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2
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2009, 131, 13888. (h) Tan, Y.; BarriosꢀLanderos, F.; Hartwig, J. F. J.
Although a lower energy process than alkyne insertion, the oxiꢀ
Am. Chem. Soc. 2012, 134, 3683. (i) Xiao, B.; Liu, Z.ꢀJ.; Liu, L.; Fu,
Y. J. Am. Chem. Soc. 2013, 135, 616.
3
4
5
6
7
8
9
dation step later in the catalytic cycle is also calculated to have a relaꢀ
tively high reaction barrier (see Supporting Information). Thus, this
step is also expected to contribute to catalyst turnover frequency
(though not selectivity), and could reasonably become turnoverꢀ
limiting if the reaction system is changed.
12
Undirected Niꢀcatalyzed C–H functionalization of pyridine Nꢀ
oxides: Kanyiva, K. S.; Nakao, Y.; Hiyama, T. Angew. Chem. Int. Ed.
2007, 46, 8872.
13 Undirected Cuꢀcatalyzed C–H functionalization of a pyridine Nꢀ
oxide: Do, H.ꢀQ.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404.
34
(a) Zhao, Y.; Truhlar, D. G. Org. Lett. 2007, 9, 1967. (b) Fey,
N.; Ridgway, B. M.; Jover, J.; McMullin, C. L.; Harvey, J. N. Dalton
Trans. 2011, 40, 11184. (c) Chen, M.; Craciun, R.; Hoffman, N.;
Dixon, D. A. Inorg. Chem. 2012, 51, 13195.
14
Pdꢀcatalyzed C(8)–H functionalization of quinoline Nꢀoxides:
Hwang, H.; Kim, J.; Jeong, J.; Chang, S. J. Am. Chem. Soc. 2014,
136, 10770.
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Interestingly, Rovis et al. have described a related Rh(III)ꢀ
15
For a review on direct functionalization of Nꢀoxides see: Yan,
catalyzed functionalization of a pyridine ring containing a neutral
directing group (oxime) at the 3ꢀposition that favors C(4)ꢀ
functionalization (see equation below). This example may reflect the
more facile C(4)–H activation of pyridine in a situation where diꢀ
rected C–H activation is apparently selectivityꢀdetermining: (a) Hysꢀ
ter, T. K.; Rovis, T. Chem. Commun. 2011, 47, 11846 and correction
(b) Hyster, T. K.; Rovis, T. Chem. Commun. 2015, 51, 5778.
G.; Borah, A. J.; Yang, M. Adv. Synth. Catal. 2014, 356, 2375.
16
Computational studies on the reactions of Oꢀacyl benzhydroxꢀ
amic acids with alkenes: (a) Xu, L.; Zhu, Q.; Huang, G.; Cheng, B.;
Xia, Y. J. Org. Chem. 2012, 77, 3017. (b) Wu, S.; Zeng, R.; Fu, C.;
Yu, Y.; Zhang, X.; Ma, S. Chem. Sci. 2015, 6, 2275.
17
For computational studies on the intramolecular annulation of
benzhydroxamic acids with tethered alkynes see: Quiñones, N.;
Seoane, A.; GarcíaꢀFandiño, R.; Mascareñas, J. L.; Gulías, M. Chem.
Sci. 2013, 4, 2874.
18
For reviews on computational studies of the mechanism of tranꢀ
36
sition metalꢀcatalyzed C–H activation, see: (a) Boutadla, Y.; Davies,
D. L.; Macgregor, S. A.; PobladorꢀBahamonde, A. I. Dalton Trans.
2009, 5820. (b) Balcells, D.; Clot, E.; Eisenstein, O. Chem. Rev. 2010,
110, 749.
For a review on the properties of pyridine Nꢀoxides, including
spectroscopic studies comparing them to pyridine, see: Katritzky, A.
R.; Lam, J. N. Heterocycles 1992, 33, 1011.
37
In the absence of an alkyne, some deuterium incorporation ocꢀ
19
A similar mechanism of C–H activation has been calculated for
curs at both C(2) and C(6) of substrate 1b (see ref 10). We now beꢀ
lieve that the observed exchange at C(6) is facilitated by a different
Rh species resulting from catalyst decomposition, as there is no eviꢀ
dence of D incorporation at C(6) in the presence of an alkyne.
the Rhꢀcatalyzed annulation reaction of aryl pyrazoles with alkynes:
Algarra, A. G.; Cross, W. B.; Davies, D. L.; Khamker, Q.; Macgregor,
S. A.; McMullin, C. L.; Singh, K. J. Org. Chem. 2014, 79, 1954.
38
20
Because eq 1 indicates that some isotope scrambling may occur
Neutral ligandꢀdirected cyclorhodation of arenes and hetꢀ
in the reaction with 4ꢀoctyne, KIE studies with this alkyne were run in
both CH3OH and CD3OD. It cannot be ruled out that the smaller KIE
seen in both solvents using 4ꢀoctyne, compared to using TESꢀ
acetyelene, may be partially due to isotope scrambling. However, H/D
exchange is only a minor pathway and the true KIE is expected to be
within the range indicated by these experiments.
eroarenes: Carr, K. J. T.; Davies, D. L.; Macgregor, S. A.; Singh, K.;
VillaꢀMarcos, B. Chem. Sci. 2014, 5, 2340.
21
Frisch, M. J. et al. Gaussian 09, Revision C.1; Gaussian, Inc.:
Wallingford, CT, 2009.
22 (a) Zhao, Y.; Truhlar, D. G.; Theor. Chem. Acc. 2008, 120, 215.
(b) Zhao, Y.; Truhlar, D. G. Acc. Chem. Res. 2008, 41, 157.
23 Hay, P. J.; Wadt., W. R. J. Chem. Phys. 1985, 82, 299.
24 (a) Gonzalez, C.; Schlegel, H. B. J. Chem. Phys. 1989, 90, 2154.
(b) Gonzalez, C.; Schlegel, H. B. J. Phys. Chem. 1990, 94, 5523.
39
(a) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc.
2008, 130, 10848. (b) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J.
Org. Chem. 2012, 77, 658. (c) Petit, A.; Flygare, J.; Miller, A. T.;
Winkel, G.; Ess, D. H. Org. Lett. 2012, 14, 3680. (d) Gorelsky, S. I.
Coord. Chem. Rev. 2013, 257, 153. (e) Stephens, D. E.; LakeyꢀBeitia,
J.; Atesin, A. C.; Atesin, T. A.; Chavez, G.; Arman, H. D.; Larionov,
O. V. ACS Catal. 2015, 5, 167.
25
(a) Dolg, M.; Wedig, U.; Stoll, H.; Preuss, H.; J. Chem. Phys.
1987, 86, 866. (b) Andrae, D.; Haussermann, U.; Dolg, M.; Stoll, H.;
Preuss, H.; Theor. Chim. Acta 1990, 77, 123.
26
40 For calculated pKa values, see Supporting Information.
41 This trend is consistent with previously calculated pKa values for
pyridine CH acidities: Shen, K.; Fu, Y.; Li, J.ꢀN.; Liu, L.; Guo, Q.ꢀX.
Tetrahedron 2007, 63, 1568.
Andrae, D.; Haeussermann, U.; Dolg, M.; Stoll, H.; Preuss, H.
Theor. Chim. Acta 1990, 77, 123.
27 Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B
2009, 113, 6378.
28 Scalmani, G.; Frisch, M. J.; J. Chem. Phys. 2010, 132, 114110.
42
For studies on the correlation between C–metal and C–H bond
29
Legault, C. Y. CYLView, 1.0b; Université de Sherbrooke, Canꢀ
strengths, and their relationship to C–H activation, see (a) Jones, W.
D.; Hessell, E. T. J. Am. Chem. Soc. 1993, 115, 554. (b) Bennett, J.
L.; Wolczanski, P. T. J. Am. Chem. Soc. 1997, 119, 10696. (c) Wick,
D. D.; Jones, W. D. Organometallics 1999, 18, 495. (d) Clot, E.;
Mégret, C.; Eisenstein, O.; Perutz, R. N. J. Am. Chem. Soc. 2006, 128,
8350. (e) Clot, E.; Mégret, C.; Eisenstein, O.; Perutz, R. N. J. Am.
Chem. Soc. 2009, 131, 7817.
30
NMR evidence of cleavage of [Cp*RhCl2]2 by acetate: (a) Daꢀ
vies, D. L.; AlꢀDuaij, O.; Fawcett, J.; Giardiello, M.; Hilton, S. T.;
Russell, D. R. Dalton Trans. 2003, 4132. (b) Li, L.; Brennessel, W.
W.; Jones, W. D. Organometallics 2009, 28, 3492.
31
Kozuch, S.; Shaik, S. Acc. Chem. Res. 2011, 44, 101.
43
32
Energy span for C(2) = (+20.1) – (ꢀ0.5) = +20.6 kcal molꢀ1. Enꢀ
NBO 6.0. E. D. Glendening, J. K. Badenhoop, A. E. Reed, J. E.
ergy span for C(2) = (+22.4) – (ꢀ0.5) = +22.9 kcal molꢀ1. Note that the
TDI is the same for both the 2ꢀ and 4ꢀfunctionalization pathway (4b-
iv, located at ꢀ0.5 kcal molꢀ1 on the free energy surface). This is beꢀ
cause 4b-ii and 4b-iv are readily interconvertible intermediates (Curꢀ
tinꢀHammett conditions).
Carpenter, J. A. Bohmann, C. M. Morales, C. R. Landis, and F.
Weinhold (Theoretical Chemistry Institute, University of Wisconsin,
Madison, WI, 2013).
Notably, we have previously found that pyridine substrates with
smaller 5ꢀsubstituents (5ꢀBr, 5ꢀOH, and 5ꢀOMEM) show poor site
44
selectivity during annulation with an alkene (norbornene). See ref 10.
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