Computational Studies on the Electrocyclizations of 1-Amino-1,3,5-hexatrienes Vildan Adar Guner,†,‡ K. N. Houk,*,† and Ian W. Davies*,§ Department of Chemistry and Biochemistry, University of California, Los Angeles, 405 Hilgard Avenue, Los Angeles, California 90095-1569, Department of Chemistry, Hacettepe University, 06532, Beytepe, Ankara, Turkey, and Department of Process Research, Merck & Co., Inc., PO Box 2000, Rahway, New Jersey 07065-0900
[email protected];
[email protected] Received August 19, 2004
Electrocyclizations of 1,3,5-hexatrienes containing up to four electron-donating and/or electron withdrawing substituents have been studied computationally using the hybrid density functional, B3LYP. Electron donating substituents at positions C-1 and C-5 decrease activation barriers by 0.3 to 2.3 kcal/mol. Introducing of an electron-withdrawing group, CO2Me, at C-4 further decreases the activation energy by 7 kcal/mol. Electron-withdrawing groups (NO2, SO2Ph and CdN+Me2) at C-2 have a profound effect of 17-25 kcal/mol on the activation energy. Introduction Vinamidinium salts react with methylacetoacetate to form dienones. In the case of protio-,1 phenyl-,2 chloro-,3 fluoro-,4 and cyano-substituted5 dienones they do not undergo subsequent spontaneous downstream chemistry. However, we have demonstrated that ring closure to provide aromatic products occurs in the case of nitro-, phenylsulfonyl-, and dimethylaminomethylene substitution.6,7 The major reaction pathway has been formalized as (1) enamine or enol formation, (2) electrocyclization, and (3) elimination of dimethylamine to provide the aromatic product (Scheme 1).8 The electrocyclization of 1,3,5-hexatrienes having a 1-dimethylamino latent leaving group has been previously observed9 and similarly occurs for the 1-SMe10 and 1-Cl11 hexatrienes. †
University of California, Los Angeles. Hacettepe University. Merck & Co., Inc. (1) Kiesel, M.; Haug, E.; Kantlehner, W. J. Prakt. Chem. 1997, 339, 159. For ethyl ester, see: Nair, V.; Cooper, C. S. Tetrahedron Lett. 1980, 21, 3155. (2) Krasnaya, Z. A.; Prokofev, E. P.; Yakovlev, I. P.; Lubuzh, E. D. Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Ed.) 1980, 29, 2325. (3) Krasnaya, Z. A.; Stytsenko, T. S.; Bogdanov, V. S.; Daeva, E. D.; Dvornikov, A. S. Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Ed.) 1985, 34, 1075. (4) Krasnaya, Z. A.; Stytsenko, T. S.; Bogdanov, V. S.; Monich, N. V.; Kul’chitskii, M. M.; Pazenok, S. V.; Yagupol’skii, L. M. Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Ed.) 1989, 38, 562. (5) Krasnaya, Z. A.; Stytsenko, T. S.; Bogdanov, V. S.; Dvornikov, A. S. Bull. Acad. Sci. USSR, Div. Chem. Sci. (Engl. Ed.) 1989, 38, 1206. (6) Davies, I. W.; Marcoux, J.-F.; Taylor, J. D. O.; Dormer, P. G.; Deeth, R. J.; Marcotte, F.-A.; Hughes, D. L.; Reider, P. J. Org. Lett. 2002, 4, 439. (7) Davies, I. W.; Marcoux, J.-F.; Taylor, J. D. O.; Dormer, P. G.; Deeth, R. J.; Marcotte, F.-A.; Hughes, D. L.; Reider, P. J. Org. Lett. 2002, 4, 3017. (8) Davies, I. W.; Marcoux, J.-F.; Kuethe, T. F.; Lankshear, M. D.; Taylor, J. D. O.; Tsou, N.; Dormer, P. G.; Hughes, D. L.; Houk, K. N.; Guner, V. J. Org. Chem. 2004, 69, 1298. (9) (a) Jutz, C.; Wagner, R. M. Angew. Chem. 1972, 11, 315. (b) Jutz, C. J. Top. Curr. Chem. 1978, 73, 125. (10) Matsumo, S.; Takahashi, S.; Ogura, K. Heteroatom Chem. 2001, 12, 385. ‡
The ring closure of 1,3,5-hexatriene to form 1,3-cyclohexadiene, the simplest disrotatory electrocyclization described by Woodward and Hoffmann,12 has been studied computationally.13 One of us has previously studied the electrocyclization reaction of 1-substituted 1,3,5hexatrienes (F, CH3, CN, CHO, NO, BH2) using AM1, HF with the 3-21G* and 6-31G* and MP2 with the 6-31G* method.14 Introducing electron-withdrawing groups F, CN, BH2, and NO lowers the activation barrier by 3.2, 0.8, 1.8, and 12.0 kcal/mol by MP2/6-31G* calculations, respectively. In this paper, electrocyclization of 1-amino1,3,5-hexatrienes has been studied extensively by using the B3LYP method for both gaseous and condensed phases. Our goals were to explain how electron-donating and electron-withdrawing substituents influence the electrocyclizations of 1-amino-1,3,5-hexatriene and to develop a theoretical framework for understanding the experimentally observed products.
§
Computational Studies All calculations were performed with GAUSSIAN 98.15 All structures, reactants, transition structures, and products were optimized with the B3LYP functional,16 and the 6-31G*17 and 6-31++G** basis sets.18 The effect of solvent was explored with the Cosmo Polarized Continuum Model (CPCM)19 for THF solvent. All minima and transition states were characterized by their vibrational frequencies. All energy changes reported in this paper include zero-point energies which are scaled by 0.9804. The initial conformational searches were performed with (11) Ogura, K.; Takeda, M.; Xie, J. R. Akazome, M.; Matsumoto, S. Tetrahedron Lett. 2001, 42, 1923. (12) Woodward, R. B.; Hoffmann, R. The Conservation of Orbital Symmetry; Academic Press: New York, 1970. (13) (a) Sakai, S.H.; Takane, S. J. Phys. Chem. A 1999, 103, 2878. (b) Jiao, H.; Schleyer, R. J. Am. Chem. Soc. 1995, 117, 1129. (14) Evanseck, J. D.; Thomas, B. E., IV; Spellmeyer, D. C.; Houk, K. N. J. Org. Chem. 1995, 60, 7134. 10.1021/jo048540s CCC: $27.50 © 2004 American Chemical Society
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Published on Web 10/21/2004
Computational Studies on 1-Amino-1,3,5-hexatrienes SCHEME 1. Formation of Anilines or Phenols via Electrocyclic Ring Closure with Downstream Elimination of Dimethylamine
CHART 1
CHART 2. Enamine
All Possible Conformers of Enol and
FIGURE 1. Minimized conformations for hexatrienes 8, 11, enol 12, and enamine 13 (distances in Å).
All possible conformations with respect to two single bonds are defined below in A-F (Chart 2). The letters t
Monte Carlo calculations employing the Macromodel program (MM2 force field).20 To explore how substituents affect transition structures and activation energies for electrocyclic ring closure, we performed calculations on 1,3,5-hexatrienes, 8-17 (Chart 1).
(15) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98, Revision A.9; Gaussian, Inc.: Pittsburgh, PA, 1998. (16) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652. (b) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785-789. (c) Becke, A. D. J. Chem. Phys. 1993, 98, 1372.
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Guner et al. TABLE 1. Calculated Activation Energies and Geometry Parameters for the Transition State of Electrocyclic Closure of Substituted Hexatrienes
compd 8 9 10 11 12 13 14 15 16 17
R1
R2
R3
R5
∆Hq (kcal/mol)
C1-C6 (Å)
C1C2C3C4 (deg)
C6C5C4C3 (deg)
C2C3C4C5 (deg)
C2C1C6C5 (deg)
H NMe2 NMe2 NMe2 NMe2 NMe2 NMe2 NMe2 NMe2 NMe2
H H H H NO2 NO2 CdNMe2+ CdNMe2+ SO2Ph SO2Ph
H H H CO2Me CO2Me CO2Me CO2Me CO2Me CO2Me CO2Me
H H OH OH OH NMe2 OH NMe2 OH NMe2
29.9 29.6 27.6 23.2 12.5 10.0 11.1 4.3 7.5 10.0
2.281 2.318 2.339 2.370 2.495 2.281 2.315 2.493 2.486 2.384
-33.0 29.9 19.9 17.4 11.8 18.8 19.7 36.1 11.5 17.6
33.0 22.9 32.3 31.0 33.6 46.8 44.8 59.3 33.5 44.3
0.0 6.6 2.8 9.6 12.5 4.4 7.0 1.5 12.3 7.0
0.0 21.1 19.7 33.5 43.5 39.3 38.3 24.9 42.9 38.3
and c denote the s-trans and s-cis conformation, respectively, with respect to the C-C single bonds. E and Z stand for the cis and trans configuration relative to the CdC double bond. In addition, the ester bond may be syn or anti. All calculated conformers are nonplanar. In 11 and 12, the conformer with the carbonyl group s-trans to the central double bond is more stable than that of the s-cis form because of the hydrogen bond between the hydroxyl group and the carbonyl group. Conformers 12-C (for E) and 13-C (for E and Z) could not be located because of steric interactions between hydroxyl and dimethylamino and two dimethylamino groups, respectively. In the case of enamine 13 the s-cis form is more stable than s-trans because there are no hydrogen bonds between the two groups in the latter. The rotational barriers about CdC double bonds are quite low in push-pull ethylenes containing electrondonor groups (typically amino groups) at one terminus and an acceptor group (-NO2, -CN, etc.) at the other end of the double bond.21 The CdC rotational barrier ranges from 10 to 25 kcal/mol for a variety of substituted compounds. The low barriers are explained in terms of the capacity of the donor and acceptor groups to stabilize the dipolar transition states for rotation.22 The experimentally determined rotational barrier for 1,1-diamino-2,2-dicyanoethylene is 11.2 kcal/mol.23 The (17) (a) Harihar, P. C.; Pople, J. A. Theor. Chem. Acta 1973, 28, 213. (b) Ditchfield, R.; Hehre, W. J.; Pople, J. A. J. Chem. Phys. 1971, 54, 724. (c) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972, 56, 2257. (18) Hehre, W. J.; Radom, L.; Schleyer, P. V.; Pople, J. A. Ab initio molecular orbital theory; Wiley: New York, 1986. (19) (a) Barone, V.; Cossi, M. J. J. Phys. Chem. A 1998, 102, 1995. (b) Barone, B.; Cossi, M.; Tomasi, J. J. Comput. Chem. 1998, 19, 404. (20) Mohamadi, F.; Richard, N. G. J.; Guida, W. C.; Liskamp R.; Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. MacroModel - an Integrated Software System for Modeling Organic and Bioorganic Molecules Using Molecular Mechanics. J. Comput. Chem. 1990, 11, 440. (21) (a) Sandstrom, J. Top Stereochem. 1983, 14, 83-176. (b) Taddei, F. J. Mol. Struct. (THEOCHEM) 1996, 363, 139. (c) Benassi, R.; Bertarini, C.; Taddei, F.; Kleinpeter, E. J. Mol. Struct. (THEOCHEM) 2001, 541, 101. (d) Benassi, R.; Taddei, F. J. Mol. Struct. (THEOCHEM)2001, 572, 169. (22) Dwyer, T. J.; Jasien, P. G. J. Mol. Struct. (THEOCHEM) 1996, 363, 139. (23) Didkovskii, V. E.; Iksanova, S. V.; Egorov, Y. P. Teor. Eksp. Khim. 1986, 22, 316.
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FIGURE 2. Optimized transition structures for electrocyclization of hexatriene 8, 9, 10, and 11 (energies are in kcal/ mol, distances in Å).
initial addition/elimination step of ketone to the vinamidinium leads to a ∼3:1 mixture of 3(E,Z)-isomers of the dienone.24 Energy differences between the most and the least stable conformations are 12.6, 9.7, and 7.7 kcal/mol for 11, 12, and 13, respectively.25 The calculations show that molecules 12 and 13 have the minimum energy conformations that are essentially aligned for electrocyclization (Figure 1). The structural features of transition structures and energies for the electrocyclic ring closing process are given in Figures 2-5 together with Table 1. The activation energy for electrocyclization is strongly linked to substitution on the triene. As shown in Figure 2, introduction of oxygen or nitrogen substituents at C-1 and (24) This level of selectivity is common for a range of enolate additions to vinamidinium salts: Malleron, J. L.; Roussel, G. F.; Gueremy, G.; Ponsinet, G.; Robin, J. L. J. Med. Chem. 1990, 33, 2744. (25) Conformations correspond to the following: 10A, s-transcarbonyl, E-dimethylamine; 10F, s-cis-carbonyl, Z-dimethlyamine; 14F, s-trans-carbonyl, E-dimethylamine; 14B, cis-carbonyl, Z-dimethylamine; 11F, s-cis-carbonyl, Z-dimethylamine; 14B, s-cis-carbonyl, Z-dimethylamine. The most and the least stable conformations are A and F for 10, F and B for 14 and 11.
Computational Studies on 1-Amino-1,3,5-hexatrienes
FIGURE 3. Optimized transition structures for electrocyclizations of the nitro-substituted case for enol 12 and enamine 13 (energies are in kcal/mol).
FIGURE 5. Optimized transition structures for electrocyclizations of the sulfonyl-substituted case for enol 16 and enamine 17 (energies are in kcal/mol).
tion required for the ring closure. Transition structures are shown in Figure 3. The lowest activation energy calculated for any of the electrocyclizations (4.3 kcal/mol) was observed for enamine with the conformation 15 (Figure 4). In the case of phenyl sulfonyl substituent, the minimum energy conformers for enol 16 and enamine 17 were also calculated and again exhibited the F conformation (Figure 5). The calculated activation barriers for electrocyclization were 7.5 and 10.0 kcal/mol, respectively. Conclusion
FIGURE 4. Optimized transition structures for electrocyclizations of the iminium-substituted case for enol 14 and enamine 15 (energies are in kcal/mol).
C-5 has a small impact versus the parent 1,3,5-hexatriene 8.26 Introduction of a conjugating, electronwithdrawing group at C-4 reduces the activation energy by 6-7 kcal/mol. In the nitro-substituted cases, 12 and 13, which have an electron-withdrawing group at C-2, activation barriers are lowered by 17-19 kcal/mol. One of the reasons for this is that the reactants 12 and 13 have the conforma(26) Since anionic substitution has important consequences, e.g., oxy-Cope rearrangement, we studied the neutral and anionic closures of 2-hydroxy-1,3,5-hexatriene. The activation energies for these processes were calculated to be 29.9 and 29.6 kcal/mol, respectively, i.e., there is essentially no effect of the deprotonation of the alcohol in this case. Therefore the corresponding anionic reactions of 9, 10, and 11 were not considered as alternatives.
1,3,5-Hexatrienes containing one, two, three, and four electron-donating and/or electron-withdrawing substituents have been studied to examine how substituents influence activation barriers of electrocyclic ring closures. Electron-donating substituents at position 1 and 5 decrease the activation barrier by 0.3 to 2.3 kcal/mol. The electron-withdrawing group CO2Me, at C-4 of species 10, further decreases the activation energy by 6.6 kcal/mol. Electron-withdrawing groups (NO2, SO2Ph, and CdN+Me2) at C2 have a profound effect of 17-25 kcal/mol. The iminium-substituted triene 15 has the lowest activation energy (4.3 kcal/mol), which agrees with the experimentally observed rate of reaction. The mechanistic pathway from dienone through a remarkably facile electrocyclization is strongly dependent upon substituents on the 1-amino-1,3,5-hexatriene; the process can be made facile by sulfonyl, nitro, and dimethylaminomethylene substitution.
Acknowledgment. We are grateful to the National Science Foundation for financial support of the computational research. We also thank the San Diego Supercomputing Center and the UCLA Office of AcaJ. Org. Chem, Vol. 69, No. 23, 2004 8027
Guner et al.
demic Computing for computational resources. V.A.G. thanks the Scientific and Technical Research Council (TUBITAK) for a NATO Science Fellowship.
of 1,3,5-hexatrienes and their transition structures for electrocyclic ring closure. This material is available free of charge via the Internet at http://pubs.acs.org.
Supporting Information Available: B3LYP/6-31G* optimized Cartesian coordinates for the most stable conformers
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