Establishment of the C-NO bond dissociation energy scale in solution and its application in analyzing the trend of NO transfer from C-nitroso compound to thiols

Article abstract of DOI:10.1021/jo900732b

(Chemical Equation Presented) The first set of experimentally determined C-NO bond homolytic and heterolytic dissociation enthalpies in solution is derived by using direct titration calorimetry combined with appropriate electrode potentials through thermodynamic cycles. The homolytic bond dissociation energy scale (BDEs) of the corresponding C-NO bonds in the gas phase was also calculated at the MP2/6-311+G**//B3LYP/6-31G* level and BP86/6-31G*//B3LYP/6-31G* level of theory for the purpose of comparison. The C-NO and S-NO bond thermodynamic parameters were used to predict the trend of NO transfer from C-nitroso substrates to thiols in acetonitrile solution.

Full text of DOI:10.1021/jo900732b

Establishment of the C-NO Bond Dissociation Energy Scale in
Solution and Its Application in Analyzing the Trend of NO Transfer
from C-Nitroso Compound to Thiols
Xin Li,†,‡ Hui Deng,† Xiao-Qing Zhu,† Xiaoxiao Wang,† Hao Liang,† and
Jin-Pei Cheng*,†,‡
State Key Laboratory of Elemento-Organic Chemistry, Department of Chemistry, Nankai UniVersity,
Tianjin 300071, China, and Beijing National Laboratory for Molecular Sciences, Institute of Chemistry,
Chinese Academy of Science, Beijing 100190, China
chengjp@most.cn; chengjp@nankai.edu.cn
ReceiVed April 7, 2009
The first set of experimentally determined C-NO bond homolytic and heterolytic dissociation enthalpies
in solution is derived by using direct titration calorimetry combined with appropriate electrode potentials
through thermodynamic cycles. The homolytic bond dissociation energy scale (BDEs) of the corresponding
C-NO bonds in the gas phase was also calculated at the MP2/6-311+G**//B3LYP/6-31G* level and
BP86/6-31G*//B3LYP/6-31G* level of theory for the purpose of comparison. The C-NO and S-NO
bond thermodynamic parameters were used to predict the trend of NO transfer from C-nitroso substrates
to thiols in acetonitrile solution.
Introduction
as vehicles for the controlled delivery of NO among biological
systems. In this regard, several relevant categories of NO donor
compounds such as S-nitrosothiols, organic nitrites, metal-NO
complexes, etc. have been investigated in recent years.5 Though
substantial progress have already been achieved, one other
important NO-carrier molecule, the C-nitroso compound, re-
mains almost untouched during the same period.
In the past decade, the C-nitroso compounds have received
renewed interest from chemists and biochemists due to the recent
discoveries of their physiological roles in a number of important
bioactivities.5-7 It is now realized that aliphatic C-nitroso
compounds can undergo C-NO bond scission to release the
Nitric oxide (NO), now known as the simplest biomessenger
in the living body, plays significant roles in many important
physiological activities such as transmitting neurostimulation,
balancing blood pressure, defending health in the immune
system, and so on.1-4 Consequently, extensive research has been
carried out in the last twenty years from the viewpoints of
biochemistry, physiology, pharmacy, and chemistry. Because
NO is a free radical and cannot exist “freely” in the human
body in large quantity, a deeper understanding of its physi-
ological functions should require the knowledge of the NO-
carrier compounds (NO donors), which are believed to serve
† Nankai University.
(5) (a) Wang, P. G.; Xian, M.; Tang, X.; Wu, X.; Wen, Z.; Cai, T.; Janczuk,
A. J. Chem. ReV. 2002, 102, 1091.
‡ Chinese Academy of Science.
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Averill, B. A. Chem. ReV. 1996, 96, 2951. (c) Palmer, R. M.; Ferrige, A. G.;
Moncada, S. Nature 1987, 327, 524. (d) Ignarro, L. J. Annu. ReV. Pharmacol.
Toxicol. 1990, 30, 535.
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20, 26. (b) Fukuto, J. M.; Ignarro, L. J. Acc. Chem. Res. 1997, 30, 149.
(3) (a) Moncada, S.; Palmer, R. M. J.; Higgs, E. A. Pharmacol, ReV. 1991,
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2009, 74, 1450.
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4472 J. Org. Chem. 2009, 74, 4472–4478
10.1021/jo900732b CCC: $40.75 2009 American Chemical Society
Published on Web 05/19/2009

The C-NO Bond Dissociation Energy Scale
SCHEME 1
energies in solution mainly by experimental approaches. The
main purpose of this program is to clarify the thermodynamic
driving forces NO delivers in living system and to provide the
much needed Y-NO bond dissociation energy information to
biochemists and pharmaceutists as a useful tool for their rational
research such as designing NO drugs. Consequently, some
biologically significant N-NO, O-NO, S-NO, and metal-NO
bond dissociation energy scales in solution were established.14
On continuation of this endeavor, we here report the first C-NO
bond heterolytic and homolytic dissociation energy scale of 8
C-nitroso compounds in acetonitrile solution (1-8, Scheme 1).
The C-nitroso compounds chosen for this study can serve as
the models of some archetypal C-nitroso compounds which have
been used as efficient NO donors.6,9-11,15 Moreover, we believe
that it would be a helpful practice to exemplify how these
thermodynamic data can be applied to analyze the trend for
NO to transfer among different receptors. In this paper, a
detailed thermodynamic analysis of the NO transfer reaction
between 2-nitro-2-nitrosopropane and various thiols was con-
ducted in this regard on the basis of the derived energetic data.
NO molecule under photo or thermal conditions,8 rendering
them good candidates to serve as efficient NO donors and thus
to affect the life processes. For instance, it was observed that
2-methyl-2-nitrosopropane (MNP) could deliver NO under
photochemical conditions and induce relaxation of the precon-
stricted rat pulmonary artery rings.9 Some pseudonitroles (e.g.,
5 and 7, in Scheme 1) were found to inhibit aggregation of
blood platelets.10 It was also reported that pseudonitroles are
capable of in vitro vasodilatation and raising the basal level of
GMP.11 Without doubt, these interesting properties of C-NO
compounds should be associated with their inherent ability to
release NO by bond breaking. Though the mechanism of the
physiological functions of C-nitroso compounds has not yet been
fully disclosed, and it should not be expected to be universally
simple, the knowledge of their intrinsic ability to deliver NO
radical or NO+ cation upon C-NO bond scission in solution,
i.e., the homolytic/ heterolytic BDEs, will, nevertheless, be the
key information to study the possible mechanisms and to
understand the related biological behaviors of this category of
NO donors. Unfortunately, most of the C-NO BDEs known
today are those derived in the gas phase and were only
determined for bond homolysis of a small number of very simple
molecules.12 For potentially feasible C-NO-type NO donor
candidates, there is only one computational study13 handling
the situation in solution and one very recent report on
experimental determination of the ∆G value for R-cyano
C-nitroso compounds in various solvents.6b To our knowledge,
there was essentially no work on experimental determination
of the C-NO BDEs in solution for molecules of relatively large
size until now.
Results and Discussion
The heterolytic C-NO bond dissociation energies [∆Hhet-
(C-NO)] of the C-nitroso compounds 1-8 in acetonitrile
solution were directly obtained from the reaction heat (∆Hrxn
)
measurements of the corresponding parent carbanions (C-) with
NO+ (ClO4- as counterion) at 25 °C in deaerated dry acetonitrile
with use of titration calorimetry.16,17 The homolytic C-NO bond
dissociation energies [∆Hhomo(C-NO)] were derived from the
corresponding ∆Hhet(C-NO)s combined with relevant electrode
potentials through a thermodynamic cycle (eq 3, Scheme 2),
where the difference between ∆Hhet and ∆Hhomo of the C-NO
bond is equal to the enthalpy of electron transfer.18 The present
method, in which the ∆Hhet values are used in conjunction with
redox data to derive the corresponding ∆Hhomo values, is
(14) (a) Cheng, J.-P.; Xian, M.; Wang, K.; Zhu, X.-Q.; Yin, Z.; Wang, P. G.
J. Am. Chem. Soc. 1998, 120, 10266. (b) Cheng, J.-P.; Wang, K.; Yin, Z.; Zhu,
X.-Q.; Lu, Y. Tetrahedron Lett. 1998, 39, 7925. (c) Xian, M.; Zhu, X.-Q.; Lu,
J.; Wen, Z.; Cheng, J.-P. Org. Lett. 2000, 2, 265. (d) Zhu, X.-Q.; He, J.; Xian,
M.; Cheng, J.-P. J. Org. Chem. 2000, 65, 6729. (e) Lu, J.-M.; Wittbrodt, J. M.;
Wang, K.; Wen, Z.; Schlegel, H. B.; Wang, P. G.; Cheng, P. J. Am. Chem. Soc.
2001, 123, 2903. (f) Zhu, X.-Q.; Li, Q.; Hao, W.-F.; Cheng, J.-P. J. Am. Chem.
Soc. 2002, 124, 9887. (g) Zhu, X.-Q.; Hao, W.-F.; Tang, H.; Wang, C.-H.; Cheng,
J.-P. J. Am. Chem. Soc. 2005, 127, 2696. (h) Zhu, X.-Q.; Zhang, J.-Y.; Cheng,
J.-P. Inorg. Chem. 2007, 46, 592. (i) Li, X.; Zhu, X.-Q.; Wang, X.-X.; Cheng,
J.-P. Gaodeng Xuexiao Huaxue Xuebao 2007, 28 (12), 2295. (j) Li, X.; Zhu,
X.-Q.; Cheng, J.-P. Gaodeng Xuexiao Huaxue Xuebao 2007, 28 (12), 2327. (k)
Li, X.; Cheng, J.-P. Gaodeng Xuexiao Huaxue Xuebao 2008, 298 (8), 1569.
(15) (a) Rehse, K.; Herpel, M. Arch. Pharm. (Weinheim, Ger.) 1998, 331,
104. (b) Rehse, K.; Herpel, M. Arch. Pharm. (Weinheim, Ger.) 1998, 331, 111.
(16) The model compounds studied in this work are all tertiary C-nitroso
molecules with both sterically bulky and electron-withdrawing groups, which
are significantly disfavored for dimerization in solution. Furthermore, the
concentration of the C-nitroso compounds under the calorimetric titration
conditions is very low (<0.005 M), so conjugation of the C-nitroso species in
solution is negligible. Therefore the contribution from the ∆G of dimerization
could be neglected without scarifying accuracy. In a recent report by Toone et
al., an approximate range of ca.-0.5 to +2.2 kcal/mol for the ∆G of dimerization
of R-cyano C-nitroso compound at 1 M concentration at 25 °C was predicted
(see ref 6b).
Several years ago, this group initiated work on measuring
various Y-NO (Y ) N, O, S, and metal) bond dissociation
(8) (a) Wajer, T. A. J. W.; Mackor, A.; De Boer, T. J.; Van Voorst, J. D. W.
Tetrahedron 1967, 23, 4021. (b) Forrest, D.; Gowenlock, B. G.; Pfab, J. J. Chem.
Soc., Perkin Trans. 2 1978, 12. (c) Forrest, D.; Gowenlock, B. G.; Pfab, J.
J. Chem. Soc., Perkin Trans. 2 1979, 576. (d) Pfab, J. Tetrahedron Lett. 1976,
943. (e) Chow, Y. L.; Tam, J. N. S.; Colon, C. J.; Pillay, K. S. Can. J. Chem.
1973, 51, 2469. (f) Gowenlock, B. G.; Kresze, G.; Pfab, J. Tetrahedron 1973,
29, 3587. (g) Maassen, J. A.; De Boer, Th. J. Recl. TraV. Chim. Pays-Bas 1972,
91, 1329. (h) Bolsman, T. A. B. M.; de Boer, Th. J. Tetrahedron 1973, 29,
3579.
(9) Pou, S.; Anderson, D. E.; Surichamon, W.; Keaton, L. L.; Tod, M. L.
Mol. Pharmacol. 1994, 46, 709.
(10) Rehse, K.; Herpel, M. Arch. Pharm. (Weinheim, Ger.) 1998, 331, 79.
(11) Stilo, A.; Medana, C.; Ferrarotti, B.; Gasco, A. L.; Ghigo, D.; Bosia,
A.; Martorana, P. A.; Gasco, A. Pharmacol. Res. 2000, 41, 469.
(12) (a) Batt, L.; Milne, R. T. Int. J. Chem. Kinet 1973, 5, 1067. (b) Pepekin,
V. I.; Lebedev, V. P.; Balepin, A. A.; Lebdev, Y. A. Dokl. Akad. Nauk. SSSR
1975, 221, 1118. (c) Choo, K. Y.; Mendenhall, G. D.; Golden, D. M.; Benson,
S. W. Int. J. Chem. Kinet. 1974, 6, 813. (d) Boyd, A. A.; Noziere, B.; Lesclaux,
R. J. Phys. Chem. 1995, 99, 10815. (e) Carmichael, P. J.; Gowenlock, B. G.;
Johnson, C. A. F. Int. J. Chem. Kinet. 1972, 4, 339. (f) Carmichael, P. J.;
Gowenlock, B. G.; Johnson, C. A. F. J. Chem. Soc., Perkin Trans. 2 1973, 1853.
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J. Chem. Soc., Perkin Trans. 2 1978, 1110.
(17) The reaction of carbanions (C-) (generated upon removing a proton
from the parent C-H compound by KH) with nitrosonium perchlorate
(NO+ClO4-) in acetonitrile solution can yield the corresponding C-nitroso
compounds quantitatively (the reverse reaction of eq 1, Scheme 2). According
to the reaction in eq 1, the heterolytic C-NO bond dissociation energy of
the C-nitroso compounds [∆Hhet(C-NO)] should be equal to the reaction
enthalpy change (∆Hrxn) of the carbanion (C-) with NO+ simply by switching
the sign of ∆Hrxn (eq 2, Scheme 2). The latter can be directly determined by
titration calorimetry for fast and quantitative reactions as in the present
practice.
(13) Fu, Y.; Mou, Y.; Lin, B.; Liu, L.; Guo, Q. X. J. Phys. Chem. A 2002,
106, 12386.
J. Org. Chem. Vol. 74, No. 12, 2009 4473

Li et al.
SCHEME 2
reason is that oxidation of carbanions is energetically easier than
reduction of NO+ (electrode potentials: Eox of -0.760 to -0.068
V vs. Ered of 0.863 V, Fc+/0 as reference). However, it should
be pointed out that in reality the fashion of the Y-NO bond
dissociation in solution, i.e., either to release NO• by homolysis
or release NO+ (or NOs) by heterolysis, should not only be
governed by the relative magnitude of the dissociation energetics
of the corresponding Y-NO bonds, but also be affected by the
driving forces of the follow-up reactions.
It is noteworthy that when the ∆Hhet(C-NO) values of the
C-NO compounds in acetonitrile are plotted against the pKa
values of the corresponding C-H compounds in DMSO,20 an
excellent straight line is obtained (r ) 0.999, Figures 1),
indicating that the ∆Hhet(C-NO) values depend mainly on the
stability of the carbanions, which, in turn, suggests an alternative
way to estimate the C-NO bond heterolysis energy if the
corresponding pKa is available or is more convenient to
determine. Similar linear correspondence was also observed in
our earlier works on the ∆Hhet values of N-nitrosoureas,14a
N-nitrosodiphenylamines,14d N-methyl-N-nitrosobenzenesulfon-
amides,14g and O-nitrosobenzoates.14c The much greater energy
required for Y-NO (Y ) C, N, O) bonds to undergo heterolysis
than that of the corresponding Y-H bonds should be mainly
attributed to the much lower stability of the nitrosonium ion
compared to that of proton in solution. On the other hand, the
substantially higher stability of the NO• radical than that of the
H• radical should be responsible for the huge weakening effect
on the Y-NO (∆Hhomo) bonds compared to the corresponding
Y-H bonds.
Examination of the substituent effect on the heterolytic
C-NO bond dissociation energies shows that the strength of
the C-NO bonds, i.e. the ∆Hhet(C-NO), relies heavily on the
size of the substituents at the central carbon. For example,
among the subseries 3, 4, and 6, which respectively bears tert-
butyl, isopropyl, and ethyl groups, the bond energy was found
to be in a decreasing order: 63.3 kcal/mol > 57.6 kcal/mol >
53.0 kcal/mol. A similar phenomenon was observed between
compounds 1 (66.2 kcal/mol) and 2 (65.9 kcal/mol), and
between 5 (53.9 kcal/mol) and 7 (52.9 kcal/mol), though the
differences are not as large. This may be understood by
considering that the large alkyl groups at the central carbon
would make its carbanion less solvated so that it becomes less
stable. This is also in accordance with the observed decreasing
order of oxidation potentials of the related carbanions
(Table 1).
analogous to that of Arnett for evaluation of the C-C bond
energies.18 Similar approaches to estimate experimentally inac-
cessible quantities from feasible solution measurements have
been widely practiced in the last twenty years in literature.19
The ∆Hrxn, ∆Hhet(C-NO), and ∆Hhomo(C-NO) values together
with the relevant electrochemical data are summarized in Table
1. The homolytic C-NO bond dissociation energies in the gas
phase calculated by DFT method, as well as the literature pKa20
values of the corresponding C-hydrogen compounds, are also
included in Table 1 for the purpose of comparison.
Heterolytic and Homolytic C-NO Bond Dissociation
Energies in Acetonitrile. Table 1 shows that the ∆Hhet(C-NO)
values of the 8 C-nitroso compounds in acetonitrile range from
49.3 to 66.2 kcal/mol, whereas the ∆Hhomo(C-NO) values range
from 26.2 to 31.4 kcal/mol. It is obvious that the C-NO bond
heterolytic dissociation energies are considerably greater than
the corresponding C-NO bond homolytic dissociation energies
by 37.4-21.5 kcal/mol, suggesting that the C-nitroso compounds
be good NO• donors. This is similar to the characteristics of
the N-nitroso and S-nitroso compounds in our previous studies,14
and should explain the observations that NO• (rather than NO+)
was the key player in many physiological processes. The main
(18) Arnett has shown that the temperature dependence of the redox processes
for resonance-delocalized anions and for the reversible cation-to-radical conver-
sions was experimentally observed to be negligible. Then the corresponding
entropy changes for redox processes should be insignificant. For previous
validation of similar treatment, see: (a) Arnett, E. M.; Amarnath, K.; Harvey,
N. G.; Cheng, J.-P. Science 1990, 247, 423. (b) Arnett, E. M.; Amarnath, K.;
Harvey, N. G.; Cheng, J.-P. J. Am. Chem. Soc. 1990, 112, 344. (c) Troughton,
E. B.; Molter, K. E.; Arnett, E. M. J. Am. Chem. Soc. 1984, 106, 6726.
(19) (a) Bordwell, F. G.; Cheng, J.-P.; Harrelson, J. A. J. Am. Chem. Soc.
1988, 110, 1229. (b) Bordwell, F. G.; Bausch, M. J. J. Am. Chem. Soc. 1986,
108, 1979. (c) Cheng, J. P.; Handoo, K. L.; Parker, V. D. J. Am. Chem. Soc.
1993, 115, 5067. (d) Parker, V. D. J. Am. Chem. Soc. 1992, 114, 7458. (e) Cheng,
J. P.; Zhao, Y.; Huan, Z. Sci. China, Ser. B 1995, 38, 1417. (f) Zhu, X.-Q.;
Xian, M.; Wang, K.; Cheng, J.-P. J. Org. Chem. 1999, 64, 4187. (g) Cheng,
J. P.; Liu, B.; Zhang, X. J. Org. Chem. 1998, 63, 7574. (h) Cheng, J.-P.; Liu,
B.; Zhao, Y.; Zhang, X. M. J. Org. Chem. 1998, 63, 7072. (i) Cheng, J.-P.; Lu,
Y.; Zhu, X.-Q.; Mu, L. J. Org. Chem. 1998, 63, 6108. (j) Li, X.; Zhu, X.-Q.;
Zhang, F.; Wang, X.-X.; Cheng, J.-P. J. Org. Chem. 2008, 73, 2428.
(20) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
(21) Wayner, D. D. M.; Parker, V. D. Acc. Chem. Res. 1993, 26, 287.
(22) In this paper, all of the calculations were done with Gaussian 98.23 The
geometry was optimized by using B3LYP/6-31G*, with each optimized structure
verified by B3LYP/6-31G* frequency calculations as a real minimum without
any imaginary frequency.
(23) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; Stratmann,
R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.;
Strain, M. C.; Farkas, O.; Tomasi, J.; Batone, V.; Cossi, M.; Cammi, R.;
Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.; Petersson,
G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Stefanov, B. B.;
Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkare, A.; Gonzalez,
C.; Challacombe, M.; Gill, P. M. W.; Johnson, B. G.; Chen, W.; Wong, M. W.;
Abdres, J. L.; Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98,
revision A.7; Gaussian, Inc.: Pittsburgh, PA, 1998.
Interestingly, the C-NO bond homolytic dissociation energies
(∆Hhomo) of the same subseries show, however, an opposite order
as 3 (27.5 kcal/mol) ≈ 4 (27.6 kcal/mol) < 6 (30.4 kcal/mol).
This, again, could be rationalized by considering the size effect
of the substituents at the central carbon atom. For radicals of
no net charge, the solvation-induced differentiation of stability
in solution would be minimized, whereas the size-dependent
inhibition to radical dimerization would become a dominant
factor in varying radical stability. In such cases, the bulky tert-
butyl and i-Pr should contribute more to the radical stability to
cause a decrease in the homolysis energy of the C-NO bond.
With the C-NO bond energy scale in hand, it is now possible
to compare the feasibility of Y-NO bond breaking in solution
with different Y atoms. Comparison of the data derived in this
work with those reported earlier by this group14 reveals that
the ease of the homolytic C-NO bond scission is in a decreasing
order of CoIII-NO bonds (15.2 to 17.5 kcal/mol for T(G)-
4474 J. Org. Chem. Vol. 74, No. 12, 2009

The C-NO Bond Dissociation Energy Scale
TABLE 1. ∆Hrxn, ∆Hhet(C-NO), and ∆Hhomo(C-NO) Values of C-Nitroso Compounds (kcal/mol), Oxidation Potentials of Corresponding
Carbanions (V vs. Fc+/0), Theoretical Homolytic BDEs (kcal/mol), and pKa Values of Corresponding C-H Compounds
∆Hhomo
a
b
c
compds
∆Hrxn
Eoox(C0/-
)
∆Hhet
exptd
calcde
calcdf
solv(MP2)g
pKah
1
2
3
4
5
6
7
8
-66.2
-65.9
-63.3
-57.6
-53.9
-53.0
-52.9
-49.3
-0.760
-0.730
-0.691
-0.437
-0.339
-0.116
-0.068
-0.133
66.2
65.9
63.3
57.6
53.9
53.0
52.9
49.3
28.8
29.2
27.5
27.6
26.2
30.4
31.4
26.3
29.4
33.4
30.7
30.3
29.7
34.2
33.5
26.8
25.4
28.3
24.6
23.8
25.6
23.9
26.7
25.5
0.9
1.0
1.5
1.3
2.3
4.1
0.4
4.0
26.25
26.15
24.7
20.5
17.9
16.9
15.05
-
a Measured in CH3CN at 25 °C by titration calorimetry. The reproducibility is (0.5 kcal/mol. b The standard redox potentials were derived from the
corresponding irreversible redox potentials calibrated by using Wayner and Parker’s method,21 respectively. The irreversible redox potentials were
measured in acetonitrile solution at 25 °C in volts by CV method vs. ferrocenium/ferrocene redox couple. Reproducible to 5 mV or better. c Derived
from eq 2 in Scheme 2. d Derived from eq 3 in Scheme 2, taking E1/2(NO+/0) ) 0.863 V (vs. Fc+/0). Relative uncertainties were estimated to be smaller
than 1 kcal/mol.14g e Computed at the MP2/6-311+G**//B3LYP/6-31G* level of theory with zero-point energy (ZPE) and thermal corrections to
enthalpy at 298 K.22,23 f Computed at the BP86/6-31G*//B3LYP/6-31G* level of theory with zero-point energy (ZPE) and thermal corrections to
enthalpy at 298 K. g The solvent effect was computed at the MP2/6-311+G**//B3LYP/6-31G* level with the dielectric polarized continuum model
(DPCM). h From ref 20.
level are included in Table 1. It is noted from comparison that
the theoretical BDE results, which range from 26.8 to 34.2 kcal/
mol with a standard deviation of +2.4 ( 1.9 kcal/mol (by MP2)
and from 23.8 to 28.3 kcal/mol with a deviation of -3.0 ( 1.7
kcal/mol (by BP86), agree reasonably well with the experimental
values. However, the gaps between theory and experiment
observed in this work are notably greater than most of those in
the earlier reports (ca. 1-2 kcal/mol),14e,19a,24 and are believed
to be attributed to the complication caused by the bulky structure
and the multipolar centers of the present C-NO compounds.
The good agreement found between the present ∆Hhomo(C-NO)
of 31.4 kcal/mol for 7 and the reported BDE of 29.2 kcal/mol
of a structurally similar R-cyano C-nitroso substrate in the vapor
phase6b also gives credence to the experimental measurements
of the current work.
Driving Force Analysis of NO Transfer from C-NO
Compound to Thiols. It is well-known that transfer of NO
from donors to target species occurs widely in chemical and
FIGURE 1. Correlation of the C-NO bond heterolytic dissociation
biochemical processes, and this transportation is believed to
be responsible for many biological and physiological effects
of NO. Among the NO initiated reactions, transferring NO
from a donor compound to thiol has been a focus of interest
since the early years of NO research due to the revelation
that S-nitrosothiols may be an important NO vehicle in vivo.
Understanding of the NO transfer process, especially at
molecular level, is believed to be crucial for exploring the
NO storage and transfer mechanisms in biological systems.
However, attention in this regard has only been paid to kinetic
aspects by far,25 and there was almost no energetic study in
the literature on the basis of quantitative evaluation of the
thermodynamic driving forces for NO transfer reactions.14h
The main reason is due to the lack of relevant thermodynamic
data of the Y-NO (Y) C, N, O, S, metals, etc.) bonds for
the interested compounds. In the present study, we chose the
energies of the C-nitroso compounds in acetonitrile with the corre-
sponding pKa values of the parent C-hydrogen molecules in DMSO.
PPCoIIINO14f) > S-NO bonds (18.6 to 21.4 kcal/mol for
S-nitrosophenylthiols14e) > CoII-NO bonds (21.1 to 24.6 kcal/
mol for T(G)PPCoIINO14f) ≈ N-NO bonds (21.4 to 24.3 kcal/
mol for N-nitrosodiphenylamines14d) > C-NO bonds (26.3 to
31.4 kcal/mol, present work) > O-NO bonds (32.5 to 38.6 kcal/
mol for O-nitrosobenzoates14c) ≈ N-NO bonds (33.0 to 34.9
kcal/mol for N-methyl-N-nitrosobenzenesulfonamides14g) >
N-NO bonds (34.5 to 40.4 kcal/mol for N-nitrosophos-
phoramidates14a) > N-NO bonds (36.1-43.8 kcal/mol for
N-nitrosoacetanilides14b). Obviously, the C-NO bonds are
weaker than O-NO bonds and most N-NO bonds investigated,
indicating that the C-NO compounds should be quite promising
candidates for good NO donor compounds. The overall spectrum
of these Y-NO bond energetic scales should thus provide useful
information to guide the design and synthesis of desired NO
donor compounds and to understand the mechanisms and the
likely trend of NO transfer reactions.
(24) (a) Bartberger, M. D.; Mannion, J. D.; Powell, S. C.; Stamler, J. S.;
Houk, K. N.; Toone, E. J. J. Am. Chem. Soc. 2001, 123, 8868. (b) Bordwell,
F. G.; Cheng, J.-P.; Ji, G.; Satish, A. V.; Zhang, X. J. Am. Chem. Soc. 1991,
113, 9790. (c) Bordwell, F. G.; Zhang, X.-M. Acc. Chem. Res. 1993, 26, 510.
(25) (a) Barnett, D. J.; McAninly, J.; Williams, D. L. H. J. Chem. Soc., Perkin
Trans. 2 1994, 1131. (b) Barnet, D. J.; Rios, A.; Williams, D. L. H. J. Chem.
Soc., Perkin Trans. 2 1995, 1279. (c) Meyer, D. J.; Kramer, H.; Ozer, N.; Coles,
B.; Ketterer, B. FEBS Lett. 1994, 345, 177. (d) Rossi, R.; Lusini, L.; Giannerini,
F.; Giustarini, D.; Lun-garella, G.; Di Simplicio, P. Anal. Biochem. 1997, 254,
215. (e) Zhang, H.; Means, G. E. Anal. Biochem. 1996, 237, 141. (f) Hogg, N.
Anal. Biochem. 1999, 272, 257.
To verify the experimental observations, density functional
theory (DFT)22,23 was used to calculate the homolytic C-NO
BDEs in the gas phase for the same C-nitroso family studied
by experiment. The computation results at the MP2/6-311+G**//
B3LYP/6-31G* level and at the BP86/6-31G*//B3LYP/6-31G*
J. Org. Chem. Vol. 74, No. 12, 2009 4475

Li et al.
SCHEME 3
SCHEME 5
of the corresponding RSNOs are summarized in Table 2,
together with the evaluated ∆Gtr values and other quantities
necessary for estimating the free energy changes of NO
transfer by eq 4 in Scheme 4.
SCHEME 4
Table 2 shows that the differences between the C-NO
bond heterolysis energy of NNP and the S-NO bond
heterolysis energies of S-nitrosothiols (∆∆Hhet) are all
negative values, ranging from -4.6 to -0.9 kcal/mol, and
become less negative as the para-substituent G is going from
electron-donating to electron-withdrawing. This indicates that
transferring an NO moiety from carbon to sulfur is energeti-
cally feasible for the model reaction in Scheme 4 especially
for thiols bearing a strong electron-donating group. Table 2
also shows that the Gibbs free energy changes (∆Gtr) of the
NO transfer reactions are from -6.0 to -4.0 kcal/mol. This,
again, is indicative of favorable reactions of NO transfer from
NNP to thiols.
reaction of 2-nitro-2-nitrosopropane (NNP, 7) with thiols as
a model reaction for NO transfer between the C-NO-type
donors and SH-containing substrates. We applied the mea-
sured C-NO bond energies and the S-NO bond energies
together with the pKa values to derive the driving forces of
NO transfer from NNP (7) to thiols (Scheme 3).
To evaluate the free energy changes of NO transfer from
NNP to thiols, an indirect approach has to be used. The
thermodynamic cycle was thus constructed and is shown in
Scheme 4. In eq 4 in Scheme 4, ∆Gtr represents the free
energy of NO transfer, ∆∆Ghet is the difference between the
free energies of the C-NO bond heterolysis and S-NO bond
heterolysis, and ∆pKa is the acidity difference between the
corresponding S-H compound and the C-H compound.24c,26
It should be pointed out that an assumption has to be made
there to allow a reasonable use of eq 4 in Scheme 4 to
estimate the energetics of NO transfer, that is, the entropy
change of the C-NO bond heterolysis of NNP was ap-
proximated to be similar to that of the S-NO bond heterolysis
of thiols in the same solvent. Then, the corresponding ∆∆Ghet
To further examine the trend of NO transfer, a different
approach, i.e., the equilibrium constant (Keq) measurement
for the same NO transfer model reaction (Scheme 6), was
performed with UV-vis spectroscopy.28 The results evaluated
from eq 6 in Scheme 6 are listed in Table 3.
Table 3 demonstrated that the Keq values range from 7.07
to 10.22, clearly indicating that there exists a favorable trend
for NO to transfer from NNP to all the thiols under the
conditions of this study, which is in good accordance with
the prediction based on bond energy analysis. This, together
with the ∆Gtr data in Table 2, suggests that the C-NO
compounds, as represented by 7, could be even better an NO
donor than S-nitrosothiols, which have been applied so widely
as the most famous NO donors in biological studies. The
correlation of ∆Gtr values vs. Keq values (Figure 2) revealed,
though not perfect, a quite good linear relationship (r )
0.968) between the two sets of data of totally different
measurements, providing confidence to the overall conclusion
about the trend of NO transfer drawn from the bond energy
analysis.
In conclusion, the C-NO bond cleavage energies of eight
model C-nitroso compounds in acetonitrile solution were
determined by using titration calorimetry combined with
electrochemical measurement. The first quantitative energetic
scale of the C-NO bond scission in solution was thus
established. Substituent effect on the cleavage energies of
the C-NO bonds was rationalized. The homolytic BDEs of
can be equated to the experimentally determined ∆∆Hhet
.
Application of the similar assumption was found useful in
our earlier study on other types of NO transfer reactions.14g
It is obvious that, in addition to the knowledge of
∆Hhet(C-NO) and the pKa of the corresponding C-H
compound (Table 1), to apply eq 4 in Scheme 4 to estimate
the free energy change of NO transfer, determination of the
∆Hhet(S-NO) and the pKa values of the related thiols are
necessary. However, due to the complication induced likely
by formation of the S-S bond when direct calorimetric
titration of NO+ to RS- was performed, the direct NO+-to-
anion titration in the normal heat measurements should be
avoided and a thermochemical cycle that involves the heat
of reaction (∆Hrxn) of RSH with NO+ and the pKa of the
relevant S-H compound (Scheme 5) has to be used
instead.14e The pKa values of thiols in DMSO,27 the measured
∆Hrxn values of NO+ with RSH, and the ∆Hhet(S-NO) values
(27) Matthews, W. S.; Bares, J. E.; Bartmess, J. E.; Bordwell, F. G.;
Cornforth, F. J.; Drucker, G. E.; Margolin, Z.; McCallum, R. J.; McCollum,
G. J.; Vanier, N. R. J. Am. Chem. Soc. 1975, 97, 7006.
(28) In this study, NNP has a maximum absorption at 640 nm, while λmax
for S-nitrosobenzylthiols is around 540 nm, and λmax for Ph3CSNO is 590 nm.
Transnitrosation between NNP and different thiols can be readily analyzed by
using UV-vis spectrometric measurement (Figure S1 in the Supporting
Information). UV-vis spectra of the reaction mixtures were obtained by adding
an equimolar amount of thiol to a cuvette containing NNP. After the equilibrium
was reached, the concentrations of the reactants and products can be calculated
from the change of the absorption of NNP at 640 nm according to the Beer-
Bouger-Lambert law. The equilibrium constant (Keq) of NO transfer between
NNP and different thiols can then be determined from the calculated concentra-
tions as shown in eq 6 in Scheme 6.
(26) The factor 1.364 in the 1.364∆pKa term is to convert the equilibrium
acidity from pK unit to kcal/mol. The application of this expression widely
appears in the study of acidity equilibrium. See ref 20 and: (a) Cheng, J. P.;
Liu, B.; Zhang, X. J. Org. Chem. 1998, 63, 7574. (b) Cheng, J.-P.; Liu, B.;
Zhao, Y.; Zhang, X. M. J. Org. Chem. 1998, 63, 7072. (c) Cheng, J.-P.; Lu, Y.;
Zhu, X.-Q.; Mu, L. J. Org. Chem. 1998, 63, 6108.
4476 J. Org. Chem. Vol. 74, No. 12, 2009

The C-NO Bond Dissociation Energy Scale
TABLE 2. The pKa Values of Thiols in DMSO, ∆Hrxn Values of NO+ with RSHs in Acetonitrile at 25°C, ∆Hhet(S-NO) Values of RSNOs
(kcal/mol), pKa Values of RSHs in Acetonitrile, Differences of C-NO Bond Heterolytic Dissocaition Energy of NNP between the S-NO Bond
Heterolytic Dissociation Energy S-Nitrosothiols and Differences of pKa Values between the Corresponding Parent Alkane Thiols, As Well As the
Free Energy Changes (∆Gtr) of NO Transfer from NNP to Thiols (kcal/mol)
b
f
RSNOs, G )
pKaa
∆Hrxn
∆Hhet(S-NO)c
pKa(RSH)d
∆∆Hhet
1.364∆pKae
∆Gtr
CH3O
H
F
Cl
15.8
15.4
15.3
15.1
15.0
14.5
-22.7
-22.0
-21.8
-21.5
-21.5
-20.8
57.5
56.2
55.9
55.3
55.2
53.8
25.5
25.1
25.0
24.7
24.8
24.2
-4.6
-3.3
-3.0
-2.4
-2.3
-0.9
-1.4
-1.9
-2.1
-2.3
-2.5
-3.1
-6.0
-5.2
-5.1
-4.7
-4.8
-4.0
Br
Ph3CSNO
a Determined in this work by “overlapping indicator methods” in DMSO,27 with the uncertainty of (0.05. b Measured in CH3CN at 25 °C by titration
calorimetry. The reproducibility is (0.5 kcal/mol. c Derived from eq5 in Scheme 5. d pKa value of R-SHs in acetonitrile were derived from their pKa
values in DMSO according to the known relation of pKa(CH3CN) ) 0.982pKa(DMSO) + 9.94.14e e The pKa value of 2-nitropropane in acetonitrile is
26.5, which is derived from its pKa of 16.9 in DMSO,20 using the equation in a.14e f Derived from eq4 in Scheme 4.
SCHEME 6
was refluxed over KMnO4 and K2CO3 for several hours and was
distilled over P2O5 under argon before use. The commercial
tetrabutylammonium hexafluorophosphate (Bu4NPF6) was re-
crystallized from CH2Cl2 and was vacuum dried at 110 °C
overnight before preparation of a supporting electrolyte solution.
The nitrosating reagent NO+ClO4- was prepared according to a
literature method.29 Redox potentials were obtained by the CV
method on an electrochemical analyzer. The heats of reaction
of NO+ with carbanions and NO+ with thiols were determined
on a titration calorimeter. UV-visible measurements were
carried out on a UV-visible spectrometer.
TABLE 3. Equilibrium Constant of NO Transfer Reaction
between NNP and Thiols
a
RSH, G )
Keq
CH3O
H
F
Cl
Br
Ph3CSH
10.22
9.56
9.30
8.67
8.80
7.07
Titration Calorimetry for C-Nitroso Compounds. Reaction
of NO+ (NO+ClO4-) with carbanions (K+ as counterion) in dry
CH3CN was rapid and gave the C-NO coupling product
quantitatively. The reaction heat (∆Hrxn) was measured at 25
°C by a standard procedure similar to that of Arnett.18 The
performance of the calorimeter was checked by measuring the
standard heat of neutralization of an aqueous solution of sodium
hydroxide with a standard aqueous HCl solution. The MeCN
a Derived from eq 6 in Scheme 6.
solution of NO+ClO4 (0.1 M) was prepared inside the argon-
-
filled drybox with an analytical balance and volumetric flask
before each calorimetric run. The calibrated motor-driven buret,
filled with 2 mL of NO+ solution, and the reaction vessel,
containing about 40 mL of a carbanion solution (in excess), were
connected to the calorimeter insert assembly. A dry argon
atmosphere was maintained at the top of the reaction vessel to
protect anions from unexpected reaction. The heat of dilution
of nitrosonium perchlorate was small enough to be neglected
for heat of reaction measurements. The reported ∆Hrxn is the
average value of two or three independent runs, which consisted
of up to six titrations with the same stock solution.
Measurement of Redox Potentials. All electrochemical ex-
periments were carried out by CV (sweep rate, 100 mV/s) in
dry acetonitrile solution under an argon atmosphere at 25 °C as
described previously. n-Bu4NPF6 (0.1 M) was employed as the
supporting electrolyte. A standard three-electrode cell consists
of a glassy carbon disk as working electrode, a platinum wire
as counter electrode, and 0.1 M AgNO3/Ag (in 0.1 M Bu4N-
PF6-MeCN) as reference electrode. All sample solutions were
1.0 mM. The ferrocenium/ferrocene redox couple (Fc+/0) was
taken as the internal standard. The reproducibility of the
potentials was smaller than 5 mV.
FIGURE 2. Correlation of the equilibrium constants (Keq) of the NO
transfer reaction between 2-nitro-2-nitrosopropane and thiols with the
Gibbs free energy changes (∆Gtr) of the transfer reaction.
the C-NO bond in these C-nitroso compounds were also
computed and the calculated results agreed reasonably well
with the experimental observations. In addition, the derived
C-NO bond energy was applied to estimate the trend of NO
transfer from NNP to thiols in solution, and the prediction
drawn from thermodynamic driving force analysis was found
to correspond quite well with the spectraphotometrically
determined equilibrium constants.
Titration Calorimetry for S-Nitrosothiols. The heats of
reactions (∆Hrxn) of thiols with NO+ (as from a NO+-
ClO4--MeCN solution) were measured under argon by titration
calorimetry in dry acetonitrile at 25 °C. After a certain amount
of MeCN solution of NO+ClO4 was titrated in through a
-
carefully calibrated motor-driven buret to the reaction vessel
containing an excess amount of thiol, heat was generated and
was computer-processed to give the heat of nitrosation (∆Hrxn).
The ∆Hhet values of the S-NO bond (i.e., NO+ affinities) can
then be calculated from eq 5 in Scheme 5.
Experimental Section
All reagents were of commercial quality from freshly opened
containers or were purified before use. Reagent grade acetonitrile
J. Org. Chem. Vol. 74, No. 12, 2009 4477

Li et al.
Equilibrium Study of Transnitrosation between 2-Nitro-2-
nitrosopropane and Thiols. The equilibrium constants (Keq) for
transnitrosation were determined by reacting equimolar amounts
of thiols and 2-nitro-2-nitrosopropane. Briefly, 2-nitro-2-nitroso-
propane in acetonitrile was placed in a quartz cell at 25 °C. The
absorption at 640 nm was monitored for 60 min to obtain the
slow decomposition rate. An equimolar amount of thiol was
added and the exchange reaction was monitored until equilibrium
was reached. Keq was then calculated based on the change of
the UV absorption. Experiments were repeated at least once.
20472038, 20421202, 20672060, and 20072020) is gratefully
acknowledged. We thank the reviewers for setting high
standards and for good suggestions on this work.
Supporting Information Available: Experimental proce-
dures, UV-vis spectra of PhCH2SNO and Ph3CSNO, and
detailed results of theoretical calculations. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO900732B
Acknowledgment. Financial support from the National
Natural Science Foundation of China (Grant Nos. 20332020,
(29) Markowitz, M. M.; Ricci, J. E.; Goldman, R. J.; Winternitz, P. F. J. Am.
Chem. Soc. 1957, 99, 3659.
4478 J. Org. Chem. Vol. 74, No. 12, 2009