Studies on the C/O-regioselectivity in Electrophilic Fluoromethylations of β-Ketoesters based on Thermodynamics by Ab initio Calculations
Studies on the C/O-regioselectivity in Electrophilic Fluoromethylations of β-Ketoesters based on Thermodynamics by Ab initio Calculations
Bulletin of the Korean Chemical Society. 2014. Jun, 35(6): 1851-1854
Copyright © 2014, Korea Chemical Society
  • Received : January 01, 2014
  • Accepted : February 16, 2014
  • Published : June 20, 2014
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About the Authors
Yu-Dong Yan
Xin Wang
Seiji Tsuzuki
Research Initiative of Computational Sciences (RICS), Nanosystem Research Institute (NRI), National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Umezono, Tsukuba, Ibaraki 305-8568, Japan
Etsuko Tokunaga
Norio Shibata

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Results and Discussion
Ab initio calculations were carried out for studying the reaction of the naked anion of methyl 1-indanone carbox-ylate 3 with cation or radical species of CF 3 , CF 2 H, or CFH 2 providing C -alkylated or O -alkylated products.
First, the most stable rotamer of anion 3 was obtained at the MP2/6-311G** level ( Figure 1 ). The interactions of 3 with + CF 3 , + CF 2 H and + CFH 2 cations were next studied by ab initio molecular orbital calculations. The geometries of the complexes of 3 with the three cations were optimized. The C - or O -alkylated products 4-6 were spontaneously generated by the geometry optimizations, which indicates that there exists no potential energy barrier for the formation of the C–C and C–O bonds ( Figure 2 ). The C–C bond was formed with the carbon atom between two carbonyl groups of 3 . The C–O bond was formed with an oxygen atom of the carbonyl group. The optimized geometries and relative ener-gies of the products are shown in Figure 2 . The calculations show that the C -alkylated products are significantly more stable than the O -alkylated products. The O -alkylated pro-ducts with the + CF 3 cation ( 4b and 4c ) are 14.01 and 30.54 kcal/mol less stable than the C -alkylated product ( 4a ), respectively. The O -alkylated products with the + CF 2 H ( 5b and 5c ) are 15.64 and 29.73 kcal/mol less stable than the C -alkylated products ( 5a ), respectively. The O -alkylated pro-ducts with the + CFH 2 ( 6b and 6c ) are 18.19 and 31.42 kcal/ mol less stable than the C -alkylated products ( 6a ), respec-tively. The larger stability of the C -alkylated 4a , 5a and 6a suggests that the reactions of 3 with the cations, + CF 3 , + CF 2 H, and + CFH 2 , prefer to produce C -alkylated products independent of the number of fluorine molecules. The com-plete C -regioselectivity for the trifluoromethylation can be explained by the cationic process. This result is similar to the case of the products obtained from the calculations based on an acyclic β-ketoester anion ( Scheme 2(a) ). 15 This result indicates the electronic character of trifluoromethyl sulf-oxinium salt 1a is different from the dibenzothiophenium salts which were developed by Umemoto. Magnier and co-workers identified a radical pathway should be responsible for the trifluoromethylation of silyl-enol ethers with Umemoto’s reagent and they were also confident that this route is involv-ed in the reaction with other soft nucleophiles, such as β-ketoesters. 16
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The most stable rotamer of anion 3 at the MP2/6-311G** level.
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(a) The optimized geometries and relative energies of C–CF3 product 4a, and O–CF3 products 4b and 4c at the MP2/6-311G** level. Energy in kcal/mol. (b) The optimized geometries and relative energies of C–CF2H product 5a, and O–CF2H products 5b and 5c. (c) The optimized geometries and relative energies of C–CFH2 product 6a, and O–CFH2 products 6b and 6c.
The geometries of anion 3 complexed with fluoromethyl radicals CF 3 , CF 2 H, CFH 2 were next investigated ( Figure 3 ). The optimized geometries of complexes 7-9 and the stabilization energies ( E form ) are shown in Figure 3. 17 The carbon atom of the CF 3 radical that entered into contact with the oxygen atoms of two carbonyl groups was found to be the most stable geometry 7c . Meanwhile, optimized geo-metries 8a and 9a , in which the hydrogen atoms of CF 2 H or CFH 2 radicals were in contact with the oxygen atoms of the two carbonyl groups, were found to be the most stable. The E form for 8a and 9a (–10.52 and –7.69 kcal/mol, respectively) are substantially larger (more negative) than that for 7c (–4.48 kcal/mol), which shows that the attractive interactions of 3 with CF 2 H and CFH 2 radicals are stronger than that with the CF 3 radical. Despite the initial geometries before calculations where the CF 2 H and CFH 2 radicals are located several positions around 3 , the geometries converged to 8a and 9a after the optimizations in most cases. The local minimum structures in which the CF 2 H and CFH 2 radicals were in contact with the carbon atom between the two carbonyl groups of 3 were not obtained by the geometry optimizations. These results show that CF 2 H and CFH 2 radicals prefer to locate close to the oxygen atoms of the two carbonyl groups of 3 , producing O -alkylated products. The complete O -regioselectivity found in the monofluorometh-ylation can be explained by the radical-like mechanism involving the SET process although the free radical mono-fluoromethylation is rare. 18 In addition, more recently, Hu et al. disclosed that a CFH 2 species was involved in the mono-fluoromethyltion of O -, S -, N - and P - nucleophiles with a monofluorinated sulfoximine, PhSO(NTs)CH 2 F. 14a This report would also somewhat support our results. For the difluoro-methylation of 3 with 1b , both cationic and radical processes are suggested based on the above calculations ( Figures 2(b) and 3(b) ). They are consistent with the computational results based on the acyclic β-ketoester and the experimental results for difluoromethylation of 3 in which a mixture of O - and C - alkylated products was obtained. 15
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(a) Four optimized geometries of 3 with CF3 and their stabilization energies at the MP2/6-311G** level. Energy in kcal/mol. (b) Two optimized geometries of 3 with CF2H and their stabilization energies. (c) Two optimized geometries of 3 with CFH2 and their stabilization energies.
Finally, we attempted the calculations of the methyl 1-indanone-2-carboxylate radical with fluoromethyl radicals CF 3 , CF 2 H, CFH 2 . However, the initial combination of the carboxylate radical and fluoromethyl radicals spontaneously converted into a combination of the anion 3 and fluoro-methyl cations, + CF 3 , + CF 2 H and + CFH 2 which gave the same results for the calculations of 3 and radicals as mentioned in the first investigation.
Based on the computations, plausible schematic reaction mechanisms for trifluoromethylation and monofluorometh-ylation are shown in Figure 4 . Similar to the mechanism shown in our previous paper, 15 + CF 3 , would be generated directly from the reagent 1a with the reaction of 3 via SN2-like pathway ( Figure 4(a) ) providing C -alkylated product with dimethylamino phenyl sulfinamide. On the other hand, monofluoromethylation would proceed via an attack of the enolate oxygen to the sulfur center of 1b to afford a sulfurane-type intermediate TS-I , 8 9 which collapses into [CFH 2 ] and [PhS(O)NMe 2 ] •+ with the regeneration of 3 . The 3 attacks [CFH2] to provide O -alkylated product via TS-III ( Figure 4(b) ).
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Plausible schematic reaction mechanisms, (a) trifluoro-methylation and (b) monofluoromethylation.
In conclusion, the C/O regioselectivity in fluoromethyl-ations of β-ketoesters with fluorinated methylsulfoxinium salts 1a-c was re-investigated based on the thermodynamics by MP2/6-311G** level ab initio calculations of the inter-actions of a cyclic β-ketoester anion 3 with fluoromethyl cations or radicals. The computational results are in accor-dance with previous results based on an acyclic β-ketoester. This result supports our proposed mechanism and view-points regarding the electrophilic fluoromethylation of β-ketoesters. That is, a + CF 3 cation is formed and is respon-sible for the complete C -alkylated products in trifluoro-methylation, while a more radical-like species such as CFH 2 is possibly generated to furnish O -alkylated species in monofluoromethylation. For difluoromethylation, a weaving cationic and radical species participates to afford a mixture of C - and O -isomers. In the case of difluoromethylation, a difluorocarbene mechanism is also should be concerned, however, Prakash denied it and suggested electrophilic type reaction. 14g Although our conclusion is just one of the hypotheses based on the calculations of the thermodynamics, it might be helpful to further the discussion of the reaction mechanism not only about trifluoromethylation but also about C/O -regioselectivity in the conventional alkylation of enolates. Further investigation is now on going based on the calculations of transition states.
Computational Methods. The Gaussian 03 program 17 was used for the ab initio molecular orbital calculations. Electron correlation was accounted for by the second-order Møller-Plesset perturbation (MP2) method. 19 20 The 6-311G** basis set was used for the calculations. The stabilization energy by the formation of a complex from isolated species ( E form ) was calculated as the sum of the interaction energy ( E int ) and the deformation energy ( E def ). E def is the sum of the increase of the energies of monomers by the deformation associated with the formation of the complex. E int was cal-culated by the supermolecule method. The basis set super-position error (BSSE) 21 was corrected for the interaction energy calculations using the counterpoise method. 22 The geometries of the complexes were optimized from 22 initial geometries. The atomic charges were obtained by electrostatic potential fitting using the Merz-Singh-Kollman scheme 23 24 from the MP2/6-311G** level wave functions of the isolated molecules.
This study was financially supported in part by Grants-in-Aid for Scientific Research from MEXT (Ministry of Education, Culture, Sports, Science and Techno-logy) (24105513, Project No. 2304: Advanced Molecular Transformation by Organocatalysts). We thank the Asahi Glass Foundation and Hori Science & Arts Foundation for support.
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