Billone et al.
JOCArticle
SCHEME 1. Irreversible Reduction of Nitroxides by 1,4-Cyclo-
hexadiene (eqs 1 and 2) and Hydrogen-Atom Transfer Equilibrium
between Nitroxides and Hydroxylamines (eq 3)
benzene are both very weak HBAs.13 The reaction of 1 with
excess 3 follows first-order kinetics, and the reaction is also
first-order in 3 (Figure S1 in Supporting Information). The
second-order rate constant for the 2a þ 3 (ꢀ 1 þ 3) reaction,
k1, corrected for the 2:1 stoichiometry, is 3.5 ꢁ 10-5 M-1 s-1
at 21 °C.
Measurement of Keq for Nitroxide/Hydroxylamine Reac-
tions. Under pseudo-first-order conditions with respect to 3,
Keq can be written as
•
•
½15NO - Hꢂ½14NO•ꢂ
½15NO•ꢂ½14NO - Hꢂ
½ NO ꢂ½ NO ꢂ0ð1 - e- k ½3ꢂt
Þ
Þ
14
15
1
Keq
¼
¼
•
•
15
14
½ NO ꢂ½ NO ꢂ0ð1 - e- k ½3ꢂt
2
ð4Þ
At long times, eq 4 simplifies to
½14NO•ꢂ½15NO•ꢂ0
½15NO•ꢂ½14NO•ꢂ0
Keq
¼
ð5Þ
stable nitroxide radicals in n-heptane, a nonpolar, nonpolariz-
able, non-hydrogen bond acceptor (non-HBA), and non-HB
donor (non-HBD) solvent, thus ensuring that the ΔBDEs
required no correction for solvent effects (which are particu-
larly large for O-H BDEs).4-6 This solvent also ensured that
the nitroxides’ N hyperfine coupling constants (hfcc, aN) were
also free of otherwise very large solvent effects.7,8 ΔBDE values
were determined with respect to that of 15N-labeled 2,2,6,6-
tetramethylpiperid-4-one-1-hydroxyl (1H) because the 15N-
labeled nitroxide (1) is commercially available. The O-H
BDE of 2aH was determined to be 71.8 kcal/mol by calorim-
etry in 1973.9 However, this value must be revised downward
by 1.2 kcal/mol to 70.6 kcal/mol (-1.1 kcal/mol because of a
revised heat of formation of E-azobenzene,10 plus a -0.1 kcal/
mol correction for HB effects10,11).
Measurement of the 15N/14N ratio (by double integration
of the corresponding EPR signals) before addition of 3 and
following equilibration19 after its addition yielded Keq for
each 2x/2xH and 1/1H pair. The very slow reduction by 3
compared to the rates of the forward and reverse reactions20
in eq 3 allowed for the use of eq 5 while using low starting
concentrations of nitroxides (see Experimental Section).
The values of Keq so obtained correspond to the differences
in free energies for each pair, ΔG. These quantities yield
ΔBDEs (eq 6) for the O-H bonds of the corresponding
hydroxylamines based on the assumption that ΔS = 0 for
3.21 This assumption is reasonable considering that the
measurements were made in solvents that are neither hy-
drogen-bond-donating nor -accepting.22 Equilibrium con-
stants for reaction 3 with 10 2x/2xH couples are presented
in Table 1. Errors are the standard deviation from a
minimum of three separate experiments (see Experimental
Section for details). For the near-identity reaction between
1/1H and 2a/2aH, Keq=1.00 ( 0.05, a result that validates
our experimental procedure because no significant N-iso-
tope effect would be expected. Values of Keq for the 1/1H
and nine 2x/2xH (x=b-j) pairs were all greater than 1.0,
Results
Reduction of Nitroxide Radicals by 1,4-Cyclohexadiene.
The slow, irreversible reduction of nitroxides by 1,4-cyclo-
hexadiene, 3 (Scheme 1, eqs 1 and 2), was exploited to
determine the equilibrium constant, Keq, for hydrogen atom
transfer (HAT) between the nitroxide/hydroxylamine cou-
ples 1/1H and 2x/2xH (eq 3; the 15N gives 1 a 2-line EPR
spectrum that is readily distinguished from the 3-line spectra
of 14N-nitroxides, 2). Diene 3 was chosen as the in situ
reducing agent because the cyclohexadienyl radical is
rapidly oxidized to benzene by a second nitroxide, which
makes reactions 1 and 2 irreversible.12 In addition, 3 and
(13) Abraham, M. H.; Grellier, P. L.; Prior, D. V.; Morris, J. J.; Tayloer,
P. J. J. Chem. Soc. Perkin Trans. 2 1990, 521–529.
(14) Frisch, M. J., et al. Gaussian 03, D.01; Gaussian, Inc.: Wallingford,
CT, 2004.
(15) Becke, A. D. J. Chem. Phys. 1993, 98 (7), 5648–5652.
(16) Lee, C. T.; Yang, W. T.; Parr, R. G. Phys Rev B 1988, 37 (2), 785–789.
(17) Barone, V., Structure, Magnetic Properties and Reactivities of Open-
Shell Species from Density Functional and Self-Consistent Hybrid Methods.
In Recent Advances in Density Functional Methods; Chong, D. P., Ed.; World
Scientific: Singapore, 1995.
ꢀ
(4) Wayner, D. D. M.; Lusztyk, E.; Page, D.; Ingold, K. U.; Mulder, P.;
Laarhoven, L. J. J.; Aldrich, H. S. J. Am. Chem. Soc. 1995, 117, 8737–8744.
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(18) See ref 37 of Foti, M. C.; Daquino, C.; Mackie, I. D.; DiLabio, G. A.;
Ingold, K. U. J. Org. Chem. 2008, 73, 9270–9282.
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Ingold, K. U. J. Am. Chem. Soc. 2004, 126, 10667–10675.
(7) Knauer, B. R.; Napier, J. J. J. Am. Chem. Soc. 1976, 98 (15), 4395–
4400.
(19) Note that this equilibration refers to the time it takes for the
nitroxide/hydroxylamine bimolecular reaction to establish equilibrium.
The ratio [14NO]/[15NO] was measured periodically for each experiment
until it became constant.
(8) Beckwith, A. L. J.; Bowry, V. W.; Ingold, K. U. J. Am. Chem. Soc.
1992, 114, 4983–4992.
(9) Mahoney, L. R.; Mendenhall, G. D.; Ingold, K. U. J. Am. Chem. Soc.
1973, 95, 8610–8614.
(20) Wu, A.; Mader, E. A.; Datta, A.; Hrovat, D. A.; Borden, W. T.;
Mayer, J. M. J. Am. Chem. Soc. 2009, 131, 11985–11997.
(21) See also: Lucarini, M.; Pedulli, G. F.; Cipollone, M. J. Org. Chem.
1994, 59, 5063–5070.
(10) Mulder, P.; Korth, H.-G.; Pratt, D. A.; DiLabio, G. A.; Valgimigli,
L.; Pedulli, G. F.; Ingold, K. U. J. Phys. Chem. A 2005, 109, 2647–2655.
(11) Astolfi, P.; Greci, L.; Paul, T.; Ingold, K. U. J. Chem. Soc. Perkin
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(22) A referee has suggested that conformational entropy may result in
ΔS in 3 that is not strictly zero. We believe that the effects of conformational
flexibility will likely cancel in cases where 3 describes H exchange between
two six-membered rings. However, this assumption may break down in the
exchange between 2aH and the five-membered rings, 2h and 2i, and with 2j.
(12) Doba, T.; Ingold, K. U. J. Am. Chem. Soc. 1984, 106, 3958–3963.
632 J. Org. Chem. Vol. 76, No. 2, 2011