A Synergy between Experiment and Theory for the Formation of

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Organometallics 2009, 28, 5848–5856 DOI: 10.1021/om900242g

A Synergy between Experiment and Theory for the Formation of Pyridine and Pyrrole Derivatives from Selected Butadienes and Organolithium Reagents: Mechanism, Solvent, and Substituent Effect Wei-Hua Mu,† Gregory A. Chasse,‡,^ and De-Cai Fang*,§,^ †

Faculty of Chemistry and Chemical Engineering, Yunnan Normal University, Kunming 650092, Yunnan, P. R. of China, ‡School of Chemistry, University of Wales, Bangor, Gwynedd, LL57 2UW, U.K., §College of Chemistry, Beijing Normal University, Beijing 100875, P. R. of China, and ^Global Institute Of Computational Molecular and Materials Science (GIOCOMMS), Toronto/Budapest/Beijing Received March 30, 2009

Due to the exponential growth of pyridine and pyrrole use, focus is shifting to more completely understanding their syntheses and toward more effective preparation and application. Herein, we present a series of density functional theory (DFT) models, employing differing treatments of solvent effects, quantitatively characterizing the formation mechanism of a series of pyridine and pyrrole derivatives from multisubstituted 1-cyano-1,3-butadienes and organolithium reagents. Results indicated that pyridine and pyrrole formations are multistep processes, in which the rate-determining step involves a free-energy barrier of 18 kcal 3 mol-1, as determined using a novel microsolvation method. Both solvent (tetrahydrofuran or ether) and organolithium reagent identity are shown to play instrumental roles in affecting the pyridine/pyrrole product ratios. The microsolvation results are more plausible than those emerging from traditional approaches to treating solvent effects (i.e., dielectric continuum). Specifically, solvent identity plays an important role in these reactions, with THF facilitating the formation of pyrroles, while Et2O pushes the reaction toward pyridine formation. 1. Introduction Heterocyclic chemistry encompasses one of the largest divisions of chemistry, with important applications in biological,1 pharmaceutical,1f,h,2 therapeutic,3 medicinal,4 catalytic,5 and advanced materials1e,f,h,3a chemistry and the production of (non)-natural compounds.6 The synthesis of complex hetero*Corresponding author. E-mail: [email protected]. (1) (a) Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.; Zanatta, N.; Bonacorso, H. G. Chem. Rev. 2008, 108, 2015. (b) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395. (c) Larrosa, I.; Romea, P.; Urpí, F. Tetrahedron 2008, 64, 2683. (d) Nising, C. F.; Br€ase, S. Chem. Soc. Rev. 2008, 37, 1218. (e) Mori, A.; Sugie, A. Bull. Chem. Soc. Jpn. 2008, 81, 548. (f) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338. (g) Wang, M.-X. Chem. Commun. 2008, 4541. (h) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41, 1013. (2) Riveira, M. J.; La-Venia, A.; Mischne, M. P. J. Org. Chem. 2008, 73, 8678. (3) (a) Vereschagin, L. I.; Pokatilov, F. A.; Kizhnyaev, V. N. Chem. Heterocycl. Compd. 2008, 44, 1. (b) Hulme, C.; Lee, Y.-S. Mol. Diversity 2008, 12, 1. (4) See examples: (a) Isambert, N.; Lavilla, R. Chem.;Eur. J. 2008, 14, 8444. (b) Groenendaal, B.; Ruijter, E.; Orru, R. V. A. Chem. Commun. 2008, 5474. (5) (a) Hahn, F. E.; Jahnke, M. C. Angew. Chem., Int. Ed. 2008, 47, 3122. (b) Ma, Y.; Wei, S.; Lan, J.; Wang, J.; Xie, R.; You, J. J. Org. Chem. 2008, 73, 8256. (c) Tommasi, I.; Sorrentino, F. Tetrahedron Lett. 2009, 50, 104. (d) Bezerra, C. W. B.; Zhang, L.; Lee, K.; Liu, H.; Marques, A. L. B.; Marques, E. P.; Wang, H.; Zhang, J. Electrochim. Acta 2008, 53, 4937. (6) See examples: (a) Dooleweerdt, K.; Ruhland, T.; Skrydstrup, T. Org. Lett. 2009, 11, 221. (b) Shawali, A. S.; Farghaly, T. A. ARKIVOC 2008, i, 18. (c) Ye, L.-W.; Zhou, J.; Tang, Y. Chem. Soc. Rev. 2008, 37, 1140. (d) Warkentin, J. Acc. Chem. Res. 2009, 42, 205. (e) Philip, A.; Gale, P. A. Chem. Commun. 2008, 4525. (f) Flick, A. C.; Padwa, A. Tetrahedron Lett. 2008, 49, 5739. (g) Corberan, R.; Marrot, S.; Dellus, N.; Merceron-Saffon, N.; Kato, T.; Peris, E.; Baceiredo, A. Organometallics 2009, 28, 326. pubs.acs.org/Organometallics

Published on Web 09/24/2009

cycles continues to lead the field of synthetic organic chemistry, and much focus has been on their efficient production through novel synthetic protocols,1a,7 with the discovery of the DNA structure in 1950s boosting focus on these systems.8 As a large number of pesticides, antibiotics, alkaloids, and cardiac glycosides are also based on heterocyclic natural products of significance to human and animal health, activity has been on the rational design of heterocyclic analogues of natural models.1a Pyridine and pyrrole are two classic examples of common, useful heterocycles, derivatives of which are growing exponentially in number each year. They may be used as structural components in chemical systems,9 pharmaceutical ingredients,9,10 herbicides, insecticides, vitamins, adhesives, and synthons11 or as building blocks of functional compounds such as polymers,9,12 stereoselective products,13 (7) See examples: (a) Fukamizu, K.; Miyake, Y.; Nishibayashi, Y. J. Am. Chem. Soc. 2008, 130, 10498. (b) Ma, D.; Qian, C. Q. Acc. Chem. Res. 2008, 41, 1450. (c) Shen, H. C. Tetrahedron 2008, 64, 3885. (d) Míriam, A.-C.; Manuel, M.-D.; Ignacio, R.-G. Chem. Rev. 2008, 108, 3174. (e) Rudolph, A.; Rackelmann, N.; Turcotte-Savard, M.-O.; Lautens, M. J. Org. Chem. 2009, 74, 289. (f) Buchlovic, M.; Man, S.; Potacek, M. Tetrahedron 2008, 64, 9953. (g) Barluenga, J.; Tomas-Gamasa, M.; Moriel, P.; Aznar, F.; Valdes, C. Chem.;Eur. J. 2008, 14, 4792. (8) (a) Watson, J. D.; Crick, F. H. C. Nature 1953, 171, 737. (b) Watson, J. D.; Crick, F. H. C. Nature 1953, 171, 964. (9) Higashio, Y.; Shoji, T. Appl. Catal. A: Gen. 2004, 260, 251. (10) Zajac, M. A. J. Org. Chem. 2008, 73, 6899. (11) Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G. Chem. Soc. Rev. 2000, 29, 109. (12) See examples: (a) Hasegawa, D.; Teramoto, Y.; Nishio, Y. J. Wood Sci. 2008, 54, 143. (b) Jesus, M. C. D.; Fu, Y.; Weiss, R. A. Polym. Eng. Sci. 1997, 37, 1936. (13) Brasholz, M.; Reissig, H.-U.; Zimmer, R. Acc. Chem. Res. 2009, 42, 45. r 2009 American Chemical Society

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phase-transfer catalysts,14 DNA sequence recognizers,15 nanoparticles,16 antitumors,17 and others.18 These compounds’ corresponding preparations from pyridine and pyrrole have always been the principle research area in heterocyclic organic chemistry.19 More recently, however, focus has been shifting to characterizing the specific synthetic fine-tuning achieved through manipulation of the identity of organolithium reagents in these reactions.20 Despite this growing interest, and due in part to the complexity and challenge of theoretically characterizing Li-containing reactions in solution,21 only a few theoretical works are found in the literature.22 In 2007, Xi and co-workers reported that reaction of multisubstituted 1-cyano-1,3-butadienes and organolithium reagents could lead to high yields of a series of pyridine and (14) Tu, T.; Assenmacher, W.; Peterlik, H.; Schnakenburg, G.; D€ otz, K. H. Angew. Chem., Int. Ed. 2008, 47, 7127. (15) (a) Bando, T.; Sugiyama, H. Acc. Chem. Res. 2006, 39, 935. (b) Dervan, P. B.; Edelson, B. S. Curr. Opin. Struct. Biol. 2003, 13, 284. (c) Melander, C.; Burnett, R.; Gottesfeld, J. M. J. Biotechnol. 2004, 112, 195. (16) Wang, Y.; Wei, G.; Wen, F.; Zhang, X.; Zhang, W.; Shi, L. J. Mol. Catal A: Chem. 2008, 280, 1. (17) (a) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F. Chem. Rev. 2008, 108, 264. (b) Gupton, J. T. Top. Heterocycl. Chem. 2006, 2, 53. (18) See examples: (a) Duan, X.-F.; Ma, Z.-Q.; Zhang, F.; Zhang, Z.-B. J. Org. Chem. 2009, 74, 939. (b) Feng, Z.; Yu, S.; Shang, Y. Appl. Organomet. Chem. 2008, 22, 577. (c) Cheng, Y.-Q.; Bian, Z.; Kang, C.-Q.; Guo, H.-Q.; Gao, L.-X. Tetrahedron: Asymmetry 2008, 19, 1572. (d) Lazzaroni, R.; Settambolo, R.; Rocchiccioli, S.; Guazzelli, G. J. Organomet. Chem. 2007, 692, 1812. (e) Kunz, D. Angew. Chem., Int. Ed. 2007, 46, 3405. (f) Davenport, A. J.; Davies, D. L.; Fawcett, J.; Russell, D. R. J. Organomet. Chem. 2006, 691, 3445. (g) Chelucci, G. Chem. Soc. Rev. 2006, 35, 1230. (h) Trofimov, B. A.; Sobenina, L. N.; Demenev, A. P.; Mikhaleva, A. I. Chem. Rev. 2004, 104, 2481. (i) Ghos, A. Angew. Chem., Int. Ed. 2004, 43, 1918. (j) Dubois, M. R. Coord. Chem. Rev. 1998, 174, 191. (k) Newkome, G. R.; Sauer, J. D.; Roper, J. M.; Hager, D. C. Chem. Rev. 1977, 77, 513. (l) Baltazzi, E.; Krimen, L. I. Chem. Rev. 1963, 63, 511. (19) See examples: (a) Donohoe, T. J.; Fishlock, L. P.; Procopiou, P. A. Chem.;Eur. J. 2008, 14, 5716. (b) Corbet, M.; Greef, M. de; Zard, S. Z. Org. Lett. 2008, 10, 253. (c) Popowycz, F.; Routier, S.; Joseph, B.; Merour, J.-Y. Tetrahedron 2007, 63, 1031. (d) Balme, G. Angew. Chem., Int. Ed. 2004, 43, 6238. (e) Pinder, A. R. Nat. Prod. Rep. 1992, 491. (20) See examples: (a) Konrad, T. M.; Gr€ unwald, K. R.; Belaj, F.; M€ osch-Zanetti, N. C. Inorg. Chem. 2009, 48, 369. (b) Foubelo, F.; Yus, M. Chem. Soc. Rev. 2008, 37, 2620. (c) Wang, C.; Wang, C.; Wang, Q.; Wang, Z.; Sun, H.; Guo, X.; Xi, Z. Chem.;Eur. J. 2007, 13, 6484. (d) Freitas, D. M. D.; Castro, M. M. C. A.; Geraldes, C. F. G. C. Acc. Chem. Res. 2006, 39, 283. (e) Paradies, J.; Erker, G.; F€ohlich, R. Angew. Chem., Int. Ed. 2006, 45, 3079. (f) Wu, G.; Huang, M. Chem. Rev. 2006, 106, 2596. (g) Gossage, R. A.; Jastrzebski, J. T. B. H.; Koten, G. v. Angew. Chem., Int. Ed. 2005, 44, 1448. (h) Pratt, L. M. Mini-Rev. Org. Chem. 2004, 1, 209. (i) Basu, A.; Thayumanavan, S. Angew. Chem., Int. Ed. 2002, 41, 716. (21) See examples: (a) Collum, D. B.; McNeil, A. J.; Ramirez, A. Angew. Chem., Int. Ed. 2007, 46, 3002. (b) Mahmoudkhani, A. H.; Rauscher, S.; Grajales, B.; Vargas-Baca, I. Inorg. Chem. 2003, 42, 3849. (c) Fraenkel, G.; Qiu, F. J. Am. Chem. Soc. 1997, 119, 3571. (d) Jackman, L. M.; Scarmoutzos, L. M. J. Am. Chem. Soc. 1984, 106, 4627. (22) (a) Pratt, L. M.; Jones, D.; Sease, A.; Busch, D.; Faluade, E.; Nguyen, S. C.; Thanh, B. T. Int. J. Quantum Chem. 2009, 109, 34. (b) Pratt, L. M.; Fujiwara, S.; Kambe, N. Tetrahedron 2009, 65, 1017. (c) Mu, W.-H.; Chasse, G. A.; Fang, D.-C. J. Phys. Chem. A 2008, 112, 6708. (d) Khartabil, H. K.; Gros, P. C.; Fort, Y.; Ruiz-Lopez, M. F. J. Org. Chem. 2008, 73, 9393. (e) Mu, W.-H.; Chasse, G. A.; Fang, D.-C. Int. J. Quantum Chem. 2008, 108, 1422. (f) Ramírez, A.; Lobkovsky, E.; Collum, D. B. J. Am. Chem. Soc. 2003, 125, 15376. (g) Mu, W.-H.; Wang, C.; Fang, D.-C. THEOCHEM 2007, 806, 171. (h) Brandt, P.; Haeffner, F. J. Am. Chem. Soc. 2003, 125, 48. (i) Saa, J. M. Helv. Chim. Acta 2002, 85, 814. (j) Hashimoto, K.; Kamimoto, T. J. Am. Chem. Soc. 1998, 120, 3560. (k) € Håkansson, M. J. Am. Hilmersson, G.; Arvidsson, P. I.; Davidsson, O.; Chem. Soc. 1998, 120, 8143. (l) Jedlicka, B.; Crabtree, R. H. Organometallics 1997, 16, 6021. (m) Pate, F.; Gerard, H.; Oulyadi, H.; de la Lande, A.; Harrison-Marchand, A.; Parisel, O.; Maddaluno, J. Chem. Commun. 2009, 319. (n) Fernandez, I.; O~na-Burgos, P.; Armbruster, F.; Krummenacher, I.; Breher, F. Chem. Commun. 2009, 2586. (o) De Vries, T. S.; Goswami, A.; Liou, L. R.; Gruver, J. M.; Jayne, E.; Collum, D. B. J. Am. Chem. Soc. ASAP, DOI: 10.1021/ja9047784.

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Scheme 1

Table 1. Product Ratios and Yields (%) for the THF- and Et2OMediated Reactions of Selected Organolithium Reagents (Scheme 1) yielda [%] reaction

R0 Li

R þ PhLi R þ PhLi R þ nBuLi R þ nBuLi

PhLi PhLi nBuLi nBuLi

a

solvent

temperature

P1

P2

THF Et2O THF Et2O

rt rt reflux reflux

7 61 0 16

73 27 90 71

Yield of the isolated products P1 and P2.20c

pyrrole derivatives, even under mild reaction conditions,20c with the pyridine/pyrrole product ratio being highly sensitive to the reaction medium and the organolithium reagents. Moving from tetrahydrofuran (THF, ε = 7.58 at 298.15 K) to ether (Et2O, ε = 4.34 at 298.15 K) pushes the ratio from 7:73 to 61:27 in the R þ PhLi reaction (Scheme 1 and Table 1).20c However, despite this large difference, perhaps one of the most important findings in the work, no explanation for these results was provided. This is most probably due to the inherent complexity of the reactions in the solvent, coupled with the limitations of the experimental methods in exploring the fundamental bases of chemical reactions (i.e., at the molecular level). Considering the growing importance of organolithium compounds, in the face of such powerful solvent effects, it is imperative to advance the mechanistic understanding of these reactions. Therefore we embarked upon high-level theoretical determinations of the most probable reaction paths, including solvent and substituent effects as well as the role of organolithium reagents, toward determining the thermodynamic driving forces for the observed pyridine/ pyrrole product ratios.

2. Computational Details The Gaussian 03 program package23 using default geometric convergence thresholds (3.0  10-4, 4.5  10-4, 1.2  10-3, 1.8  10-3 for the gradients of the root-mean-square (rms) force, maximum force, rms displacement, and maximum displacement vectors, respectively) and the Becke-3-Lee-Yang-Parr (B3LYP) density functional theory (DFT) method24 employing the 6-31G(d,p) Pople basis set25 for all atoms were used for all calculations in this work. Single-point energy calculation at the MP2(full)//B3LYP/6-31G(d,p) level was also conducted for some stationary points when necessary. The location of all structures on their associated potential energy hypersurfaces (PEHSs) was identified and characterized by the number of imaginary frequencies, employing the explicit (23) Frisch, M. J.; et al. et al. Gaussian 03, Revision C.02; Gaussian, Inc.: Pittsburgh, PA, 2003. (24) See examples: (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785. (25) Scott, A. P.; Radom, L. J. Phys. Chem. 1996, 100, 16502.

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two-solvent microsolvation model (S2MM) method. This is consistent with the novel microsolvation model method developed within this work employing the term SnMM, where n is the number of explicit solvent particles. The self-consistent reaction field (SCRF)26 polarizable continuum model (PCM/Bader)22e was also employed as required. Intrinsic reaction coordinate (IRC)27 computations were also used to trace selected reaction paths, in order to confirm that key transition state (TS) structures obtained linked the minima proposed as being adjacent to the TS in question. The total energy of each geometry-optimized structure was corrected by its corresponding scaled zero-point vibrational energy (ZPE); the latter scaled by a factor of 0.9806, as recommended.28

3. Results and Discussion 3.1. Comparison of Explicit and Implicit Solvent Models. Both implicit and explicit solvent models were used to account for experimental solvent conditions and subsequently compared to the gas-phase results. In the explicit placement of solvating particles, consideration was taken that Li is in the second row of the periodic table (no dorbitals), thus able to conjugate up to two or three polar solvent molecules through its 2s- and 2p-orbitals, rendering it three- or four-coordinate.29 Ideally, four-coordinate Li could be pseudoplanar (distorted/flattened tetrahedron); however, due to spatial hindrance between the ligands (R or R0 ) and the solvating molecules, a tetrahedral geometry results (Figure 1). With the relatively large size and structural characteristics of the systems investigated (Scheme 1), explicit solvation of the Li-mediated reactions was limited to one and two solvent molecules, defined as one- (S1MM) and two-solvent microsolvation models (S2MM), respectively. The S1MM and S2MM methods were tested on selected portions of the gas-phase optimized reaction profiles (Figure 2). With aims to quantitatively account for solvent effects in their entirety, the SCRF-PCM26 with THF (dielectric constant (ε) = 7.58, at 298.15 K) or ether (ε = 4.34, at 298.15 K) as solvent was also used on the same part of the reaction energy profile as in Figure 2, to determine the efficacy of the method. Our previous work22e indicated that the default PCM/UA0 method in G03 underestimates the van der Waals’ (VdW) radius for Li atoms and that Bader’s atomic radii30 are more suitable in PCM calculations. The PCM/ Bader method was therefore used in place of the default PCM/UA0 method, in addition to a more complete explicit/ implicit solvent method comparison using a two-solvent microsolvation model plus PCM/Bader (S2MMpPCM) method. The segments of the reaction potential energy surfaces (PESs) presented in Figure 2 show the explicit S1MM method giving near-identical relative energies as the gasphase calculations; differences in activation energies (Ea) for TS2 and TS3 are within 0.5 kcal 3 mol-1. As gas-phase characterization of reactions in solution generally produces (26) See examples: (a) Miertus, S.; Scrocco, E.; Tomasi, J. Chem. Phys. 1981, 55, 117. (b) Miertus, S.; Tomasi, J. Chem. Phys. 1982, 65, 239. (c) Tomasi, J.; Persico, M. Chem. Rev. 1994, 94, 2027. (d) Cossi, M.; Barone, V.; Cammi, R.; Tomasi, J. Chem. Phys. Lett. 1996, 255, 327. (27) (a) Gonzalez, C.; Schlegel, H. B. J. Chem. Phys. 1989, 90, 2154. (b) Gonzalez, C.; Schlegel, H. B. J. Phys. Chem. 1990, 94, 5523. (28) Scott, A. P.; Radom, L. J. Phys. Chem. 1996, 100, 16502. (29) See examples in refs 20g, 21a, 22b, 22d, 22f, 22h-22l. (30) Bader, R. F. W. Atoms in Molecules: A Quatum Theory; Clarendon Press: Oxford, U.K., 1990.

Figure 1. Tetracoordination of Li atoms in organic molecules, showing three (top) and two (bottom) THF solvent molecules binding the central second-row atom through its 2s- and 2porbitals.

erroneous results,22g,29 the matching explicit S1MM results become doubtful (although this may be only for these particular systems). However, a useful finding is that within the S1MM geometry-optimized structures, there remains sufficient physical space for an additional explicit THF molecule to bind Li (Figure S1 in the Supporting Information for details). Similar conclusions regarding solvating particle attachment in related reaction systems29 render the S1MM method results questionable at best and not appropriate for further consideration within this work. The relative energy differences between the explicit S2MM and S2MMpPCM methods are within 1.0 kcal 3 mol-1 (except for INT2, in which the N-Li bond is loose and the whole structure is very noncompact), but the latter is much more (computationally) resource-intensive. Taking spatial hindrance and computational expense (CPU time) into consideration, optimization using the explicit S2MM method is more practical and provides reasonable results. Thus, only explicit S2MM method results are included in the following sections. The implicit PCM/Bader method, suitable in the characterization of some Li-containing compounds,22c,e shows large deviation from the S2MM and S2MMpPCM methods in the systems investigated herein. 3.2. Reaction Mechanism. Both the explicit S2MM and implicit PCM/Bader methods were employed toward quantitative characterization of the R þ PhLi reaction mechanism in THF solvent, as outlined in Scheme 1. Competing reaction profiles for the formation of products P1 and P2 are displayed in Figures 3 and S2, respectively. The mechanism proceeds via a common reaction pathway, with the organolithium reagent (PhLi) binding the multisubstituted 1-cyano-1,3-butadiene (R) to surmount the 3.0 kcal 3 mol-1 (S2MM method in THF solvent) TS1 barrier, to form intermediate INT1 (Figure 3). At this point, two

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Figure 2. Comparison of reaction enthalpy (free-energy) profiles (kcal 3 mol-1) obtained from gas-phasea, one- and two-solvent microsolvation models (S1MMb and S2MMc, respectively), S2MM-plus-PCM/Bader (S2MMpPCMd), and implicit (PCM/Badere) methods in THF solvent, computed at the B3LYP/6-31G(d,p) level of theory. The non-, S1MM-, and S2MM-explicitly solvated structures are provided at each step along the profiles.

Figure 3. Competing R þ PhLi reaction potential enthalpy surfaces (kcal 3 mol-1) for the formation of P1 and P2, using the explicit S2MM method in THF, computed at the B3LYP/6-31G(d,p) level of theory.

pathways become operative via transition states TS2 and TS3, leading to the formation of products P1 and P2, respectively, with the latter requiring several steps to reach completion. Therein, although P2 is the thermodynamically

favored product, it is not the kinetically favored one. The difference in energy between TS2 and TS3 (9.2 kcal 3 mol-1) would result in an insignificant amount of INT2 being formed relative to INT3.

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Figure 4. Competing R þ PhLi reaction potential enthalpy (free-energy) surfaces (kcal 3 mol-1) for the formation of P1 and P2, using the explicit S2MM method in THF (top), and Et2O (bottom), computed at the B3LYP/6-31G(d,p) level of theory, including selected geometry-optimized structures along the profile.

The 17.9 kcal 3 mol-1 TS2 activation barrier on the P1 pathway is approximately double that of the P2 route; TS3 (8.7 kcal 3 mol-1) becomes the rate-determining step, with the pyrrole derivative (P2), the dominant product of the R þ PhLi reaction in THF, in good agreement with experimental results.20c For comparison, the reaction potential energy surfaces (PESs) using the S2MM method were repeated using the implicit PCM/Bader model (Figure S2 in the Supporting Information), producing very similar energetic topology, with the exception of some minor differences in geometric structures of the stationary points found. 3.3. Solvent Effect. Solvent has been shown essential for the majority of solution-based reactions to proceed, particularly for systems containing species that easily interact with solvent particles, such as when Li-containing reagents are involved.29 Despite this, Xi’s results epitomize this phenomenon, with the reported product ratios under similar reaction conditions being beyond expectation, i.e., P1:P2 ≈ 1:10 in THF and ≈ 2:1 in Et2O for the R þ PhLi reaction (Scheme 1 and Table 1).20c The S2MM method with explicit Et2O solvent particles, was also employed toward characterizing the fundamental

bases of this huge difference in product ratios (Figure 4). The two potential energy surfaces (PESs) obtained in THF and Et2O solution immediately show small relative enthalpy (free-energy) differences at INT1: -20.1 (-5.0) and -19.0 (-3.2) kcal 3 mol-1, respectively. The differences grow from this point, with 9.2 (8.0) and 4.7 (3.4) kcal 3 mol-1 differences in the TS2 and TS3 energy gap in THF and Et2O, respectively, with TS3 retaining its lower barrier (relative to TS2) for both solvents. The rate-determining step’s (TS2 and TS3) relative activation enthalpy (free-energy) barriers are 17.9 (9.6) and 8.7 (11.6) kcal 3 mol-1 in THF as well as 18.4 (21.0) and 13.7 (17.6) kcal 3 mol-1 in Et2O, respectively, slightly larger for Et2O. Subsequent steps show the TS4 relative enthalpy (freeenergy) barriers to be 7.9 (8.8) and 14.3 (14.5) kcal 3 mol-1 in THF and Et2O, respectively, large enough to render the smaller respective 7.0(6.6) and 1.1(0.2) kcal 3 mol-1 THF and Et2O TS5 barriers inconsequential to product ratio. The larger TS4 Et2O barriers to P2 product formation along the multistepped pathway drastically reduce P2 yield, showing that P1 formation proceeds more easily in Et2O solution, shifting the product ratio of P1:P2, as supported by experiment.20c

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Figure 5. Key structural parameters (bond length in A˚) of TS2 (left) and TS3 (right) for the R þ PhLi (outside dashed red box) and R þ nBuLi (inside dashed red box) reactions of the B3LYP/6-31G(d,p)-S2MM method geometry-optimized structures in THF (above green line) and Et2O (below green line) solution.

For the sake of comparison, the R þ PhLi reaction was further characterized using the PCM/Bader model (Figure S3 in the Supporting Information), generating very similar enthalpy and free-energy topologies. The largest relative enthalpy (free-energy) difference between TS2 and TS3 in THF and Et2O solution is 6.9 (6.7) and 7.3 (6.8) kcal 3 mol-1 respectively, favoring P1 formation. This translates to the PCM/Bader model predicting a more energetically “costly” P1 formation in Et2O solution (relative to THF), the inverse of experimental findings.20c Additionally, the PCM/Bader model predicts very small energy barrier differences for TS2 (or TS3) in both THF and Et2O solution, wherein such small energetic differences would not lead to differentiable product ratios, especially not the P1:P2 change from 7:73 to 61:27

(Table 1), further lending support to the conclusion that the PCM/Bader model is ineffective at quantitatively characterizing the energetic profile for this reaction. Hence, only S2MM method results are reported form here onward. Key geometrical parameters of the THF and Et2O optimized TS2 and TS3 first-order saddle points showed solvent to be instrumental in affecting structure, itself influential in the final P1:P2 product ratio. For the R þ PhLi reaction (Figure 5), when the THF solvent is replaced by Et2O, changes in key geometric parameters (C(1)-N, C(1)-Cl, N-Li, and Cl-Li bonds) for TS2 are less than ∼0.03 A˚, while the C(2)-N and N-Li bonds in TS3 are shortened and elongated by 0.19 and 0.04 A˚, respectively. Both of these geometric changes push TS3 further from INT1, making the

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Figure 6. Competing R þ PhLi (top) and R þ nBuLi (bottom) reaction potential enthalpy (free-energy) surfaces (kcal 3 mol-1) for the formation of P1 and P2, using the explicit S2MM method in THF, computed at the B3LYP/6-31G(d,p) level of theory, including selected geometry-optimized structures along the profile. Scheme 2

relative TS3 energy barrier higher, translating to facilitated P1 formation and reduction of P2 yield in Et2O, in agreement with experimental results.20c Although not apparent in Figure 5, the TS3 structure has slightly different geometries in Et2O and THF, with an observed lengthening of the N-C2 bond from 1.86 A˚ to 2.05 A˚. This is accompanied by the formation of a Li-C1 interaction (2.25 A˚, in red, Scheme 2), effectively withdrawing e density from and increasing the N-C2 distance. This lengthening is accompanied by a retention of more e density by N, C1, and C2, confirmed by a corresponding (slight) shortening of all adjacent interatomic distances, shown schematically (in A˚) above their corresponding Fb values (defined below) in Scheme 2. Although threshold interatomic separation is indicative of an interaction (i.e.,