effects of counter cations of base catalysts on nitrosation mechanisms

Article abstract of DOI:10.1248/cpb.49.1651

Reaction of 2-butanone (1) with tert-butyl nitrite (tert-BuONO) was performed using base catalysts (RO^-M⁺: R=CH₃, C₂H₅; M⁺=Li⁺, Na⁺, K⁺) in alcohols (CH₃OH or C₂H₅OH). In this report, the effects of M⁺ of RO^-M⁺ on the nitrosation mechanisms were investigated. The yield of E-hydroxyimino compound (5E) increases much better in the reaction using Na⁺ or K⁺ as M⁺ compared with that using Li⁺. It is also observed that the yield of 5E increases by addition of crown ether as a cation-capturing agent. The experimental results suggested that under the conditions lowering the effects of M⁺ of RO^-M⁺ on the nitrosation mechanisms, because the reactivity of naked enolate of 1 increases and the reaction in the C-N bond formation process tends to proceed via open-chain transition state without M⁺, the yield of 5E tends to increase.

Full text of DOI:10.1248/cpb.49.1651

December 2001
Notes
Chem. Pharm. Bull. 49(12) 1651—1652 (2001)
1651
Effects of Counter Cations of Base Catalysts on Nitrosation Mechanisms
Hirohito IKEDA,* Miho YUKAWA, Tokihiro NIIYA, and Yoshinobu GOTO
Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
Received July 12, 2001; accepted October 1, 2001
Reaction of 2-butanone (1) with tert-butyl nitrite (tert-BuONO) was performed using base catalysts
(RO؊M؉: R؍CH3, C2H5; M؉؍Li؉, Na؉, K؉) in alcohols (CH3OH or C2H5OH). In this report, the effects of M؉
of RO؊M؉ on the nitrosation mechanisms were investigated. The yield of E-hydroxyimino compound (5E) in-
creases much better in the reaction using Na؉ or K؉ as M؉ compared with that using Li؉. It is also observed that
the yield of 5E increases by addition of crown ether as a cation-capturing agent. The experimental results sug-
gested that under the conditions lowering the effects of M؉ of RO؊M؉ on the nitrosation mechanisms, because
the reactivity of naked enolate of 1 increases and the reaction in the C–N bond formation process tends to pro-
ceed via open-chain transition state without M؉, the yield of 5E tends to increase.
Key words nitrosation; counter cation; crown ether; open-chain transition state; hydroxyimino compound
It is well known that the nitrosation is one of the most sig- mental result described above is closely related to the reactiv-
nificant synthetic methods of carbonyl derivatives. To study ity and the thermodynamic stability of enolate produced by
the reaction mechanisms is useful for not only understanding deprotonation with a base catalyst. The reactivity and ther-
the reactivity of active alkyl groups with electrophiles but modynamic stability of 2M and 4M were investigated using
also the synthesis of medicines.1) The mechanisms of nitrosa- ab initio MO calculation performed with Gaussian 98 pro-
tion of ketones are similar to those of aldol condensations. gram.6) The results of calculation showed that the eigenvalue
The aldol condensations are investigated in detail and the of HOMO of 4M is higher than that of 2M and the electron
mechanisms have been made clear gradually accompanied by density of C3 in HOMO of 4M is larger than that of C1 of
the progress of enolate chemistry. On the contrary, the study 2M.7) Therefore, the reactivity of 4M is relatively higher than
of the mechanisms of nitrosation has not been much devel- that of 2M. Compound 4M is more stable than 2M thermo-
oped. We tried to examine this reaction experimentally and dynamically.8)
theoretically in order to clarify the reaction mechanisms.2,3)
The experimental results of the nitrosation of 1 with tert-
The nitrosation of 1 with tert-butyl nitrite (tert-BuONO) BuONO using ROϪMϩ in an alcohol are shown in Table 1.
using a base catalyst is shown in Chart 1. In our study, the ni- The yield of 5E was determined by gas chromatography.
trosation was divided into three steps, that is, the deprotona-
The yield of 5E given by the reaction in C2H5OϪ–C2H5OH
tion process of 1 by a base catalyst, the C–N bond formation was obviously better than that in CH3OϪ–CH3OH. Because
process involving enolate and tert-BuONO, and the elimina- the electron density of oxygen atom of C2H5OϪ is larger than
tion process that the proton and the tert-butoxyl group are that of CH3OϪ, the yield of 4M increases in the deprotona-
eliminated from the complex of reactants with a base catalyst tion step using C2H5OϪMϩ. And the yield of 5E increased
as described in the previous papers.2) The rate determining much better in the reaction using Naϩ or Kϩ as Mϩ com-
step of this reaction is the C–N bond formation process. pared with that using Liϩ. It is considered that these results
Though it can be considered that four kinds of hydroxyimino were caused by high eigenvalues of HOMO and large elec-
compounds (3E, 3Z, 5E, 5Z) are formed simultaneously in tron densities of C3 in HOMO in the case of using Naϩ or Kϩ
the nitrosation of 1 shown in Chart 1, 5E is obtained exclu- as Mϩ (Table 2).9)
sively as a final product under these reaction conditions.4) It
It may be assumed that Mϩ of ROϪMϩ plays an important
is well known that there is an equilibrium between 2M and role in the transition state, i.e. metal-chelated pericyclic tran-
4M in protic solvent.5) Because 5E is obtained as an only sition state in the C–N bond formation process of the nitrosa-
product, 4M exists predominantly in this equilibrium before tion.2) This concept is similar to that of the illustration of
addition of tert-BuONO. It may be thought that the experi- the reaction mechanism in the aldol condensation.10) On the
Chart 1
To whom correspondence should be addressed. e-mail: ikeda@fukuoka-u.ac.jp
© 2001 Pharmaceutical Society of Japan

1652
Vol. 49, No. 12
the conditions lowering the effects of Mϩ of ROϪMϩ on the
nitrosation mechanisms, the E-hydroxyimino compound is li-
able to be obtained. This result supports our theoretical in-
vestigation by ab initio MO calculations in the previous
paper.2b)
Table 1. The Product Yields of Nitorosation of 1
Entry
Base
Solvent
Yield of 5E (%)
1
2
3
4
5
6
CH3OLi
CH3ONa
CH3OK
C2H5OLi
C2H5ONa
C2H5OK
CH3OH
CH3OH
CH3OH
C2H5OH
C2H5OH
C2H5OH
12
17
16
20
39
32
Experimental
To a solution of alkoxide (2.0ϫ10Ϫ3 mol) in alcohol or alkoxide
(2.0ϫ10Ϫ3 mol) and crown ether (2.1ϫ10Ϫ3 mol) in alcohol, 1 (5.0ϫ10Ϫ4
mol) was added. After stirring for 1 h, tert-BuONO (7.5ϫ10Ϫ4 mol) was
added dropwise with stirring. The temperature of the solution was kept at
0 ˚C during carrying out this reaction. The reaction mixture was allowed to
stand for 18 h in a refrigerator. Afterward the reaction mixture was acidified
with dilute H3PO4, and then 5E was obtained. The yield of 5E was deter-
mined by gas chromatography (GC). GC analysis was performed on a Shi-
madzu GC-6AM connected to a System Instruments Chromatocorder 11 in-
tegrator. Triton X-305 (5%) (2 mmϫ0.5 m, packed glass) column was used.
Table 2. The Eigenvalues of HOMO and Electron Densities of C3 in
HOMO of 4M
Entry
Mϩ
Eigenvalue/a.u.
Electron density
1
2
3
Liϩ
Naϩ
Kϩ
Ϫ0.25643
Ϫ0.23242
Ϫ0.22654
0.68
0.72
0.74
Acknowledgements Thanks are due to the Information Technology
Center of Fukuoka University for use of the Fujitsu GP7000S1000 com-
puter, and to the Reserch Center for Computational Science, Okazaki Na-
tional Research Institutes for use of the NEC SX5 and Fujitsu VPP5000
computers.
Table 3. The Product Yields of Nitrosation of 1 Using Crown Ether in
Ethanol
References and Notes
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Entry
Base
Crown ether
Yield of 5E (%)
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4
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C2H5OLi
C2H5ONa
C2H5OK
C2H5ONa
C2H5OK
15C5
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condensation reaction which proceeds via open-chain transi-
tion state.11) Thus in the C–N bond formation process also, it
is considered that there are possibilities of existence of two
transition states, i.e. Mϩ-chelated pericyclic transition state
and open-chain transition state without Mϩ. But it is difficult
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in the presence of crown ether was examined. When 15-
crown-5 (15C5) or dicyclohexyl-18-crown-6 (DC18C6) was
added to the reaction mixture before addition of tert-
BuONO, the yield of 5E increased remarkably (Table 3).
When DC18C6 was added to the reaction mixture in
C2H5OLi–C2H5OH, the solution was solidified and the reac-
tion did not proceed. On the basis of these experimental re-
sults, it is assumed that the coordination of Mϩ of ROϪMϩ to
naked enolate 4 is inhibited in the reaction using crown ether
and the reaction in the C–N bond formation process tends to
proceed via open-chain transition state without Mϩ. The MO
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HOMO and electron density of C3 in HOMO of 4 are
Ϫ0.06490 a.u. and 0.90, respectively. This calculation result
indicates that the reactivity of 4 is relatively higher than that
of 4M (see Table 2) and supports the experimental results in
the presence of crown ethers.
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It can be concluded that when the reaction proceeds under