Chemical & Pharmaceutical Bulletin

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CHEMICAL& PHARMACEUTICAL BULLETIN

Vol. 35, No. 1 January 1987

Regular Articles

Chem. Pharm. Bull. 35(1) 1-8 (1987)

Reactive Intermediates Produced in the Decomposition of 2-Diazoketone: Mechanism of the Wolff Rearrangement

MINORU TSUDA,* SETSUKOOIKAWA and KIYOSHI NAGAYAMA

Laboratory of Bio-physicalChemistry, Faculty of Pharmaceutical Sciences,Chiba University,Chiba 260, Japan

(ReceivedJuly 2, 1986)

Potential energy hypersurfaces of the nitrogen elimination and the Wolff rearrangement were investigated for both cyclic and open-chain 2-diazoketones by means of semi-empirical MINDO/3 molecular orbital calculations with configuration interaction. In the case of 2-diazobenzen-1-one, the nitrogen elimination takes place simultaneously with the Wolff rearrangement in a concerted fashion and neither ketocarbene nor oxirene is produced. In contrast to the cyclic 2-diazoketone, 2- diazoethan-1-one produces oxirene through nitrogen elimination in a concerted fashion. The oxirene isomerizes to ketene via the Wolff rearrangement, passing over a second saddle point of low energy. No ketocarbene intermediate is produced in either case.

Keywords•\Wolff rearrangement; reaction mechanism; molecular orbital method; MINDO/3; potential energy hypersurface; lowest energy path; 2-diazoethan-1-one; 2-diazobenzen-1-one; oxirene; ketene

Introduction 4-(2-Aminoethyl)-2-diazobenzen-1-one is a mutagen recently found by Nagao et al. to be formed from 4-(2-aminoethyl)phenol-1, a component of soy sauce, after nitrite treatment .1,2) Experiments on the carcinogenicity of the mutagen are in progress ,3) because a benzenediazonium derivative, 4-(hydroxymethyl)benzenediazonium cation, which is a component of mushrooms, was found to induce glandular stomach tumors in mice.3,4) Many carcinogenic alkylating agents are believed to owe their activity to conversion to a highly reactive diazoniumion.5) Theoretical chemistry confirmed that the benzenediazonium cation produces a reactive intermediate, phenyl cation, by loss of nitrogen in the first step of its decomposition.6) In the decomposition of 2-diazoketone, ketocarbene is postulated to be the first product, formed by loss of nitrogen, and then migration of the group next to the carbonyl group takes place to give the corresponding ketene (the Wolff rearrangement),7- 20)as shown in Fig. 1(a). The ketene formation has been established experimentally. Theoretical studies of the Wolff rearrangement have been carried out starting from the ketocarbene.7-10) However, the ketocarbene has not been isolated, and no theoretical research has been done on the step of nitrogen elimination from 2-diazoketone: i.e., ketocarbene formation has not yet been confirmed. Cyclic 2-diazoketones, for example, 2-diazobenzen-l-ones and 2-diazo- 2 Vol. 35 (1987)

( a ) (b )

( 1 )

( 2 )

Fig. 1(a). Old Mechanism of the Wolff Rear- Fig. 1(b). New Mechanism of the Wolff Rear- rangement 13,19) rangement Because ketocarbene intermediate plays an im- No ketocarbene intermediate is produced. (1) portant role in the mechanism, oxirene is naturally Ketene is the one-step reaction product. Therefore, no produced and the scrambling of 13C must be observed scrambling is observed in the cyclic 2-diazoketone. (2) in every case. refers to both cyclic and open- Oxirene intermediate is produced only in the case of chain compounds. the open-chain 2-diazoketone, where scrambling is observed. naphthalen-1-ones are widely used in the semiconductor industry in the microfabrication of VLSI (very large scale integrated circuits). One problem with the ketocarbene mechanism is why the ketocarbene produced in the first step does not react with atmospheric oxygen during the microfabrication process, although a nitrene produced from azide by loss of nitrogen reacts strongly with atmospheric oxygen under the same conditions.18) Another question concerns the participation of the oxirene intermediate in the Wolff rearrangement mechanism. Strausz showed the importance of the oxirene pathway in the cases of 3-diazobutan-2-one, 3-diazopropan-2-one and 1,2-dipheny1-2-diazoethan-1-one.14) However, the experiments on cyclic compounds, 5-diazohomoadamantan-4-one19) and 2- diazonaphthalen- l-one,20) excluded the formation of the oxirene intermediate. If 2-ketocarbene were produced, oxirene would be the subsequent product for both cyclic and open-chain 2-diazoketones. What is the origin of this difference? If no ketocarbene is formed in the reaction of 2-diazoketone, the mechanism of carcinogenesis may be different from that in the case of benzenediazonium. This paper reports the lowest potential energy path of the Wolff rearrangment starting from 2-diazoketone to the final product, ketene, for both cyclic and open-chain 2-diazoketones. The results clearly explain the experimental findings and resolve the above problems.

Method

Determination of the Lowest Energy Path•\The intrinsic reaction co-ordinate (IRC) is the lowest energy path connecting a reactant and a product through the saddle point (the transition state) on the 3N-6 dimensional potential energy hypersurface.21) For simplicity, the IRC calculations were done on the mass-weighted 3N dimensional hypersurface. Then, the results were revised in such a manner that the center of mass and the three kinds of principal axes of inertia in the structure of the reaction system were always fixed throughout the IRC path. Starting from the saddle point, the IRC path was determined point by point following the procedure proposed by Ishida et al.22) Geometry Optimization•\A systematic method was applied which overcomes the difficulty of finding the stable and the transition state (TS) structures of the reaction system on the multidimensional hypersurface. The details of the method were reported elsewhere.23) By this method, we can easily obtain the minima (the stable structures) and the saddle points (the transition state structures) by using the first and second derivatives of the potential energy with respect to the structure change for the determinations of the former and the latter, respectively. No. 1 3

For the potential energy evaluation in the geometry optimization and IRC calculations, the spin-restricted Hartree Fock (RHF) molecular orbital method was adapted with the semi-empirical MINDO/324) parametrization, since ab initio calculations are still prohibitive because of the economical and computational limits. The potential energy surfaces were elaborated with configuration interaction (CI) calculations,25) which consider the singly and doubly excited electronic configurations less than 14eV from the ground state (SDCI). In the present cases, however, the potential energy surfaces with or without CI have the same profile, as shown later. This means that the state function of the ground state is essentially expressed by a single RHF configuration function in these cases. The potential energy change obtained here on the reaction path from oxirene to ketene in the case of 2-diazoethan-l-one is very similar to the results obtained by an ab initio method with configuration interaction.8) Thus, the results obtained in the present calculations should be reliable, at least qualitatively.

Results Potential Energy Change Following the Lowest Energy Path of the Reaction of 2-Diazobenzen- 1-one Potential energy change following the lowest energy path of the nitrogen loss reaction is shown in Fig. 2 in the case of 2-diazobenzen-1-one. This result will be astonishing to the chemist who has accepted the ketocarbene mechanism (Fig. 1(a)). The Wolff rearrangement to ketene occurs simultaneously with the nitrogen molecule liberation. The reaction takes place in one step and there is only one saddle point throughout the reaction path. Neither ketocarbene nor oxirene is formed in the reaction path. Therefore, the experiments which found no influence of atmospheric oxygen on the ketene formation and no oxirene

Fig. 2. Potential Energy Change Following the Lowest Energy Path of the Nitrogen Loss Reaction in the Case of 2-Diazobenzen-1-one

Fig. 3. The Structure at the Saddle Point in the Reaction Path of 2-Diazobenzen-1-one 4 Vol. 35 (1987) participation are quite reasonable from the theoretical point of view. Molecular Structure Change Following the Lowest Energy Path of the Reaction of 2- Diazobenzen-1-one The structure at the saddle point is shown in Fig. 3, and is planar. The unique normal mode of vibration of imaginary frequency (166.2 icm -1) is shown by an arrow at each of the atoms. The forward progress of the reaction following the arrows leads to loss of nitrogen and the backward reaction recovers the reactant, 2-diazoketone. Molecular structure changes following the lowest energy path are shown in Fig . 4 from the reactant, 2-diazoketone, to the product, ketene, based on six points on the path of Fig . 2. With the separation of the diazo group from C6 of the aromatic ring, C6 approaches C2 at the meta position. Over the saddle point, the bond formation between C2 and C6 proceeds together with the bond fission between C2 and C1, and finally, ketene is produced. The reaction takes place in a concerted fashion throughout the process.

Fig. 4. Molecular Structure Change Following the Lowest Energy Path from the Reactant, 2-Diazobenzen-1-one, to the Product, a Ketene

Fig. 5. Potential Energy Change Following the Lowest Energy Path of the Nitrogen Loss Reaction in the Case of 2-Diazoethan-1-one No. 1 5

Potential Energy Change Following the Lowest Energy Path of the Reaction of 2-Diazoethan-1- one Potential energy change following the lowest energy path of the nitrogen loss reaction of 2-diazoethan-1-one is shown in Fig. 5. In contrast to the case of the cyclic 2-diazoketone , the first product obtained by loss of nitrogen is oxirene. Ring opening passes over a second saddle point of low energy to produce the final product, ketene. A ketocarbene-like structure appears in the process of the ring opening. However, the ketocarbene has no life time for reacting with any other molecule, since the structure does not exist at a minimum of the potential energy hypersurface. RHF level calculation using the 4-31G basis set10)and the same level calculation using the double-zeta plus polarization basis set (DZ+P)8) gave formylmethylene, a ketocarbene, at a minimum point. However, the minimum disappears in the higher level

( a ) ( b )

(c )

Fig. 6(a). The Structure of the Saddle Point 1 in Fig. 5 (b). The Structure of the Saddle Point 2 in Fig. 5 (c). The Structure of the Saddle Point in the cis-trans Isomerization of 2- Diazoethan-1-one in Fig. 7 6 Vol. 35 (1987) calculation with CI(DZ+P),8) where the ring opening of oxirene passes over a saddle point of low energy to give the final product, ketene. The results obtained by CI(DZ+P) agree with the conclusion of the present MINDO/3 calculation. Molecular Structure Change Following the Lowest Energy Path of the Reaction of 2- Diazoethan-1-one The structure at the saddle point 1 is shown in Fig. b(a), and is non-planar in spite of the planar structure of the starting reactant, 2-diazoethan-1-one. The non-planar structure is

Fig. 7. The Lowest Potential Energy Change in the cis-trans Isomerization of 2- Diazoethan-1-one

saddle point 1

saddle point 2 (formylmethylene) Fig. 8. Molecular Structure Change Following the Lowest Energy Path from the Reactant, 2-Diazoethan-1-one, to the Final Product, a Ketene No. 1 7

essential for oxirene formation. In the case of 2-diazobenzen-1-one, the oxirene formation may be inhibited because the benzene ring strongly maintains its planar structure. The produced oxirene is also non-planar. The structure at the saddle point 2 is shown in Fig. 6(b), and is a non-planar ketocarbene. The structure at the saddle point in the cis-trans isomerization of 2-diazoethan- 1-one is shown in Fig. 6(c), and is non-planar. The lowest potential energy change in the isomerization is shown in Fig. 7. In Fig. 8, the isomerization process of 2-diazoethan-1-one is shown in the first line, and then the second and third lines show the molecular structure changes following the lowest potential energy path in Fig. 6. Starting from a planar trans-2-diazoethan-1-one, loss of a nitrogen molecule takes place with the torsion of the molecule around the C1-C2 bond , and oxirene is formed in a concerted fashion. The produced oxirene isomerizes to ketene via a formylmethylene structure at the saddle point. In contrast to the cyclic 2-diazoketone , the open-chain 2-diazoethan-1-one produces an oxirene at a minimum point of its potential energy hypersurface. Therefore, scrambling in the Wolff rearrangement is naturally observed in experiments by the carbon-13 labeling technique in the open-chain case (see Fig. 1), because of the long life time of the oxirene.

Discussion The results of many experiments on the Wolff rearrangement7-20) can be successfully explained, provided that the reaction proceeds through the lowest potential energy path which is shown in Fig. 2 for the cyclic 2-diazoketone and in Fig. 5 for the open-chain 2-diazoketone . These potential energy hypersurfaces are on the ground state where thermolysis occurs . However, a majority of the experiments involved photolysis. Why are the photochemical experiments explained by the potential energy hypersurface of the ground state? The reason is considered to be that the key steps of the photochemical reactions which give the observed products occur in the ground state and not in the excited states. In the simplest way, we can explain the results by assuming that the transition from the excited states to the ground state takes place at the right side of the saddle point of Fig. 2 or the saddle point 1 of Fig. 5. The elucidation of the exact mechanism of photolysis, however, must wait untill the potential energy hypersurfaces of the excited states are calculated . The highly reactive intermediate produced in the first step of the nitrogen elimination is ketene in the case of 2-diazobenzen-1-one, but phenyl cation in the case of benzenediazonium.6) However, it is reasonable to consider that both ketene and phenyl cation may react with the amino group of guanine in deoxyribonucleic acid as the first step of mutagenesis or carcinogenesis.26)

Acknowledgment The main part of the computation was carried out at the Computer Centre , the University of Tokyo, and the Computer Center, Chiba University. The authors thank the Computer Center , Institute for Molecular Science, Okazaki, for the use of an M-200H computer in a part of the computation .

References

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