Letter Cite This: Org. Lett. 2017, 19, 5689-5692
pubs.acs.org/OrgLett
Esterification of Carboxylic Acids with Difluoromethyl Diazomethane and Interrupted Esterification with Trifluoromethyl Diazomethane: A Fluorine Effect Shan-Qing Peng,† Xiao-Wei Zhang,† Long Zhang,*,‡ and Xiang-Guo Hu*,† †
National Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang, 330022, China Key Laboratory for Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, China
‡
S Supporting Information *
ABSTRACT: It is demonstrated that difluoromethyl diazomethane (HCF2CHN2) can react with a broad range of carboxylic acids. The reaction is convenient, operationally simple, mild, and tolerant of a variety of different functional groups. In sharp contrast, trifluoromethyl diazomethane (CF3CHN2) fails to react with carboxylic acids in most solvents, and in acetonitrile this reagent instead undergoes an interrupted esterification (a Mumm reaction) to yield N-trifluoroethyl imides. This striking example of the ability of a single F-for-H substitution to alter a reaction pathway was rationalized through a DFT study. he incorporation of fluorine-containing moieties often imparts desirable physical and biological properties to organic molecules.1 It is estimated that 20% of pharmaceuticals and 30% of agrochemicals contain at least one fluorine atom, with trifluoromethyl (CF3) and difluoromethyl (CF2) substituents being prevalent. 1 Utilizing trifluoromethyl diazomethane (CF3CHN2)2 and difluoromethyl diazomethane (HCF2CHN2)3 as building blocks for the introduction of fluoroalkyl groups into molecules has become an area of intensive research, and more than 50 publications have appeared since 2010.4 Various modes of reactivity of these building blocks, e.g. carbene5 (or carbenoid),6,7 1,3-dipole in [3 + 2] cycloaddition,8 C-nucleophile,9 C-electrophile,10 and N-nucleophile,11 have been unveiled. Another very useful mode of reactivity that is typical of substituted diazomethanes is reaction with carboxylic acids to give esters.12 However, although alkyldiazomethanes are very reactive toward carboxylic acids,12 it is generally accepted that their fluoroalkyl counterparts are inert to them (Scheme 1a). The reaction with carboxylic acids was among the first reactions evaluated for CF3CHN2, but Meese and co-workers in 1984 showed that CF3CHN2 failed to react with either acetic acid or benzoic acid.10b Since then, no examples of esterification reactions, except the work by Mykhailiuk and co-workers, involving CF3CHN2 or HCF2CHN2 have been reported.13 It is intriguing that Mykhailiuk and co-workers employed a substoichiometric amount of acetic acid (AcOH) in the first successful synthesis of HCF2CHN2, an important fluoroalkyl diazoalkane (Scheme 1b).3 Since then, the research groups of Koenigs,14 Mykhailiuk and Wu,15 Han and Chen,16 Jamison,17 and Ma8j have used AcOH in various amounts (0.1−1.6 equiv) for the in situ generation and application of HCF2CHN2 and CF3CHN2 (Scheme 1b). However, in none of these examples is any possible reaction between XCF2CHN2 and AcOH discussed.
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© 2017 American Chemical Society
Scheme 1. Reaction of CF3CHN2 and HCF2CHN2
As shown in Scheme 1b, the balanced equation does not require the consumption of a stoichiometric amount of AcOH. We therefore wondered whether the relatively large amounts of AcOH that were typically used in previous works indicated that some kind of reaction with XCF2CHN2 could take place.3,8j,14−17 To test this idea, we conducted a preliminary NMR experiment in which a mixture of HCF2CH2NH2 and tert-butyl nitrite (TBN) was heated in the presence of 1 equiv of AcOH (Scheme 1b). Indeed, difluoroethyl acetate was clearly observed in the spectra after a reaction time of 10 min (Figure S1).3 Encouraged by this result, we set out to investigate the reaction of in situ generated HCF2CHN2 with a variety of carboxylic acids. For the reaction optimization, benzoic acid 2a was chosen as the Received: September 13, 2017 Published: October 5, 2017 5689
DOI: 10.1021/acs.orglett.7b02866 Org. Lett. 2017, 19, 5689−5692
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Organic Letters
together and stirred at 35 °C, and no drying or distillation of the solvent is needed. Conversion of a carboxylic acid to its corresponding ester is an important strategy in prodrug design20 to increase the lipophilicity and membrane permeability of an active agent. In view of the well-known pharmacokinetic advantages that fluorination can provide,1 the formation of a difluoroethyl ester could be a particularly useful transformation. Previously, the formation of a difluoroethyl ester was usually achieved through either Fisher esterification or a coupling reaction,21 both of which entails the use of excess costly difluoroethanol. In this work, a range of difluoroethyl ester analogues of marketed drugs and natural products were readily prepared under the aforementioned standard conditions (Scheme 2 and Figure 1), starting from
model substrate because of the ease of purification of the ester product 4a. We found that the esterification reaction proceeded successfully in a range of solvents, such as dichloromethane, chloroform, ethyl acetate, and acetonitrile (Scheme 2 and Table Scheme 2. Reaction of HCF2CHN2 with Carboxylic Acids
Figure 1. Difluoroethyl ester analogues of marketed drugs and natural products. a 1,4-Dioxane was used because these acids have a much better solubility in this solvent than in CHCl3. b Yield on gram scale.
fenofibrate (cardiovascular diseases), cloribrate (cardiovascular diseases), indomethacin (anti-inflammatory), etodolac (antiinflammatory), oseltamivir (antiviral), gibberellic acid, and shikimic acid. Although a free amino group (10) needed to be protected, other functional groups including ether (6), ketone (7), alkene (11, 12), and hydroxyl (12) were unaffected, further showcasing the generality of this transformation. The practicality was demonstrated by running the reaction for Etodolac acid (9) on gram scale. Having successfully established a practical esterification of carboxylic acids with HCF2CH2N2, we then wanted to extend the reaction to CF3CHN2. However, to our surprise, no desired product was observed when the same reaction conditions used for HCF2CHN2 were applied using benzoic acid 1a as the substrate. An unexpected compound, later assigned as N-trifluoroethyl imide 5a, was instead isolated in 17% yield (Scheme 3). This product was deduced to be formed through an interrupted esterification reaction (a Mumm rearrangement),22 and the structure of 5a was confirmed by comparison of its spectroscopic data with those reported.23 The yield of 5a increased dramatically when the reaction was performed at a higher temperature (Scheme 3). Under similar thermal conditions, the electron-rich and electon-neutral products 5b−5j were obtained in 67−95% yield. For electron-deficient and heteroaromatic substrates, mixtures of imide and ester products were formed. For example, 5i was obtained in only 55% yield, along with 19% of ester side product 13j. Thus, an alternative CuI-catalyzed process was developed and this successfully delivered 5i−5n in 67−90% yield (Scheme 3 and Table S2).22b The structures of 5i and 5j were confirmed by means of X-ray crystallographic analysis.18 To further demonstrate the strikingly different reactivity between CF3CHN2 and HCF2CHN2, a series of comparison experiments were conducted (Scheme 4). First, virtually no reaction was observed with CF3CHN2 in any other solvents
S1). The optimized conditions were identified as 2.0 equiv of both HCF2CH2NH2 and TBN, in acetonitrile, at 35 °C. Using these conditions, the scope of the reaction was investigated with respect to the carboxylic acid component (Scheme 2). The difluoroethyl esterification reaction tolerated various substitution patterns and different functional groups on the carboxylic acid component (Scheme 2). Carboxylic acids with ortho- (4b−4e), para- (4f−4m), and meta-substituents (4n−4o) all smoothly underwent the reaction to afford the desired products in good to excellent yields. It was interesting to note that carboxylic acids with ortho-substituents reacted faster than their para- or meta-substituted counterparts. Different substituents including halo (F, Cl, Br, I), nitro, hydroxyl, alkyl, alkyloxyl, ester, phenyl, and cyano were all tolerated (4b−4o), although those with electron-donating groups (e.g., 4j and 4l) required a longer reaction time. Disubstituted aromatic carboxylic acids (4p−4q) reacted smoothly under the reaction conditions. Carboxylic acids with bicycloaryl and heteroaryl ring systems (4r−4v) were also viable substrates, irrespective of the electron-rich (4t−4v) or electron-deficient character (4s). The structures of 4m and 4t were confirmed by means of X-ray crystallographic analysis.18 It is noteworthy that the reaction exhibited good chemoselectivity, with no ring nitrated products observed even for the electron-rich compounds (4c, 4l, 4q, 4t−4v).19 The reaction was also found to be insensitive to steric hindrance, as the congested products 4x− 4z were obtained in similarly high yields. Finally, in addition to the excellent substrate scope, it should be noted that the reaction is operationally simple to perform: the reagents are simply mixed 5690
DOI: 10.1021/acs.orglett.7b02866 Org. Lett. 2017, 19, 5689−5692
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Organic Letters Scheme 3. Interrupted Esterification of Carboxylic Acids with CF3CHN2
Figure 2. Calculated direct esterification profile and the electrostatic potential surfaces of the transition states (−0.01 to +0.01 au) with red corresponding to negative and blue to positive charge density.
a
derived from HCF2CHN2 has no electrostatic repulsion but rather a weak attraction between an oxygen atom and the electropositive hydrogen atom of HCF2CHN2 (HCF2 is wellknown as a hydrogen bond donor28). Overall, the results of these calculations suggest the very different reactivities of CF3CHN2 and HCF2CHN2 are possibly due to the electrostatic repulsion and attraction, respectively, both of which resulted from the electronegativity of fluorine. In conclusion, we have investigated the important but overlooked reactivity of HCF2CHN2 and CF3CHN2 with carboxylic acids. HCF2CHN2 reacts readily with carboxylic acids; the conditions are operationally simple, mild, and tolerant of a broad range of functional groups. This allows the preparation of potentially useful difluoroethyl ester analogues of marketed drugs. For CF3CHN2, however, an unexpected interrupted esterification (a Mumm reaction) occurs to afford N-trifluoroethyl imides. A theoretical investigation suggests that this striking fluorine effect is possibly due to an electrostatic repulsion or attraction of a carboxylate ion with the electronegative fluorine atom (CF3CHN2) or an electropositive hydrogen atom (HCF2CHN2). This work provides a clear example of the different chemistries of the important CF3 and CF2 substituents and should be useful for the design and prediction of analogous reactions involving CF3 and CF2 substituted compounds.
0.05 equiv of CuI was added.
Scheme 4. Comparison Experiments
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except THF (3%), which was in sharp contrast with the results obtained with HCF2CHN2. Second, when the CuI-catalyzed reaction was attempted with HCF2CHN2 and the three representative substrates 1a, 1l, 1m, the corresponding ester products were still obtained in preference to imides.22c To understand this “fluorine effect,”24 we modeled the reaction pathway at the B3LYP25/6-31G(d,p) level of theory (see Supporting Information) based on previous mechanistic discussion.12e,g,26 Calculations were performed using the Gaussian 09 software package and the CPCM solvent model27 which accounts for the solvent acetonitrile. The esterification of benzoic acid with HCF2CHN2 has an activation barrier of 22.6 kcal/mol, which is 4.5 kcal/mol lower than that of CF3CHN2 (Figure 2). This indicates that the reaction with HCF2CHN2 should be much more facile, which corroborates the experimental results (Schemes 2, 3, 4). To further probe the intrinsic difference between these two reactions, we analyzed the electrostatic potential surface of the two transition states. As shown in Figure 2, the transition state derived from CF3CHN2 suffers from an electrostatic repulsion between the carboxylate ion and two electronegative fluorine atoms. In contrast, the transition state
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02866. Experimental details, analytical data (PDF) Crystallographic data for 4m (CIF) Crystallographic data for 4t (CIF) Crystallographic data for 5i (CIF) Crystallographic data for 5j (CIF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Xiang-Guo Hu: 0000-0002-5909-2582 Notes
The authors declare no competing financial interest. 5691
DOI: 10.1021/acs.orglett.7b02866 Org. Lett. 2017, 19, 5689−5692
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(12) For selected examples: (a) Seyferth, D.; Dow, A. W.; Menzel, H.; Flood, T. C. J. Am. Chem. Soc. 1968, 90, 1080−1082. (b) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. 1981, 29, 1475−1478. (c) Furrow, M. E.; Myers, A. G. J. Am. Chem. Soc. 2004, 126, 12222− 12223. (d) McGrath, N. A.; Andersen, K. A.; Davis, A. K. F.; Lomax, J. E.; Raines, R. T. Chem. Sci. 2015, 6, 752−755. (e) Dumitrescu, L.; AzzouziZriba, K.; Bonnet-Delpon, D.; Crousse, B. Org. Lett. 2011, 13, 692−695. (f) Audubert, C.; Marin, O. J. G.; Lebel, N. Angew. Chem., Int. Ed. 2017, 56, 6294−6297. (g) Audubert, C.; Lebel, H. Org. Lett. 2017, 19, 4407− 4410. (13) During the preparation of this manuscript, Mykhailiuk and coworkers reported the reaction of carboxylic acids with HCF2CHN2: Mykhailiuk, P. K.; Kishko, I.; Kubyshkin, V.; Budisa, N.; Cossy, J. Chem. Eur. J. 2017, 23, 13279. (14) (a) Hock, K. J.; Mertens, L.; Koenigs, R. M. Chem. Commun. 2016, 52, 13783−13786. (b) Hock, K. J.; Mertens, L.; Metze, F. K.; Schmittmann, C.; Koenigs, R. M. Green Chem. 2017, 19, 905−909. (c) Mertens, L.; Hock, K. J.; Koenigs, R. M. Chem. - Eur. J. 2016, 22, 9542−9545. (15) Li, J.; Yu, X. L.; Cossy, J.; Lv, S. Y.; Zhang, H. L.; Su, F.; Mykhailiuk, P. K.; Wu, Y. Eur. J. Org. Chem. 2017, 2017, 266−270. (16) Han, W.-Y.; Zhao, J.; Wang, J.-S.; Xiang, G.-Y.; Zhang, D.-L.; Bai, M.; Cui, B.-D.; Wan, N.-W.; Chen, Y.-Z. Org. Biomol. Chem. 2017, 15, 5571−5578. (17) Britton, J.; Jamison, T. F. Angew. Chem., Int. Ed. 2017, 56, 8823− 8827. (18) CCDC 1573604−1573607 contain the crystallographic data for this paper. (19) Examples of nitration of electron-rich arenes with TBN: (a) Koley, D.; Colón, O. C.; Savinov, S. N. Org. Lett. 2009, 11, 4172−4175. (b) Li, Y.-X.; Li, L.-H.; Yang, Y.-F.; Hua, H.-L.; Yan, X.-B.; Zhao, L.-B.; Zhang, J.B.; Ji, F.-J.; Liang, Y.-M. Chem. Commun. 2014, 50, 9936−9938. (20) Beaumont, K.; Webster, R.; Gardner, I.; Dack, K. Curr. Drug Metab. 2003, 4, 461−485. (21) For selected examples: (a) Labaree, D. C.; Reynolds, T. Y.; Hochberg, R. B. J. Med. Chem. 2001, 44, 1802−1814. (b) Ams, M. R.; Fields, M.; Grabnic, T.; Janesko, B. G.; Zeller, M.; Sheridan, R.; Shay, A. J. Org. Chem. 2015, 80, 7764−7769. (22) (a) Mumm, O. Ber. Dtsch. Chem. Ges. 1910, 43, 886−893. (b) Chen, J. J.; Shao, Y.; Ma, L.; Ma, M. H.; Wan, X. B. Org. Biomol. Chem. 2016, 14, 10723−10732. (c) Mechanistic proposal under thermal (a) and Cu-catalyzed (b) conditions:
ACKNOWLEDGMENTS We thank National Natural Science Foundation of China (21502076), Natural Science Foundation of Jiangxi province (20161BAB213068), and Outstanding Young Talents Scheme of Jiangxi Province (20171BCB23039) for funding, and Dr. Luke Hunter at UNSW for proof reading.
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REFERENCES
(1) (a) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881− 1886. (b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320−330. (c) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. J. Med. Chem. 2015, 58, 8315−8359. (2) Gilman, H.; Jones, R. G. J. Am. Chem. Soc. 1943, 65, 1458. (3) Mykhailiuk, P. K. Angew. Chem., Int. Ed. 2015, 54, 6558−6561. (4) Mertens, L.; Koenigs, R. M. Org. Biomol. Chem. 2016, 14, 10547− 10556. (5) For selected examples: (a) Fields, R.; Haszeldine, R. N. J. Chem. Soc. 1964, 1881−1889. (b) O’Gara, J. E.; Dailey, W. P. J. Am. Chem. Soc. 1994, 116, 12016. (6) For selected examples: (a) Le Maux, P.; Juillard, S.; Simonneaux, G. Synthesis 2006, 2006, 1701−1704. (b) Mykhailiuk, P. K.; Afonin, S.; Palamarchuk, G. V.; Shishkin, O. V.; Ulrich, A. S.; Komarov, I. V. Angew. Chem., Int. Ed. 2008, 47, 5765−5767. (c) Morandi, B.; Carreira, E. M. Angew. Chem., Int. Ed. 2010, 49, 938−941. (d) Morandi, B.; Carreira, E. M. Angew. Chem., Int. Ed. 2010, 49, 4294−4296. (e) Morandi, B.; Cheang, J.; Carreira, E. M. Org. Lett. 2011, 13, 3080−3081. (f) Duncton, M. A. J.; Singh, R. Org. Lett. 2013, 15, 4284−4287. (g) Artamonov, O. S.; Slobodyanyuk, E. Y.; Volochnyuk, D. M.; Komarov, I. V.; Tolmachev, A. A.; Mykhailiuk, P. K. Eur. J. Org. Chem. 2014, 2014, 3592−3598. (7) For selected examples: (a) Liu, C. B.; Meng, W.; Li, F.; Wang, S.; Nie, J.; Ma, J. A. Angew. Chem., Int. Ed. 2012, 51, 6227−6230. (b) Xiong, H.-Y.; Yang, Z.-Y.; Chen, Z.; Zeng, J.-L.; Nie, J.; Ma, J.-A. Chem. - Eur. J. 2014, 20, 8325−8329. (c) Wang, S.; Nie, J.; Zheng, Y.; Ma, J. A. Org. Lett. 2014, 16, 1606−1609. (d) Luo, H. Q.; Wu, G. J.; Zhang, Y.; Wang, J. B. Angew. Chem., Int. Ed. 2015, 54, 14503−14507. (e) Hyde, S.; Veliks, J.; Liegault, B.; Grassi, D.; Taillefer, M.; Gouverneur, V. Angew. Chem., Int. Ed. 2016, 55, 3785−3789. (8) For selected examples: (a) Fields, R.; Tomlinson, J. P. J. Fluorine Chem. 1979, 13, 147. (b) Artamonov, O. S.; Mykhailiuk, P. K.; Voievoda, N. M.; Volochnyuk, D. M.; Komarov, I. V. Synthesis 2010, 2010, 443− 446. (c) Li, F.; Nie, J.; Sun, L.; Zheng, Y.; Ma, J. A. Angew. Chem., Int. Ed. 2013, 52, 6255−6258. (d) Slobodyanyuk, E. Y.; Artamonov, O. S.; Shishkin, O. V.; Mykhailiuk, P. K. Eur. J. Org. Chem. 2014, 2014, 2487− 2495. (e) Zhang, F. G.; Wei, Y.; Yi, Y. P.; Nie, J.; Ma, J. A. Org. Lett. 2014, 16, 3122−3125. (f) Chen, Z.; Fan, S. Q.; Zheng, Y.; Ma, J. A. Chem. Commun. 2015, 51, 16545−16548. (g) Zhu, C. L.; Yang, L. J.; Li, S.; Zheng, Y.; Ma, J. A. Org. Lett. 2015, 17, 3442−3445. (h) Wang, S.; Yang, L. J.; Zeng, J. L.; Zheng, Y.; Ma, J. A. Org. Chem. Front. 2015, 2, 1468− 1474. (i) Zhu, C. L.; Ma, J. A.; Cahard, D. Asian J. Org. Chem. 2016, 5, 66− 69. (j) Chen, Z.; Zheng, Y.; Ma, J. A. Angew. Chem., Int. Ed. 2017, 56, 4569−4574. (9) For selected examples: (a) Mock, W. L.; Hartman, M. E. J. Org. Chem. 1977, 42, 459−465. (b) Morandi, B.; Carreira, E. M. Org. Lett. 2011, 13, 5984−5985. (c) Morandi, B.; Carreira, E. M. Angew. Chem., Int. Ed. 2011, 50, 9085−9088. (d) Kunzi, S. A.; Morandi, B.; Carreira, E. M. Org. Lett. 2012, 14, 1900−1901. (e) Chai, Z.; Bouillon, J. P.; Cahard, D. Chem. Commun. 2012, 48, 9471−9473. (f) Molander, G. A.; Ryu, D. Angew. Chem., Int. Ed. 2014, 53, 14181−14185. (g) Argintaru, O. A.; Ryu, D.; Aron, I.; Molander, G. A. Angew. Chem., Int. Ed. 2013, 52, 13656− 13660. (h) Pieber, B.; Kappe, C. O. Org. Lett. 2016, 18, 1076−1079. (10) (a) Mohrig, J. R.; Keegstra, K. J. Am. Chem. Soc. 1967, 89, 5492. (b) Meese, C. O. Synthesis 1984, 1984, 1041−1042. (c) Loehr, D. T.; Armistead, D.; Roy, J.; Dorn, H. C. J. Fluorine Chem. 1988, 39, 283−287. (d) Proud, A. D.; Prodger, J. C.; Flitsch, S. L. Tetrahedron Lett. 1997, 38, 7243−7246. (11) (a) Arkhipov, A. V.; Arkhipov, V. V.; Cossy, J.; Kovtunenko, V. O.; Mykhailiuk, P. K. Org. Lett. 2016, 18, 3406−3409. (b) Guo, R.; Zheng, Y.; Ma, J. A. Org. Lett. 2016, 18, 4170−4173.
(23) Cai, A. J.; Zheng, Y.; Ma, J. A. Chem. Commun. 2015, 51, 8946− 8949. (24) For general reviews: (a) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308−319. (b) Zimmer, L. E.; Sparr, C.; Gilmour, R. Angew. Chem., Int. Ed. 2011, 50, 11860−11871. Fluoroalkylation: (c) Ni, C.; Hu, J. Synlett 2011, 2011, 770−782. (d) Ni, C. F.; Hu, J. B. Chem. Soc. Rev. 2016, 45, 5441−5454. (25) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B: Condens. Matter Mater. Phys. 1988, 37, 785−789. (b) Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys. Lett. 1989, 157, 200−206. (c) Becke, A. D. J. Chem. Phys. 1993, 98, 5648−5652. (26) Kuehnel, E.; Laffan, D. D. R.; Lloyd-Jones, G. C.; del Campo, T. M.; Shepperson, I. R.; Slaughter, J. L. Angew. Chem., Int. Ed. 2007, 46, 7075−7078. (27) (a) Barone, V.; Cossi, M. J. Phys. Chem. A 1998, 102, 1995−2001. (b) Cossi, M.; Rega, N.; Scalmani, G.; Barone, V. J. Comput. Chem. 2003, 24, 669−681. (28) Erickson, J. A.; McLoughlin, J. I. J. Org. Chem. 1995, 60, 1626− 1631.
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