Journal of the American Chemical Society
Page 4 of 5
MeO
Notes
OMe
NMe2
MeO
HO
MeO
NMe
OMe
1
2
The authors declare no competing financial interests.
S
O
3
4
5
6
7
8
9
ACKNOWLEDGMENTS
Base
Ep/2 (V)
0.39
0.69
0.92
0.96
1.18
1.22
1.24
1.27
Financial support was provided by the NIH (R01
GM113105). R.R.K is a fellow of the A. P. Sloan Foun-
dation. We thank Istvan Pelczer for help with NMR ex-
periments and Laura Wilson for help with sample purifi-
cation.
2-MeO-pyridine
pKa = 9.9
'BDFE'
Yield (%)
77
0
84
0
90
0
91
0
96
0
97
0
97
<5
98
8
pyridine
pKa =12.5
'BDFE'
Yield (%)
81
0
88
0
93
0
94
<5
99
6
100
16
101
5
101
19
CF3COO−
pKa =12.5
'BDFE'
Yield (%)
81
0
88
0
93
0
94
0
99
23
100
87
101
97
101
18
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
REFERENCES
'BDFE'
Yield (%)
collidine
pKa =15
84
0
91
0
97
<5
98
7
103
86
104
86
104
41
105
84
1. (a) Majetich, G.; Wheless, K. Tetrahedron 1995, 51, 7095. (b)
Feray, L.; Kuznetsov, N.; Renaud P. Radicals in Organic Synthesis;
Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2,
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effective BDFE = 23.06 E1/2(Ar0/•+) +1.37 pKa(base) + 54.9 (rt in MeCN)
Figure 4. Effective BDFE correlations with reactivity
derived from the pKa and reduction potential of its
constituents (see equation in Figure 4).4b In our pro-
posed mechanism, the relevant reduction potential is
that of the arene radical cation that serves as an internal
oxidant. To examine the relationship between effective
BDFEs and reaction outcomes, we evaluated the isom-
erization reaction for eight substrates bearing different
arenes with oxidation potentials spanning a range of ~
900 mV. In conjunction with four different Brønsted
bases, we were able to generate a set of 32 unique
combinations with effective bond strengths ranging
from 77 to 105 kcal/mol. Remarkably, in all cases
wherein the effective BDFE of the oxidant/base com-
bination approaches or exceeds that of the substrate
(O-H BDFE ~ 102 kcal/mol),13 the reactions were
successful and generated the expected ketone products.
However, all combinations with effective BDFEs less
than ~ 98 kcal/mol furnished little or no ring-opened
products. These energetic correlations provide further
support for the notion that simple thermodynamic con-
siderations can be used to accurately forecast the feasi-
bility of a given PCET process.15
3. For a stoichiometric example, see: (a) Wang, D.; Farquhar, E.
R.; Stubna, A.; Munck, E.; Que, L. Nat. Chem. 2009, 1, 145. (b)
Wang, D.; Que, L. Chem. Comm. 2013, 49, 10682.
4. (a) Reece, S. Y.; Nocera, D. G. Annu. Rev. Biochem. 2009, 78,
673. (b) Warren, J. J.; Tronic, T. A.; Mayer, J. M. Chem. Rev. 2010,
110, 6961. (c) Weinberg, D. R.; Gagliardi, C. J.; Hull, J. F.; Mur-
phy, C. F.; Kent, C. A.; Westlake, B. C.; Paul, A.; Ess, D. H.;
McCafferty, D. G.; Meyer, T. J. Chem. Rev. 2012, 112, 4016.
5. (a) Choi, G. J.; Knowles, R. R. J. Am. Chem. Soc. 2015, 137,
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Soc. 2013, 135, 10022. (c) Waidmann, C. R.; Miller, A. J. M.;
Ng, C. A.; Scheuermann, M. L.; Porter, T. R.; Tronic, T. A.;
Mayer, J. A. Energy Environ. Sci. 2012, 5, 7771.
6. (a) Baciocchi, E.; Bietti, M.; Steenken, S. J. Am. Chem. Soc.
1997, 119, 4078. (b) Baciocchi, E.; Bietti, M.; Lanzalunga, O.;
Steenken, S. J. Am. Chem. Soc. 1998, 120, 11516. (c) Baciocchi, E.;
Bietti, M.; Lanzalunga, O. Acc. Chem. Res. 2000, 33, 243.
7. Select examples of β-scission of cyclic alcohols with stoi-
chiometric oxidants: (a) Chiba, S.; Cao, Z.; Bialy, S. A. A. E.;
Narasaka, K. Chem. Lett. 2006, 35, 18. (b) Zhao, H.; Fan, X.;
Yu, J.; Zhu, C. J. Am. Chem. Soc. 2015, 137, 3490. (c) Ren, S.;
Feng, C.; Loh, T.-P. Org. Biomol. Chem. 2015, 13, 5105. (d)
Wang, S.; Guo, L. N.; Wang, H.; Duan, X.-H. Org. Lett. 2015,
17, 4798. (e) Jia, K.; Zhang, F.; Huang, H.; Chen, Y. J. Am.
Chem. Soc. 2016, 138, 1514.
8. DFT predicts the BDE of the scissile C-C bond in the
alkoxy radical of 2-(4-methoxyphenyl)propan-2-ol to be ~0
kcal/mol. See SI for details.
9. (a) Nguyen, T. M.; Nicewicz, D. A. J. Am. Chem. Soc.
2013, 135, 9588. (b) Miller, D. C.; Choi, G. J.; Orbe, H. S.;
Knowles, R. R. J. Am. Chem. Soc. 2015, 137, 13492.
10. For a discussion of the compatibility of thiols with strong ex-
cited state oxidants, see: Romero, N. A.; Nicewicz, D. A. J. Am.
Chem. Soc. 2014, 136, 17024.
11. For β-scission rates as a function of ring size, see: Bietti M.;
Salamone M. J. Org. Chem. 2005, 70, 1417.
12. Kaljurand, I.; Kutt, A.; Soovali, L.; Rodina, T.; Maemets, V.;
Leito, I.; Koppel, I. A. J. Org. Chem. 2005, 70, 1019.
In conclusion, we have developed a new catalytic
method for the redox-neutral isomerization of cyclic
alkanols to linear ketones that proceeds via C-C bond
β-scission. Moreover, this work represents a rare ex-
ample of alkoxy radical generation via multisite PCET
activation of alcohol O-H bonds. Efforts to expand
these results to include simple alcohol substrates are
currently ongoing.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures and characterization data. This
material is available free of charge via the Internet at
AUTHOR INFORMATION
13. See SI for details.
14. β-scission of 31 has been studied: Baciocchi, E.; Bietti, M.;
Manduchi, L.; Steenken, S. J. Am. Chem. Soc. 1999, 121, 6624.
15. (a) Nguyen, L. Q.; Knowles, R. R. ACS Cat. 2016, 6,
2894. (b) Yayla, H. G.; Knowles, R. R. Synlett. 2014, 20, 2819.
Corresponding Author
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