Computations Reveal That Electron-Withdrawing Leaving Groups

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Computations reveal that electron-withdrawing leaving groups facilitate intramolecular conjugate displacement reactions by negative hyperconjugation Elizabeth L. Noey, Gonzalo Jiménez-Osés, Derrick L. J. Clive, and K. N. Houk J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00691 • Publication Date (Web): 21 Apr 2016 Downloaded from http://pubs.acs.org on April 24, 2016

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The Journal of Organic Chemistry

Computations reveal that electron-withdrawing leaving groups facilitate intramolecular conjugate displacement reactions by negative hyperconjugation Elizabeth L. Noey†, Gonzalo Jiménez-Osés†, Derrick J. L. Clive‡, K. N. Houk*,† †Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States. ‡ Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada. E-mail: [email protected] Abstract Intramolecular conjugate displacement (ICD) reactions, developed by the Clive group, form carbocycles and polycyclic amines by intramolecular nucleophilic attack on a Michael acceptor with an allylic leaving group. Quantum mechanical investigations with density functional theory show that ICDs involve a stepwise addition, forming an intermediate stabilized carbanion, followed by elimination. The electron-withdrawing nature of the allylic leaving group facilitates the addition by negative hyperconjugation; the twist-boat conformation of the addition and intermediate is stabilized by this interaction. In the absence of an activating electron-withdrawing group as part of the Michael acceptor a high-energy concerted SN2' reaction occurs. The reactions of carbon nucleophiles have lower activation energies than those of amines.

Introduction The Clive group has extensively developed the intramolecular conjugate displacement (IDC) reaction for ring closure with a variety of substrates (Eq 1).1 Related intermolecular reactions have also been demonstrated by Seebach.2 The reaction is basepromoted and requires a nucleophile, Michael acceptor, and leaving group. The ICD

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process is not limited to carbon3 and nitrogen nucleophiles. 4,5 ICD reactions may also be involved in biosynthetic pathways, an example with oxygen as the nucleophile is in the biosynthesis of rossinone B.6 The leaving group facilitates the ICD reaction, and reactions involving acetate as a leaving group are faster than those involving the poor leaving group, triethylsiloxy.1 Probes of the mechanism of the reaction by the Clive group examined whether the ICD reaction is stepwise, or concerted with an intramolecular SN2' mechanism (Eq 2). They 7

questioned whether intermediate 4 is formed. Trapping experiments in methanol show that the mechanism is stepwise for substrates with the poor siloxy leaving group (Eq 3). Here products formed from ICD, 6, and from Michael addition, 7, were obtained. No trapped product was obtained with the acetate leaving group, indicating either a concerted mechanism or short-lived intermediate that cannot be trapped.1b R LG

Base

R

R (1)

R EWG

EWG

1

2

Base: DBU, Cs 2CO3 or Et 3N (200 mol %) EWG: CO 2Et, CN, or SO2Ph R: CO 2Me, SO2Ph LG: OAc, or OSiEt3 Solvent: MeCN, or THF R Addition

LG R

Elimination

EWG R LG R EWG 3

4 SN 2'

R

(2)

R EWG 2


2

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MeO 2C

DBU, OSiEt3 MeOH 34h CO 2Et

MeO 2C 5

MeO 2C

MeO 2C OSiEt3

+

MeO 2C

MeO 2C

CO 2R 6 ICD product

(3)

CO 2R

R = Me or Et 7 Michael addition product

Methods All calculations were preformed with Gaussian09.8 Optimizations were performed with B3LYP/6-31G(d) and an implicit solvent model, IEF-PCM9, for acetonitrile. Single point energy calculations were run with the same solvent model with the higher accuracy density functional M06-2X/6-311+G(2d,p).10 Relative Gibbs free energies are reported in kcal/mol. Several ring conformers and rotamers are found, for reactant, intermediates and transition states, but only the lowest energy structures are reported here. Experimentally, geminal diester or phenylsulphone-derived carbanions are the nucleophiles, but we modeled these with malononitrile carbanions. These are conformationally simpler, and have similar electron-withdrawing ability.11 The acrylate Michael acceptor was also modeled by acrylonitrile. This has also been used experimentally.1 Results and Discussion We first explored the mechanism of the model reaction lacking a leaving group, shown in Figure 1. Both the twist-boat, and chair conformations were formed and these are labeled “t”, and “c” respectively. The lowest energy transition state for addition (TS89) is in a chair conformation, and gives an activation barrier of 17.0 kcal/mol, which is 1.6 kcal/mol lower in energy than that of the twist-boat conformation. The product, 9, also prefers a chair conformation, but its energy is 8.9 kcal/mol above the reactant


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energy. The product prefers the chair conformation by 5.2 kcal/mol, similar to the difference in energy in the chair and twist-boat conformations of cyclohexane, which is 5.5 kcal/mol.12

NC

NC

NC

CN

CN CN 8

TS8-9

NC NC

C N 9

1.97

twist-boat

TS8-9t +18.6

9t +14.1

chair

8 0.0

2.04

TS8-9c +17.0

9c +8.9

Figure 1. Reactant, transition states, and product for the ICD reaction of malononitrile anion with an acrylonitrile moiety. Figure 2 shows the reactant, transition states, and product for an ICD reaction. The acetate leaving group prefers the axial position in all cases. The addition is stabilized in both the twist-boat and chair conformations by the acetate leaving group. Now the transition state (TS10-11) favors the twist-boat conformation, which is stabilized more so than the chair conformation, and gives an activation barrier of 12.8 kcal/mol, 5.8 kcal/mol below that of the system lacking the acetate. The intermediate formed from the addition, 11, has an energy of 0.4 and 3.9 kcal/mol relative to the nucleophilic reactant for the chair, and twist-boat conformations, respectively. These intermediates are significantly stabilized relative to the model system lacking the acetate. Although the


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chair conformation is favored, the stabilizing effect of the acetate is greater in the twistboat conformation. Relative to the model lacking the acetate, the chair and twist-boat conformations are stabilized by 8.5 and 10.2 kcal/mol, respectively. The intermediate is in a very shallow well, and the elimination step has a barrier of only 2.1 kcal/mol in the chair conformation. This is in good agreement with the experimental observation that this intermediate could not be detected by trapping experiments. The reaction forms 12, and is exothermic by 16.4 kcal/mol.

NC

NC

NC

NC

CN

CN

OAc

OAc

CN

10

NC

NC

TS10-11

CN

OAc

C

CN

12

1.80

TS10-11t +12.8

11t +3.9

TS11-12t +6.4

+

chair

10 0.0

OAc

CN

TS11-12

2.13

twist-boat

CN +

OAc N 11

NC

2.15

1.78

TS10-11c +13.6

11c +0.4

TS11-12c +2.5

12 -16.4

Figure 2. ICD reaction stationary points. Figure 3 shows the stepwise ICD reaction with a mild promoter trimethylsiloxy (TMSO) leaving group. The addition and elimination transition states, TS13-14, TS1415, respectively, and the intermediate between them, 14, are higher in energy compared to the system with the acetate leaving group. The barrier for the addition is 15.0 kcal/mol. Here the chair is minimally favored over the twist-boat conformation (ΔG = -0.3 kcal/mol). The addition intermediate, 14, is 3.9 kcal/mol greater in energy than the


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reactants in the favored, chair conformation. The TMSO leaving group stabilizes the addition transition state and intermediate, particularly in the twist-boat conformation, but much less so than the allylic acetate. The barrier for the elimination to form the product is 15.3 kcal/mol in the favored chair conformation, which is nearly the same energy as the barrier for the addition step. With the poor TMSO leaving group, the elimination (TS14-15) is greatly disfavored compared to that of the acetate leaving group, and intermediate 14, is in a deeper energy well. This is in good agreement with the experimental trapping of this type of intermediate. This overall ICD reaction is calculated to be endergonic by 2.3 kcal/mol from the anion.

NC

NC

NC

NC

CN

CN

OTMS

OTMS

CN

13

NC

NC

TS13-14

CN

NC

+

OTMS

OTMS

C N 14

CN

CN

CN

TS14-15

2.09

OTMS

15

2.05

TS13-14t +15.3

twist-boat

14t +8.6

TS14-15t +20.3

+

chair

2.01

2.13

15 +2.3

13 0.0 TS13-14c +15.0

14c +3.9

TS14-15c +15.3

Figure 3. Stationary points calculated for the ICD reaction of OTMS derivate , 12. The calculations indicate a stepwise mechanism regardless of the leaving group. The electron-withdrawing allylic leaving group stabilizes the addition transition state and intermediate, and stabilizes the twist-boat more so than the chair conformation. Figure 4


6

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shows the CCCO dihedral angles from the cyano group to the leaving group, which is given for TS10-11, TS13-14, and intermediates 11, 14 in Table 1 and Figure 5. Table 1 gives this dihedral angle and the stabilization energy due to the leaving group, which are correlated. The stabilization is due to negative hyperconjugation13 of the leaving group. In the twist-boat conformation of the addition transition state and intermediate the leaving group is perpendicular to the cyano group of the Michael acceptor, that is able to stabilize the carbanion. There is more stabilization in the conformation that places the dihedral nearer to 90°. This enables the negative charge from the nucleophile to donate into the π orbital of the cyano group and into the σ* orbital of the leaving group. CN H Dihedral

RO

Figure 4. Newman projection of the CCCO dihedral from the cyano group to the leaving group. Table 1 gives this dihedral for conformations of TS9-10, TS12-13, 10 and 13. Table 1. The CCCO dihedral and stabilization energy for the twist-‐boat and chair conformations of TS9-10, TS12-13, 10 and 13. CCCO Stabilization Dihedral Energya (degrees) (kcal/mol) TS10-11t 111.3 -5.8 TS10-11c 136.8 -3.5 TS13-14t 111.7 -3.4 TS13-14c 138.2 -2.0 11t 91.2 -10.3 11c 93.1 -8.6 14t 94.3 -5.6 14c 107.6 -5.0 a. Stabilization energy is ΔG- ΔG(no leaving group)


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TS10-11t

11t

TS10-11c

11c

TS13-14t

14t

TS13-14c

14c

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Figure 5. Addition transition states TS10-11, and TS13-14, and intermediates 11, and 14 in the twist-boat and chair conformations, showing the dihedral between the cyano group and leaving group. We next determined the influence of the absence of the Michael acceptor as shown in Figure 6. Without a Michael acceptor, the reaction is a concerted SN2' reaction, but the activation energy is high (TS16-17c, 31.5 kcal/mol). Here the chair conformation is preferred, and the acetate leaves from the axial position. When the acetate is equatorial the reaction is stepwise, but the activation energy is even higher (37.9 kcal/mol) and


8

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would form a very high energy intermediate (33.2 kcal/mol). These barriers are prohibitively high for the reaction to occur at room temperature, and thus no reaction1 occurs under these conditions. NC

NC

CN

NC

CN +

CN

OAc

OAc

OAc 16

TS16-17

2.13

17

1.93

twist-boat

TS16-17t +34.8

+

chair 1.77 1.58

16 0.0

17 -16.7 TS16-17c +31.5

Figure 6. Stationary points calculated for the ICD reaction lacking a Michael acceptor. The reaction with an amine nucleophile follows an analogous, stepwise mechanism to that of the carbon nucleophile, and is shown in Figure 7. The reaction with the amine has higher barriers, and is endergonic. The barrier for addition with the amino group is 19.5 and 20.3 kcal/mol for the twist-boat (TS18-19t), and chair (TS18-19c) conformations, respectively. This is 6.7 kcal/mol higher than the addition of the carbanionic nucleophile, because the amine is less nucleophilic. The zwitterionic intermediate, 19, favors the chair conformation, and undergoes elimination via TS19-20c with a barrier of 19.3 kcal/mol. The addition and elimination occur with roughly the same energy. The aminuim product, 20, has an energy of 6.0 kcal/mol.


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1.86 1.69

twist-boat

TS18-19t +19.5

TS19-20t +19.7

19t +16.6

chair

+

1.90 1.91

18 0.0

TS18-19c +20.3

H 2N

NC

H 2N

NH 2

H 2N

OAc

20 +6.0

TS19-20c +19.3

19c +14.7

H 2N

OAc

+

OAc

OAc

CN

CN

CN

CN

18

TS18-19

19

TS19-20

20

OAc

Figure 7. ICD reaction mechanism with an amine nucleophile

Conclusion The mechanism by which the ICD reaction occurs is elucidated. The reaction proceeds by a stepwise mechanism as long as a Michael acceptor is present. The electronegative leaving group stabilizes the addition transition state and intermediate by negative hyperconjugation. In the transition state, the closer the leaving group is to an orientation antiperiplanar to the incoming nucleophile, and perpendicular to the cyano group, the greater the stabilizing effect. The stabilizing negative hyperconjugation results in faster reaction rates with more electron-withdrawing leaving groups. With the acetate leaving group the addition is the rate determining step. With the siloxy leaving group both the addition and elimination are slowed, especially the elimination, and the addition and elimination transition states have roughly the same energy. The reaction with a nitrogen nucleophile follows an analogous, stepwise


10

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mechanism. The reaction with the nitrogen nucleophile has higher barriers and is endergonic because the amine is less nucleophilic than the carbanion. The addition and elimination have similar activation energies. These studies enable better design of this important class of reactions, which can form pharmaceutically-relevant, complex, functionalized carbocycles and polycyclic amines. Development of the reaction to use more electron-withdrawing leaving groups and stronger nucleophiles will enable faster reaction rates. Further development of these reactions is an active area of study. Acknowledgement We are grateful to the National Science Foundation (CHE-1361104) for financial support of this research. Calculations were performed on the Hoffman2 cluster at UCLA and the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by the NSF (OCI-1053575). Supporting Information Absolute energies, imaginary frequencies, and Cartesian coordinates for all structures. References 1 (a) Prabhudas, B.; Clive, D. L. J. Angew. Chem., Int. Ed. 2007, 46, 9295–9297. (b) Wang, L.; Prabhudas, B.; Clive, D. L. J. J. Am. Chem. Soc. 2009, 131, 6003–6012. (c) Sreedharan, D. T.; Clive, D. L. J. Org. Biomol. Chem. 2013, 11, 3128-3144. (d) Malihi, F.; Clive, D. L. J.; Chang, C.-C.; Minaruzzaman J. Org. Chem. 2013, 78, 996-1013. 2 (a) Knochel, P.; Seebach, D. Nouv. J. Chim. 1981, 5, 75-77. (b) Knochel, P.; Seebach, D. Tetrahedron Lett. 1981, 22, 3223-3226. (c) Seebach, D.; Knochel, P. Helv. Chim. Acta 1984, 67, 261-283. (d) Seebach, D.; Calderari, G.; Knochel, P. Tetrahedron 1985, 41, 4861-4872.


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3 Watanabe, H.; Nakada, M. J. Am. Chem. Soc. 2008, 130, 1150-1151. 4 For example with nitrogen nucleophiles see: (a) Bauchat, P.; Le Bras, N.; Rigal, L.; Foucaud, A. Tetrahedron 1994, 50, 7815–7826. (b) Bauchat, P.; Foucaud, A. Tetrahedron Lett. 1989, 30, 6337–6338. (c) Clive, D. L. J.; Yu, M.; Li, Z. Chem. Commun. 2005, 906–908. (d) Clive, D. L. J.; Li, Z.; Yu, M. J. Org. Chem. 2007, 72, 5608–5617. (e) Chen, Z.; Clive, D. L. J. J. Org. Chem. 2010, 75, 7014–7017. (f) Cheng, P.; Clive, D. L. J. J. Org. Chem. 2012, 77, 3348−3364. 5 Liu, D.; Acharya, H.P.; Yu, M.; Wang, J.; Yeh, V.S.C.; Kang, S.; Chiruta, C.; Jachak, S.M.; Clive, D.L.J. J. Org. Chem. 2009, 74, 7417-7428. 6 (a) Löbermann, F.; Mayer, P.; Trauner, D. Angew. Chem., Int. Ed. 2010, 49, 6199-6202. (b) Zhang, Z.; Chen, J.; Yang, Z.; Tang, Y. Org. Lett. 2010, 12, 5554-5557. 7 For a related stepwise addition-elimination reaction see: Lefranc, J.; Fournier, A. M.; Mingat, G.; Herbert, S.; Marcelli, T.; Clayden J. J. Am. Chem. Soc. 2012, 134, 72867289. 8 Gaussian 09, Revision D.01, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, M. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;


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Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian, Inc., Wallingford CT, 2009. 9 Tomasi, J.; Mennucci, B.; Cancès E. J. Mol. Struc.-Theochem. 1999, 464, 211–226. 10 (a) Zhao, Y.; Truhlar, D. G. Theor. Chem. Acc. 2008, 120, 215-241. (b) Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157-167. 11 Ritchie, C. D.; Sager, W. F. Prog. Phys. Org. Chem. 1964, 2, 323-400. 12 Anet, F. A.; Bourn, A. J. R. J. Am. Chem. Soc. 1967, 89, 760-768. 13 (a) Apeloig, Y. J.C.S. Chem. Comm. 1981, 9, 396-398. (b) Karni, M.; Bernasconi, C. F.; Rappoport, Z. J. Org. Chem., 2008, 73, 2980–2994. (c) Exner, O.; Böhm, S. New J. Chem., 2008, 32, 1449-1453.


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Computations Reveal That Electron-Withdrawing Leaving Groups

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