Current Topics in Medicinal Chemistry 2005, 5, 687-705 687

C-Nitroso Compounds: Synthesis, Physicochemical Properties and

Biological Activities

David M. Gooden, Harinath Chakrapani and Eric J. Toone*

Department of Chemistry, Duke University, B120 Levine Science Research Center, Durham, NC 27708

Abstract: Because of the chemical and physical properties of nitric oxide, its effective use and delivery for therapeutic
application represents a significant challenge. Accordingly, current understanding of nitric oxide biology largely stems
from the use of nitric oxide prodrugs and adducts whose biological activities are based on their ability to release nitric
oxide or a redox-related species. Among the structurally diverse ensemble of nitric oxide donor compounds reported to
date are the C-nitroso compounds. These compounds have only recently been investigated with respect to their potential
as nitric oxide donors, although they have been known and studied for over 120 years. Here, we consider the synthesis and
physico-chemical properties of the C-nitroso compounds and the available data regarding their biological activities.
Synthetic methods reviewed include direct substitution of H by NO, oxidative approaches, and the addition of various
oxides of nitrogen across multiple bonds. The electronic spectra of C-nitroso compounds and the mechanism and
thermodynamics of monomer-dimer equilibration are described. The physico-chemical and biological properties of two
related classes of compounds, the diazetine dioxides and the furoxans, are also described.

1. INTRODUCTION Included among the organic donors are the C-nitroso

The fundamental role of nitric oxide (NO⋅) in myriad
biochemical processes is well established. Nitric oxide
mediated biological events include regulation of smooth
muscle relaxation [1, 2], inhibition of platelet activation [3,
4], stimulation of immune response against bacterial
pathogens and tumor cells [5, 6], neurotransmission [7], and
control of gene regulation [8, 9]. The pervasive nature of this
essential molecule underscores the need to better understand
the mechanism(s) by which NO⋅ exerts its bioactivity and to
apply this understanding to the development of therapeutic
agents that mimic the effects of endogenous nitric oxide.
Under ambient conditions, nitric oxide exists as a gaseous
free radical and exhibits poor solubility in aqueous solution.
Additionally, NO⋅ readily reacts with atmospheric or
dissolved O2 to produce unstable, toxic higher oxides of
nitrogen. Finally, under some biologically relevant
conditions nitric oxide may act as a progenitor of both
nitrosonium and nitroxyl; both species display unique
biological properties.
The activity of nitric oxide can be modulated via the
formation of adducts. Accordingly, much nitric oxide
biology has been deduced from studies using relatively
stable synthetic agents that contain nitric oxide and
demonstrate “NO-like” bioactivity. The development of such
agents, the so-called “NO donors”, has received considerable
attention and the primary literature is now replete with
examples of compounds whose bioactivities are based on
their ability to release nitric oxide or a redox-related species
[10-15]. The list of such donors includes inorganic
compounds, such as hydroxylamine, Angeli’s salt (Na2N2O3)
and nitroprusside (Fe(CN)5NO-2), and organic compounds
including nitrites, nitrates, thionitrites (S-nitrosothiols), diaz-
eniumdiolates (NONOates), and sydnonimines.
*Address correspondence to this author at the Department of Chemistry,
Duke University, B120 Levine Science Research Center, Durham, NC
27708; E-mail: Eric.Toone@duke.edu
(CNO) compounds. In comparison to other donor compounds,
relatively few reports have considered the ability of C-
nitroso compounds to serve as progenitors of NO [16-20]. C-
Nitroso compounds offer several significant advantages as
NO donors relative to other classes of compounds. Most
importantly, incremental alteration of substitution patterns at
the nitrogen-bearing carbon facilitates precise control over
both the rate of NO release and the redox form of the
released species. The bioactivity of those C-nitroso
compounds that have been examined is encouraging and
demonstrates the need for further development of C-nitroso
compounds for the study of nitric oxide biology.
Here, we review the physical properties of C-nitroso
compounds, their synthesis, and the biological activity of
those compounds that have been examined. Many excellent
monographs [21-23] and review articles [24, 25] regarding
the synthesis of C-nitroso compounds exist, and this review
will focus on synthetic methods employed in the preparation
of biologically active NO donors. A thorough treatment of
the physicochemical properties of aliphatic C-nitroso
compound is presented in order to facilitate an understanding
of and, perhaps, the ability to predict NO-related bioactivity
of CNO donors. Finally, we include some classes of organic
donors that, though not formally C-nitroso compounds,
contain structural similarities (e.g. the C⋅⋅N⋅⋅O bonding
arrangement), contain nitrogen in the +2 oxidation state, and
display NO-mediated bioactivity. This extended class of NO
donors includes diazetine dioxides, and furoxans (Fig. 1).
2. STRUCTURE AND BEHAVIOR OF C-NITROSO
COMPOUNDS
2.1. Physical Properties of C-Nitroso Compounds
For the purpose of this review, C-nitroso compounds are
defined as species in which a nitroso group is directly
attached to an aliphatic carbon atom by a carbon-nitrogen

1568-0266/05 $50.00+.00 © 2005 Bentham Science Publishers Ltd.

688 Current Topics in Medicinal Chemistry, 2005, Vol. 5, No. 7
O O O R1
N N N
X R3
R1 R3 N N
R2 R1 R2
1 2
Fig. (1). Organic NO donors: C-nitroso compounds (1), diazetine
dioxides (2), Furoxans (3).
single bond (C-N=O) [26]. Such compounds exist as
equilibrating mixtures of monomers (R-NO) and the nitrogen
bonded azoxy dimers (R(O)N=N(O)R). In dimeric form,
both cis and trans isomers exist. The monomer is populated
only weakly, with equilibrium constants almost universally
less than 100 M-1, and the colorless to pale yellow dimers
predominate only in the solid state. Upon dissolution, the
dimers dissociate to the highly colored monomeric species.
2.1.1. Electronic Absorption Spectra of
Compounds
The characteristic blue color of aliphatic C-nitroso
monomers is attributed to the S0 → S1 transition of non-
bonded electrons localized on nitrogen. This forbidden n →
π* transition gives rise to the low intensity (ε ≈ 1-60 mol-1 l-1)
visible absorption band between 630-790 nm. Over
appropriate concentration domains, the appearance or
disappearance of CNO monomer can be conveniently
followed by monitoring changes in this absorption [27]. A
second weak absorption maxima between 270-300 nm (ε ≈
80 mol-1 l-1) results from the n → π* transition of non-bonded
electrons localized on oxygen. A blue-shift is observed for
these two n → π* transitions in solvents of increasing
polarity [28]. Finally, a relatively intense (ε ≈ 3000 - 5000
mol-1 l-1) absorption in the UV region (220 nm) is ascribed to
an allowed π → π* transition of the N=O group. Upon
dimerization, the nitrogen lone-pair become bonding
electrons in what is formally a 6π system; 2π electrons from
each nitrogen and 1π electron from each oxygen. As a result
of this electronic reorganization, dimerization is
accompanied by a disappearance in the characteristic blue
color of the monomer. The electronic absorption spectra of
the dimer is dominated by an intense (ε ≈ 5000-10, 000 mol -1
l-1) π → π* transition between 270-300 nm.
2.1.2. Infrared Spectroscopy of C-Nitroso Compounds
The N=O stretching frequency of aliphatic CNO
monomers occurs between 1621 and 1539 cm-1. In
asymmetrically substituted monomers, rotational isomerism
my give rise to a doublet in this region. The vibrational
frequency of the NO stretching mode is lowered by
conjugation as well as by the presence of electron
withdrawing groups on the nitroso carbon [24]. Multiple
substitution by these same groups leads to even larger values
for the stretching frequency: the gas phase IR spectra for
CH3N=O (1564 cm-1) and CCl3N=O (1621 cm-1) serve as
illustrative examples of this trend [28]. The decrease in the
NO bond order going from monomer to dimer is reflected in
a lowered N→O stretching frequency in CNO dimers.
Aliphatic trans-dimers show a single absorption band of
moderate intensity between 1176-1290 cm-1 while cis-
isomers show two bands in the regions of 1323-1344 cm-1
and 1330-1420 cm-1.
Gooden et al.
R2 2.1.3. C-N Bond Strengths in C-Nitroso Monomers
In comparison to the extensive thermodynamic data
O
collected for many organic functional groups, relatively few
O studies of the thermochemistry of C-nitroso compounds are
3 available. Information regarding the relative strengths of C-
N bonds in CNO donor compounds is particularly important
for predicting and rationalizing mechanism(s) and rates of
NO release from CNO donors. The tendencies of CNO
monomers to undergo dimerization as well as isomerization
to the oxime (vide infra) complicate thermochemical
analyses and may account for the dearth of thermochemical
data.
Enthalpies of formation (∆Hfy) for a limited number of
simple CNO derivatives have been determined
calorimetrically. These values, in conjunction with ∆Hfy for
the corresponding organic radical (R⋅ ), facilitate derivation
C-Nitroso of C-N bond dissociation energies through the use of the
expression [29]:
∆Hfy(RNO) = ∆Hfy(R⋅) + ∆Hfy(NO) – D0(R-NO) (1)
By this method, the C-N bond dissociation energy for
CH3-NO and t-Bu-NO have been reported as 40.0 ± 0.8 kcal
mol-1 [30] and 37 ± 2 kcal mol-1 [31], respectively. These
values are subject to considerable uncertainty, however,
given the assumptions and estimations used in the
determination of ∆Hfy(RNO). Direct determination of C-N
bond dissociation values by gas phase kinetic studies
according to Equation 2 provide more reliable C-N bond
dissociation energies than those determined calorimetrically.
RNO → R⋅ + NO· (2)
First order rate constants for monomer decomposition are
obtained over a temperature range, typically 500-850 K, and
activation parameters are calculated from these data. In the
case of very low pressure pyrrolysis (VLPP) of t-Bu-NO
[32], a high-pressure A-factor was chosen and RRKM (Rice,
Ramsperger, Kaseel, Marcus) calculations gave a high-
pressure E a = 36.0 ± 2 kcal mol -1 (∆Hy600 K = 38.5 ± 1.5 kcal
mol-1). After correcting for heat capacity, ∆Hy298 K was
calculated as 39.5 ± 1.5 kcal mol-1. The unimolecular
decomposition of allylic and benzylic C-nitroso monomers
was studied by flash photolysis at ambient pressures over a
temperature range of 400 to 520 K [33]. The C-N bond
dissociation energy for α-nitrosotoluene (C6H5CH2NO) was
calculated to be 29 ± 1 kcal mol-1and that for 1-
nitrosopropene (CH2=CHCH2NO) at 26 ± 1 kcal mol-1.
These values seem reasonable compared to aliphatic
analogues, assuming a homolytic dissociation pathway.
C-N bond enthalpies can also be obtained through
electron impact studies, using Equation 3, where AP is the
measured appearance potential of the alkyl cation (or NO+)
and IP is the ionization potential of the alkyl radical. Using
this method, the C-N bond enthalpies for a few simple
aliphatic C-nitroso compounds of the form R-NO (R = t-Bu,
neo-pentyl, i-Pr) were determined at 34 – 40 kcal mol-1 [34].
A value for the C-N bond enthalpy for CH3-NO was
suggested to be in the range of 37-40 kcal mol-1.
C-Nitroso Compounds Current Topics in Medicinal Chemistry, 2005, Vol. 5, No. 7 689

AP(R+) = D0(R-NO) + IP(R⋅) (3) compounds. The authors suggest that the methodology likely
suffers from error limits greater than those inherent in
In some cases, electron impact studies yield BDE values normal electron impact studies. One entry that seems
in good agreement with values obtained by other methods; in questionable gives a C-N BDE value of 15.4 kcal mol-1 for
other cases the values differ significantly. Thus, for example, the case where R = CO2Me. Even though BDE values are
the C-N bond dissociation energy for 2-methyl-2- thermodynamic quantities and the energy of activation is a
nitrosopropane was determined by electron impact method at kinetic parameter, it has been shown that Ea is roughly
both 34 ± 3 kcal mol-1 and 46 ± 3 kcal mol-1, depending on approximated by bond dissociation energy for unimolecular
the value chosen for the IP of (Me3C⋅). In either case, these decompositions [37]. Assuming Ea ≈ 15.4 kcal mol-1 and a
BDEs differ from the values of 39.5 ± 1.5 kcal mol-1 and pre-exponential value of 10 13 s -1 [38], at 298 K the monomer
39.8 ± 0.1 kcal mol-1 determined by VLPP [32], and laser is calculated to have a half-life of 9.8 ms. It stands to reason
excitation [35], respectively. that with such a weak C-N bond, the monomer would
decompose before measurements could be made. Thus the
Electron impact studies were extended to C-nitroso C-N BDE value reported for this ester is likely anomalous.
compounds of the form (CH3)2CXNO to examine substituent Other BDE values seem more reliable. The C-N BDE
effects on C-N bond enthalpies (Table 1) [36]. No ions larger
determined for 3-methyl-3-nitroso-butanone (29.2 kcal mol-
than the monomer were observed, and measured appearance 1
) is in good agreement with a recent CBS-QB3 calculation
potentials were interpreted solely in terms of monomer.
of 28.7 kcal mol-1 for the same system [39]. Confidence in
BDE values calculated for C-nitroso compounds at this level
Table 1. D0(C-N) Values for (CH3)2CXNO Based on
of theory is bolstered by the recent work of Fu et al . which
AP(NO+) [36]
demonstrated the high degree of accuracy in C-N BDEs
calculated using the CBS-QB3 method [40]. In any event,
X D0(C-N) / kcal mol-1 the wide range of bond dissociation energies measured by
ion impact studies is difficult to reconcile with values
Br 43.0 measured by other techniques, and further study is required
to better understand these data.
Cl 82.7 (35)a
These issues notwithstanding, the results from these
NO2 29.2 studies and later work on substituted nitroso methanes [41]
demonstrate that geminal substitution with electron
CN 22.7
withdrawing groups weakens the C-N bond relative to the
OAc 36.1 unsubstituted parent compound. For all aliphatic C-nitroso
compounds, regardless of substitution, C-N bond enthalpies
Ac 29.2 are estimated at up to 45 kcal mol-1: as such, most C-nitroso
CH2Ac 68.7 compounds are predicted to be thermally stable [29, 34]. On
the other hand, all CNO monomers are susceptible to
CO2Me 15.4 photolytic C-N homolysis on irradiation even in the visible
a
Estimated by authors. spectrum. This susceptibility has most likely lead to an over-
generalized conclusion that aliphatic C-nitroso compounds
What appear to be anomalously large C-N bond are unstable.
enthalpies are reported for X = Cl (82.7 kcal mol-1), and X = A range of thermodynamic stabilities with respect to
CH2Ac (68.7 kcal mol-1). These values were rationalized in spontaneous homolytic scission of the C-N bond is
terms of excess kinetic energy imparted to one or both accessible through appropriate substitution. For example, the
fragments during the ionization process, an explanation that activating influence of aryl groups toward C-N homolysis is
fails to explain the much lower values observed for all other evidenced (Scheme 1) by the increasing ease of thermal

O
80 o C + NO
N
N
O

O
N
20 o C
N + NO
O

Scheme 1. Effect of phenyl substitution on C-N thermolysis [42].

690 Current Topics in Medicinal Chemistry, 2005, Vol. 5, No. 7
decomposition from phenylnitrosomethane (80 °C) to
diphenylnitrosomethane (20 °C) [42].
Qualitatively, the weakness of the C-N bond arises from
the favorable electron reorganization energy in the NO
moiety as the nitroso alkane dissociates to free NO [34]:
during this process the formal NO bond order increases to
2.5. Of particular interest is the observation that the
weakness of the C-N bond in nitroso alkanes is not reflected
in the C-N bond length, which is essentially identical to
those of the corresponding amine and nitro compounds
(Table 2).
Table 2. D0(C-N) Values and C-N Bond Lengths for
Nitrosomethane, Nitromethane, and Methylamine [34]
Compound D0(C-N) / kcal mol-1 C-N bond length / Å
CH3NO 40 1.48
CH3NO2 57 1.47
CH3NH2 79 1.47
The calculated vibrational frequencies for the S0, S 1, and
T1 electronic states in CH3NO and Me3CNO show the force
constants of the N-O bond, C-N bend and C-N stretch
decrease in the excited state relative to the ground state while
other frequencies are substantially unaffected by electronic
excitation [43]. These data demonstrate the weakening and
elongation of the C-N and N-O bonds accompany population
of the antibonding (π*) orbital during electronic excitation.
2.2. Monomer-Dimer Equilibration
The solution-state chemistry of C-nitroso compounds is
characterized by a monomer - dimer equilibrium in which
the two isomeric forms of the dimer interconvert through the
intermediacy of the monomer (Scheme 2).
This dissociative pathway of cis/trans interconversion,
rather than interconversion by rotation about the N-N bond,
was first postulated by Gowenlock and Troutman [44] and
later verified by the cross-over and trapping experiments of
Wajer and de Boer [45]. The results from these and other
kinetic studies on the cis/trans isomerization of
R' O O
H k1
N R
1/2 R N
H k -1
O R'
trans-dimer
Scheme 2. Solution-state equilibria characteristic of C-nitroso compounds.
Gooden et al.
nitrosocyclohexane demonstrated a kinetic preference for the
cis-dimer which is populated only at low temperatures (-80
°C) [46]. At higher temperatures, rapid dissociation to the
monomer is followed by rate-limiting dimerization to the
thermodynamically favored trans-isomer. The kinetic
preference for the cis- over the trans-dimer in simple
nitrosoalkanes is further reflected in the observation that
solid monomeric nitrosomethane, trapped by rapid cooling
on glass, melts and rapidly forms the colorless cis-dimer
during warming from -90 °C to -70 °C [24, 47]. For tertiary
C-nitroso compounds the cis-dimer is disfavored both
kinetically and thermodynamically over all temperatures as
the result of steric congestion. These observations support
the general conclusion that at and above ambient
temperatures the cis-dimer is not significantly populated and
its contribution to the overall monomer-dimer equilibrium of
aliphatic C-nitroso compounds is negligible. This trend
differs notably from that observed for aromatic C-nitroso
compounds, where the cis-dimer is frequently observed both
in the solid state and in solution [48-50]. Intramolecular
aliphatic C-nitroso dimers are generally geometrically
restricted to the cis isomer (Fig. 2) [51-53].
C-Nitroso compounds that possess at least one α-H atom
also equilibrate between the monomeric C-nitroso form and
its thermodynamically favored oxime tautomer (Scheme 2).
An investigation of the gas-phase nitrosomethane-
formaldoxime interconversion demonstrated the oxime was
more stable than the nitroso form by 10.2 kcal mol-1 [54].
Calculated solvent effects for this tautomerization suggest an
even greater energy difference (15.8 kcal mol-1) favoring the
oxime in aqueous solution [55]. Solution phase kinetic
studies suggest an activation energy for tautomerization of
31-37 kcal mol-1 [56] while that same barrier in the gas phase
is reported at roughly 27 kcal mol-1 [57]. These calculations
are in good accord with the general observation that
monomeric primary and secondary C-nitroso compounds are
relatively stable at low temperatures and in solvents of low
polarity but rapidly isomerize in protic solvents and at
elevated temperatures.
The mechanism of monomer-dimer interconversion has
been characterized as a non-least motion reaction pathway.
This mechanism, first proposed by Hoffmann and
H R R H
N
k2 R' R'
1/2 N N
R R' k-2
H O O
monomer cis-dimer
OH
N
R R'
oxime
C-Nitroso Compounds Current Topics in Medicinal Chemistry, 2005, Vol. 5, No. 7 691

Although the authors speculate that the higher Ea for the

N O N N
O O
N N
O O
Fig. (2). Intramolecular aliphatic cis-dimers [51-53].
Woodward [58, 59] and later confirmed experimentally by
Greene and Gilbert [53], suggests that optimum HOMO-
LUMO interactions are achieved as the nitroso groups adopt
a mutually orthogonal relationship at the transition state. The
inability to realize such stereoelectronic requirements has
been used to explain the absence of monomer in certain
bicyclic dimers (Fig. 2). In these species, access to the
necessary transition state geometry for N-N bond
dissociation is denied because of the limited torsional
flexibility available to the constrained dimers.
2.2.1. Kinetics of Aliphatic Dimer/Monomer Interchange
The kinetics of dimer dissociation were first considered
over 100 years ago [60]; it would be another 50 years before
activation parameters and solvent effects for dimer
dissociation were reported [61]. The pioneering work of
Schwartz, and a body of data that followed over a two-
decade period, constitute the bulk of the kinetic data
collected for aliphatic C-nitroso compounds [45, 48, 62-66].
Tertiary aliphatic C-nitroso dimers undergo dissociation to
the monomer in a first-order process with activation energies
ranging from 20-36 kcal mol-1. Activation barriers for
dimerization are near 6-10 kcal mol-1 although the process
has not been well studied. The effects of solvent on the
activation parameters for dimer dissociation have been
studied, but no clear trend has emerged (Table 3) [62].
dissociation observed in CCl4 results from poor solvation of
the transition state, the dielectric constants and dipole
moments of cyclohexane and CCl4 – solvents with sharply
N
O differing dissociation kinetics – are essentially identical. The
smaller ∆S‡ term encountered in EtOH is attributed to
favorable dipole interactions in the transition state relative to
the other solvents. Given the relatively small temperature
range employed in these kinetic studies (~ 17 °C), and the
fact that only three solvents were considered, the generality
of conclusions regarding solvent effects on dimer
dissociation are unclear.
A subsequent investigation extended the study of solvent
effects to include three additional solvents (Table 4) [63].
Again, no strong correlation is observed between solvent
dielectric, dipole moment and activation parameters.
Relatively little variance in ∆H‡ is observed across the series,
revealing the importance of the ∆S‡ term to differences in
reaction rates. The relatively large Arrhenius factor values
suggest a loose transition state relative to the rigid ground
state of the dimer.
Linear relationships between ∆H‡ and ∆S‡ have been
observed for the decomposition of C-nitroso dimers in
anhydrous solvents. The observation was interpreted in terms
of N-N separation in the transition state, a separation
predicted to be associated with an increase in vibrational and
rotational degrees of freedom [62]. The dangers of
interpreting enthalpy-entropy compensation effects in
physical organic chemistry are well known, and the
significance of the observation is unclear.
Although the effects of non-polar organic solvents on the
monomer-dimer interconversion are variable, the effect of
water is consistent across all studies; that the rate of

Table 3. Activation Parameters for the Dissociation of 3-Methyl-3-Nitrosobutanone Dimer [62]

Solvent Ea / kcal mol-1 ∆H‡ / kcal mol-1 ∆S‡/ e.u. T∆S‡ / kcal mol-1 ∆G‡ / kcal mol-1 Dielectric constant (ε)a Dipole moment (µ)

EtOH 28.0 ± 0.5 27.4 10.4 3.28 24.1 24.3 1.69

c-C6H12 28.3 ± 0.5 27.7 13.2 4.15 23.6 2.0 0.0

CCl4 30.2 ± 0.5 29.6 18.6 5.82 23.8 2.2 0.0

a
Value at 20 °C.

Table 4. Activation Parameters for Dissociation of 3-Methyl-3-Nitrosobutanone Dimer [62,63]

Solvent Ea / kcal mol-1 ∆H‡ / kcal mol-1 ∆S‡/ e.u. T∆S‡ / kcal mol-1 ∆G‡ / kcal mol-1 Dielectric constant (ε)c Dipole moment (µ)

c-C6H12a 28.3 27.7 13.2 4.15 23.6 2.0 0

a
CCl4 30.2 29.6 18.6 5.82 23.8 2.2 0
b
dioxane 32.7 32.1 25.1 7.96 24.1 2.2 0
b
CHCl3 31.0 30.4 20.1 6.37 24.0 4.7 1.87

EtOHa 28.0 27.4 10.4 3.28 24.1 24.3 1.69

CH3CNb 28.4 27.8 7.0 2.22 25.6 36.6 3.92

a
[62]. [63]. Value at 20 °C.
b c
692 Current Topics in Medicinal Chemistry, 2005, Vol. 5, No. 7
(C6H5CH2CH2NO)2 dissociation in 95% aqueous ethanol is
considerably slower than in absolute ethanol at the same
temperature aptly demonstrates this effect. No dissociation
of this dimer is observed in aqueous solution at 70 °C [64].
Benson first attempted to describe the interplay of kinetic
and thermodynamic parameters contributing to this effect
according to Equation 4 [67].
[D ℜ M·M]C → 2 M
In this model, the dimer dissociates within a solvent cage
to give intimately associated monomers. To complete the
dissociation, the monomers must diffuse from the solvent
cage into bulk solvent. In that event, any entropy gained in
the formation of discrete monomers is offset by the enthalpic
and entropic penalties associated with the resulting solvent
reorganization.
Substituent effects on the kinetics of aliphatic dimer-
monomer exchange have been studied. The presence of
geminal electron-withdrawing groups dramatically increases
the rate of dimer dissociation. Schwartz noted the
dissociation of 2-nitro-2-nitrosopropane in benzene was too
rapid to measure by the methods used to follow the
dissociation of other dimeric C-nitroso species [61]. The
rapid dissociation was interpreted in terms of a weak N-N
bond in the dimer. On the other hand, Gowenlock and
McCullough [68] showed that no correlation exists between
N-N bond distances in aliphatic dimers and their respective
kinetic and thermodynamic properties. A more recent
demonstration of substituent effects is observed in the nearly
five-fold difference in the rate of dimer dissociation between
(CH3)2C(NO)COCH3 and (CH3)C(NO)(COCH3)2 [69].
2.2.2. Thermodynamics of Aliphatic Dimer/Monomer
Interchange
In general, solution-state monomer-dimer equilibria for
aliphatic C-nitroso compounds lie towards dimer. Thus, for
example, the equilibrium constant for the dissociation of
nitrosophenylmethane is 1.87 x 10 -8 mol l-1 [70]. Substitution
at the nitroso carbon shifts the equilibrium in favor of the
monomer, and the equilibrium constants for dissociation of
2-methyl-2-nitrosopropane and 1-nitrosoadamantane are 2.8
mol l-1 (CCl 4) and 1.9 mol l-1 (CDCl 3), respectively, some of
the largest known values for unsubstituted aliphatic C-
nitroso compounds [71]. The comparable value of 9.1 mol l-1
(C6D6) measured for 2-nitro-2-nitrosopropane demonstrates
the tendency of geminal electron withdrawing groups to shift
equilibria towards the monomeric species [72]. This effect is
further demonstrated by studies of bicyclic dimer 4 which
exists exclusively in dimeric form in solution even at
elevated temperatures (≤ 250 °C). On the other hand, the
analogous species 5 reversibly develops a deep blue color
upon warming in a variety of solvents (Scheme 3) [51]. A
more extensive investigation of solvent effects on monomer-
dimer equilibria has been reported by Witanowski et al.
(Table 5) [73].
On the basis of the available data, the free energy of
dimer formation of acyclic, aliphatic C-nitroso compounds
includes a large entropic contribution (Table 6) [64, 70, 71,
74]. Given that these quantities were measured in nonpolar
Gooden et al.
O O
NO
N N
X ON
4
O O NO
(4) N N
ON Cl
Cl Cl
Cl
5
Scheme 3. Effect of geminal electron-withdrawing groups on
dimer-monomer equilibria [51].
Table 5. Effect of Solvent on Keq. for (t-BuNO) 2 ℜ 2 t-BuNO
at 35 °C [73]
Solvent (ε)a Kd / mol l-1
n-hexane (1.87) 9.84
CCl4 (2.21) 4.9
MeOH (30.7) 3.19
DMSO (45.8) 1.78
solvents (CDCl3, CCl4, C6H6, etc.) the entropy values
presumably arises from substrate reorganization rather than
solvation effects. Comparison of the first two entries in
Table 6 reveals that while the entropic terms are essentially
equivalent, the free energy of dimerization for 2-methyl-2-
nitrosopropane and 3-methyl-3-nitroso-butanone differ by
nearly 7 kcal mol-1. This observation clearly shows that
enthalpic contributions are largely responsible for variations
in equilibria, as noted by Snyder et al. [51].
2.3. Conclusions
The unique structural and dynamic properties of aliphatic
C-nitroso compounds distinguishes them from other major
classes of organic NO donors. The relative weakness of the
C-N bond in C-nitroso monomers was widely considered the
Achilles’ heel of this class: this generalization is clearly
incorrect. Rather, C-nitroso compounds are susceptible to
photolytic bond homolysis but are thermally stable, even at
significantly elevated temperatures. The lability of the C-N
bond can be altered over a wide range through the choice of
substituents geminal to the nitroso moiety, a property that
can be employed to “tune” the susceptibility of the bond to
both homolytic and heterolytic cleavage. The position of the
monomer-dimer equilibrium and the rate at which these
species interconvert provides an additional means by which
the NO donating potential of these compounds can be
manipulated. From the accumulated physicochemical data on
the kinetics and thermodynamics of dimer-monomer
exchange, it is evident that substituent effects are an
effective means by which to control the population of active
NO donor species in solution. These control mechanisms are
C-Nitroso Compounds Current Topics in Medicinal Chemistry, 2005, Vol. 5, No. 7 693

Table 6. Thermodynamic Quantities for Aliphatic (RNO)2 ℜ 2 RNO at 293 K [64,70,71,74]

R ∆H / kcal mol-1 ∆S/ e.u. T∆S / kcal mol-1 ∆G / kcal mol-1 Keq / mol l-1

(CH3)3Ca 11.8 41.5 12.2 - 0.38 1.9

b
CH3CO(CH3)2C 18.9 40.9 12.0 6.9 6.9 x 10-6

c-C6H12b 20.6 39.2 11.5 9.1 1.6 x 10-7

c-C6H12c 24.8 52.5 15.4 9.4 9.6 x 10-8

C6H5CH2b 20.4 34.3 10.1 10.4 1.87 x 10-8

1-norbornyld 18 46 14 4.3 7.1 x 10-4

a
[74], CCl4. b [70],C6H6. c [64], decane. d [71], toluene-d8, 298 K.

unprecedented among NO donor compounds and the full
potential of C-nitroso compounds has yet to be realized.
3. SYNTHESES OF C-NITROSO COMPOUNDS
Numerous methods for the preparation of C-nitroso
compounds exist, and extensive reviews of this methodology
have appeared [21-25]. Here, we consider only those
protocols that have been used to prepare C-nitroso
compounds with known biological (NO donor) properties.
3.1. Syntheses of Electron Deficient C-Nitroso
Compounds: Direct Substitution of –H by –NO
Electron deficient C-nitroso compounds show antiplatelet
and antithrombotic activities [16-19] and may represent the
group of C-nitroso compounds with the greatest therapeutic
potential. Methyl, methylene and methine carbons geminally
substituted with electron-withdrawing groups are readily
nitrosated by a variety of nitrosating agents, including
nitrous acid (HNO2), dinitrogen trioxide (N2O3), nitrosyl
halides, and alkyl nitrites (Scheme 4). Typically, C-
nitrosation with these reagents requires the presence of a
protic acid to generate the active nitrosating agent. Substrates
sensitive to acidic conditions can be nitrosated with an alkyl
nitrite under basic conditions, although this method has not
been employed extensively in the synthesis of C-nitroso
compounds.
R1 R3 nitrosating agent
H NO
R2
6a: R1, R 2 = alkyl, R 3 = COR, CO2R, NO2, CN
6b: R 1 = alkyl, R 2 = COR, R3 = COR, CO2R
6c: R1 = alkyl, R 2, R3 = CO2R
6d: R 1 = alkyl, R 2, R3 = CN
Scheme 4. Electron deficient substrates that readily undergo C-
nitrosation.
Aqueous HNO2 is the most commonly utilized
nitrosating agent; this reagent is prepared by combining an
aqueous solution of inorganic nitrite with a protic acid such
as HClO 4, H 2SO4, or AcOH. Either NO+ or N2O3 can act as
the active nitrosating agent, depending on the relative
concentrations of HNO2 and H3O+ [21]. Rates of C-
nitrosation are significantly accelerated by the presence of
inorganic salts (MX; M = Na+, K +, X = Cl-, Br -, SCN -). The
added nucleophile significantly shifts the equilibrium (Keq.7
>> Keq. 6), effectively increasing the amount of active
nitrosating agent present in the mixture.
HNO2 + H+ ℜ H2NO2+ (5)
H2NO2 ℜ H2O + NO
+ +
(6)
H2NO2 + X ℜ H2O + NOX
+ -
(7)
Nitrosyl halides (NOX, X = Cl-, Br-, F-) are among the
most electrophilic nitrosating agents available. Nitrosyl
chloride is available commercially, and all three gases can be
generated in situ and passed into solution [75]. Since all
three are both toxic and corrosive, it is typically of greater
practical utility to generate these reagents in situ (Equations
8-10) [21].
RONO + H+ + Cl- ℜ ROH + NOCl (8)
TiCl4 + 4 RONO ℜ Ti(OR)4 + 4 NOCl (9)
(CH3)3SiX + RONO ℜ (CH3)3SiOR + NOX (10)
3.1.1. Nitrosation of Ketones
The mechanism of nitrosation of aliphatic ketones in
R1 R3 aqueous acidic solution has been investigated by Leis et al.
[76]. The mechanism proceeds by electrophilic addition of
R2 the nitrosating agent to the enol form of the ketone
(Scheme 5).
For monoketones in the presence of nucleophilic
catalysts (Cl-, Br-, and SCN-), either enolization (k1) or
nitrosation (k2) can be rate limiting, depending on
concentrations of catalyst. In the case of acetylacetone,
nitrosation is always rate limiting. In the absence of
nucleophilic catalysts, reactive ketones (e.g. acetone and 2-
butanone) are nitrosated by N2O3 while electron-deficient
ketones such as acetylacetone and 1, 3-dichloroacetone are
nitrosated by either H2NO2+ or NO+. While simple
monoketones can be nitrosated in solutions of strongly acidic
nitrite, direct nitrosation is generally practical only for the
more reactive 1, 3-diketones [77, 78]. Here, nitrosation is
694 Current Topics in Medicinal Chemistry, 2005, Vol. 5, No. 7 Gooden et al.

typically complete on treatment with NaNO 2 in glacial acetic
acid at reduced temperature (0-5 °C) in about 1 hour.
Incubation of 1, 3-diones in excess isoamyl nitrite in the
presence of catalytic acetyl chloride provides another simple
route to 2-nitroso-1, 3-diones [17]. Again, the approach is
ineffective for monoketones: treatment of 2-
methylcyclopentanone and 2-methylcyclohexanone provided
less than 5% of 2-methyl-2-nitrosocyclopentan-1-one and 2-
methyl-2-nitrosocyclohexan-1-one even after one week.
The reaction of monoketones with alkyl nitrites in the
presence of catalytic dry HCl or acetyl chloride at slightly
elevated temperatures (45-55 °C) is an efficient procedure
for the preparation of tertiary C-nitroso dimers [79, 80]. The
use of aqueous HCl dramatically reduces the reaction yield
(Scheme 6). While this method is broadly applicable and
provides α-nitroso ketones in good yield, the relatively harsh
reaction conditions – and especially the requirement for
elevated reaction temperatures – limit the overall utility of
the approach.
A recently reported methodology for the nitrosation of
monoketones avoids many of the limitations described above
[81]. Treatment of a number of substituted acetophenones
and aliphatic ketones with TMSCl and isoamyl nitrite at
reduced temperature (-20 °C) provided nitrosated products in
excellent yield (76-95%) on reactions to 10 g. Because all
substitutions were carried out at primary or secondary
carbons, oxime products were recovered. Still, it is
reasonable to believe that analogous tertiary compounds
would yield the corresponding C-nitroso compound under
identical experimental conditions.
None of the methodologies described above afford
regiochemical control during nitrosation of unsymmetrical
ketones: a method reported by Rasmussen and Hassner
addresses this deficiency [82]. Briefly, the silyl enol ether of
either the kinetic or thermodynamic enolate is trapped and
reacted with excess NOCl in anhydrous CH2Cl2 at reduced
temperatures (-20 °C) to provide regiochemically pure
products (Scheme 7).
3.1.2. Nitrosation of Esters
As was the case for ketones, aliphatic esters can be
nitrosated in aqueous acidic solutions of HNO2, although
nitrosation is limited to activated esters such as malonates, β-
keto esters, and esters of cyanoacetic acid. With activated
substrates, the kinetics of nitrosation are comparable to those

H
O OH O O
k1 k2
~ H+
H k -1 NO NO
"NO+ "

Scheme 5. Mechanism of C-nitrosation in aqueous acidic nitrite [76].

O O O

2 EtONO / catalyst N
N
45-55 oC
O O

7
Catalyst isolated yield (7)
CH3 COCl 50.1%
HCl g 51.7%
HCl aq . 4.3%

Scheme 6. Effect of water on the isolated yield of 2, 4-dimethyl-2-nitrosopentan-3-one [80].

OTMS O OTMS
1.kinetic base 1. thermodynamic base
2. TMSCl 2. TMSCl

NOCl
NOCl

O O O
N
O
N

Scheme 7. Regioselective introduction of the nitroso group in unsymmetrical ketones [82].

C-Nitroso Compounds Current Topics in Medicinal Chemistry, 2005, Vol. 5, No. 7 695

for 1, 3-diketones and nitrosation (rather than enolization) is
always rate limiting [83]. Representative transformations of
ester substrates to give 8 and 9 using this method are given
in Scheme 8 [84, 85]. While monoesters of malonic acids
can be nitrosated under the same conditions, the C-nitroso
intermediate undergoes spontaneous nitrosative decarboxyla-
tion to yield the corresponding oxime (Scheme 9).
Unlike monoketones, for which either enolization or
nitrosation can be rate-limiting, enolization of monoesters is
always rate-limiting and direct nitrosation with acidic nitrite
is ineffective with these substrates.
A method for the synthesis of α-nitroso esters was
reported over a decade ago (Scheme 10) [86]. Deprotonation
of the ester followed by addition of TMSCl gave the
corresponding silyl ketene acetal. Transmetallation with
TiCl4 in the presence of isoamyl nitrite (or NO·) gave the C-
nitroso or, in the case of secondary esters, oxime product in
65-75% yield.
Although radical intermediates were invoked in reactions
using NO·, there is no evidence for the existence of such
species in reactions using isoamyl nitrite. In the latter case,
TiCl4 is added to a reaction mixture containing the silyl
ketene acetal and excess isoamyl nitrite. It is possible that in
the presence of the alkyl nitrite TiCl4 reacts to give NOCl
which, in turn, reacts with the acetal (cf. reference [82]) to
yield the corresponding C-nitroso species. It is of interest to

N– N–
N+ N+
N N
O NaNO2 / AcOH O
N N
O O ON
O O
O O
O O

O O
O O O
NaNO2 / AcOH N
O O
O O
O O

Scheme 8. Examples of activated ester nitrosation with acidic nitrite [84, 85].

O O
O O
R
NaNO2 / AcOH - CO2 N
O O
O OH N O OH

R R
O O
H

Scheme 9. Nitrosative decarboxylation of α-nitroso carboxylic acids.

O OTMS OTiCl3
LDA, TMSCl TiCl 4
R1 R1 R1
R 3O R3 O R3O
i-amylONO
R2 R2 or NO R2
O
R1
3
RO N O
R2
Scheme 10. Nitrosation of O-alkyl O’-silyl ketene acetals with isoamyl nitrite in the presence of TiCl4 [86].
696 Current Topics in Medicinal Chemistry, 2005, Vol. 5, No. 7 Gooden et al.

note parenthetically that silyl ketene acetals derived from
monoesters react with NOCl to give the C-nitroso dimer,
albeit in poor yields (Scheme 11) [87].
3.1.3. Nitrosation of Nitro- and Nitrile Substituted
Compounds
As with ketones and esters, aliphatic nitro compounds
react with a variety of nitrosating agents to afford the
corresponding C-nitroso compounds, although acidic nitrite
alone is insufficient to achieve nitrosation. In even strongly
acidic solutions of nitrous acid, nitro compounds remain
unchanged even after extensive reaction times, presumably
due to slow tautomerization to the required nitronic acid
(Scheme 12). On the other hand, treatment of the nitro
compound with aqueous base generates the corresponding
nitronate anion, 12. Acidification gives 11 which is
sufficiently stable to permit reaction with nitrous acid.
Kinetic data acquired in the absence of added
nucleophilic catalysts were consistent with a reversible
nitrosation by either H2NO2+ or NO+ on oxygen of the
nitronic acid [88]. Irreversible intramolecular nitroso group
transfer to carbon then yields the C-nitroso compound. In the
presence of added nucleophiles, significant nucleophilic
catalysis was observed, consistent with attack by a
nitrosonium salt (NOX, X = Cl-, Br -, SCN -) on the carbon of
the nitronic acid.
α-Nitroso nitriles can be prepared directly by treatment with
acidic nitrite (Scheme 13) [89].
3.2. Syntheses of Electron Deficient C-Nitroso
Compounds: Hydroxylamine Oxidation
Although most biologically active electron deficient C-
nitroso NO donors have been prepared by direct substitution
of an activated –H, access to these compounds is not limited
to this method. Oxidation of hydroxylamines by NaOBr
(Br2/NaOHaq.) offers a very straightforward route to α-
nitroso esters, as demonstrated by Duynstee and Mevis
(Scheme 14) [90]. The most potent NO donors screened by
Rehse and Herpel [17], α-nitroso nitriles, were prepared
(>76% yield) by the Cl2-mediated oxidation of the
corresponding α-cyano hydroxylamine (Scheme 15).

O O

1. LDA, TMSCl
O O
N
2. NOCl, 38 %
O
10
Scheme 11. Nitrosation of an O-alkyl O’-silyl ketene acetal with NOCl [87].

R1 NO2 R1 O- OH- R1 O-
Slow
+ +
N N
R2 H O-
R2 OH H+ R2

11 12
Scheme 12. Acid/base equilibria of aliphatic nitro compounds.

N N N O
NaNO2 HCl

S CN 90 % S CN
13
Scheme 13. Nitrosation of a nitrile by direct substitution [89].

O OH
O O
NH
O Br 2 N O
2 O N
NaOH O O

14
Scheme 14. Preparation of α-nitroso esters by hydroxylamine oxidation [90].

R1 H R1 N
NH2 OH-HCl R1 N Cl2
O OH O
R2 NaCN R2 CN
R2 CN

Scheme 15. Preparation of α-nitroso nitriles by hydroxylamine oxidation.

C-Nitroso Compounds
3.3. Syntheses of C-Nitroso Compounds: Addition to
Oximes
Ketoximes and aldoximes react with lead tetraacetate in
nonpolar organic solvents to yield α-nitroso acetates
(Scheme 16). Because of the instability of 1-acetoxy-1-
nitroso compounds derived from ketoximes [91], only C-
nitroso compounds derived from aldoximes, isolated as
crystalline dimers, were examined for biological activity
[17]. These analogs were prepared by treatment of the
ketoxime with lead tetrabenzoate. These salts offer a greater
range of biological activities/reactivities that can be explored
through use of variously substituted benzoic acids.
Interestingly, of all α-nitroso benzoates studied only those
derived from 4-nitrobenzoic acid resisted dimerization and
all were isolated as blue crystalline solids.
R1 Pb(OAc)4 R1 N
NOH O 4. DIAZETINE DIOXIDES
R2 R2 OAc
R1 = alkyl, R2 = alkyl or H
Scheme 16. Preparation of α-nitroso acetates by addition to
oximes.
3.4. Syntheses of Vicinally Substituted Electron Deficient
C-nitroso Compounds: Addition of N2O3 across C=C
Bonds
Aliphatic C-nitroso compounds vicinally substituted with
electron-withdrawing groups have also demonstrated
antiplatelet and antithrombotic activities (Fig. 3) [18].
NO
R1 X
R2
15a: R 1 = alkyl or aryl, R 2 = H, X = NO2
15b: R1 = CO2R, R 2 = CH3 , X = NO2
16a: R 1, R2 = CH3, X = COCH3
16b: R 1, R2 = CH3, X = CO2 H
16c: R1, R 2 = CH3, X = OCOCH3
Fig. (3). Vicinally substituted electron deficient C-nitroso
compounds with NO donor activity [18].
The primary synthetic route to compounds of structure
15a involves formal addition of N2O3 across a C-C double
bond. Experimentally, NO· gas and air are passed into a
solution containing the alkene. The rapid air oxidation of
NO· gives NO2 in a reaction described by third-order kinetics
(Equation 11).
2 NO + O2 → 2 NO2 (kgas phase = 2 x 106 mol l-2 s-1) (11)
The reaction then proceeds by attack of NO2 at the least
substituted olefinic carbon (Scheme 17) [92]. The resulting
radical is trapped by NO· to give the β-nitroso nitro
compound, the so-called pseudonitrosites [93].
Pseudonitrosites prepared in this way were isolated as
crystalline dimers in 3-15% yield.
Compounds of structure 15b were prepared using
solutions of acidic nitrite (NaNO2 40% H2SO4) according to
Current Topics in Medicinal Chemistry, 2005, Vol. 5, No. 7 697
the method of Ranganathan [94]. The mechanism of product
formation under these conditions is complex and the reaction
generates product mixtures and poor yields (4-6%) [18]. The
formation of mixtures was rationalized by the simultaneous
operation of at least three processes: a free-radical path
involving NO2, an ionic process involving NO+ or NO 2+, and
the direct reaction of N2O3 or N2O4 [92]. The β-nitroso
ketone 16a, β-nitroso acid 16b and β-nitroso acetoxy dimers
16c were isolated in 25%, 30%, and 7%, respectively, on
oxidation of the corresponding hydroxylamines with Br2.
Vicinal installation of the nitrogen functionality in
compounds 16a and 16b was accomplished by Markovnikoff
addition of hydroxyl amine across the respective alkene.
Since this addition reaction was not possible with 16c, the
hydroxylamine precursor was prepared by the O-
acetylization of 2-methyl-2-nitro-1-propanol followed by
reduction with Zn/NH4Cl.
Although diazetine dioxides are 4-membered
heterocycles that are formally intramolecular C-nitroso
dimers, the significant differences in chemical and physical
properties between the two structural classes justifies
separate treatment. Both classes of compounds
spontaneously liberate NO· (albeit by different mechanisms)
and significant substituent effects on NO release from each
of these classes is observed. In light of their ability to
decompose with concomitant release of 2 equivalents of NO,
the potential of these compounds as therapeutic NO donor
agents has been of recent interest.
4.1. Physicochemical Properties of DDs.
Diazetine dioxides are colorless, crystalline, high-melting
solids. Not surprisingly, the spectral characteristics (IR and
UV/Vis) of diazetine dioxides are essentially the same as
those of aliphatic C-nitroso dimers. Although the ring
opening of 17 to the 2, 3-dinitroso monomer 18 should be
exceptionally favorable (∆H293 = -12 kcal mol-1, ∆S293 > 0,
∆G293 = >-12 kcal mol-1), no such equilibrium is observed
upon dissolution in aqueous or organic solvents even at
elevated temperatures (Scheme 18) [53]. Rationale for the
reluctance of 17 to establish such an equilibrium presumably
arises from geometrical restrictions, as described above.
Analogous substitution by chlorine as in 4 → 5 (Scheme 3)
does not appear to effect the same response in diazetine
dioxides.
4.2. Synthesis of Diazetine Dioxides
Diazetine dioxides are most commonly synthesized by
oxidation of the corresponding 1, 2-bis hydroxylamine.
Thus, for example, treatment 2, 3-dihydroxylamino-2, 3-
dimethylbutane with NaOBr afforded 17 in 77% yield [53].
The use of dimethyldioxirane as oxidant with 2, 3-diamino-
2, 3-dimethylbutane gave 17, but in only yield (~13%).
Over-oxidation to the 2, 3-dinitro compound was significant
[95]. Halogenated diazetine dioxides are readily accessed by
treatment of α-hydroxylamino oximes with aqueous
hypohalite (Scheme 19) [96, 97]. The first step in the
reaction mechanism appears to involve initial oxidation to
the α-nitroso oxime, 19 [98]. In the second step, the halide
adds to the oxime (cf. synthesis of α-nitroso nitriles) to give
698 Current Topics in Medicinal Chemistry, 2005, Vol. 5, No. 7 Gooden et al.

NO
R1 R1 ON R1
NO2 NO2
R2 NO2 R2 R2

Scheme 17. Mechanism of N2O3 addition to alkenes to give pseudonitrosites [92].

O
N NO
ON
N
O

17 18
Scheme 18. Intramolecular dimer-monomer equilibrium; not observed in DD (17) [53].

NOH X O
NHOH excess NaOX (X = Cl, Br) R1 N
R1 R3 R2 N
H2O
R2 R3 O

1 eq. NaOX

O OH O
HO N N N
R3 HN
NaOX R3
X
R1 R2 R1 R2

19 20
Scheme 19. Synthesis of halogenated diazetine dioxides [96, 97].

the α-nitroso hydroxylamino intermediate 20 which is
oxidized to the diazetine dioxide.
5. BIOLOGICAL ACTIVITIES OF
COMPOUNDS.
5.1. Aliphatic C-Nitroso Compounds
Despite significant studies on the synthesis and physical
organic chemistry of aliphatic and aromatic C-nitroso
compounds, including their decomposition to various oxides
of nitrogen, relatively little has been reported on the
biological activities of this group of compounds. Rehese and
co-workers have authored a series of reports on the
biological activities of several C-nitroso donors [16-18]. The
first in this series considered the antithrombotic (in vitro
platelet aggregation, in vivo thrombus formation) and anti-
hypertensive activity of a series of geminal nitroso-
nitroalkanes (pseudonitroles, Fig. 4). All of the
pseudonitroles inhibited in vitro platelet activation (Born
assay) with IC50 values ranging from 2 to 23 µM. These
values compare favorably to other known inhibitors of
platelet activation, including acetyl salicylic acid (175 µM)
and SIN 1 (1 µM). A modest correlation was observed
between lipophilicity and activity, a relationship rationalized
in terms of partitioning within the platelet membrane. The
same compounds were also tested in an in in vivo model of
antithrombotic activity. Following systemic treatment by
oral administration (60 mg kg-1), thrombus formation was
induced with an argon laser. All but one of the compounds
C-NITROSO
tested produced a reduction in thrombus formation in both
arterioles and venules (measured as the number of laser
exposures required to induce thrombus) of between 8 and
24%. No correlation was observed between activities in in
vitro and in vivo assays; this observation is not surprising
and likely reflects differences in uptake and distribution
patterns of the various species during oral administration. In
contrast to the pronounced antithrombotic effects, none of
the pseudonitroles tested produced a reduction in blood
pressure following oral administration (60 mg kg-1) in
spontaneously hypertensive rats. Although it was suggested
that the lack of hypotonus activity might result from an
inability of the endothelium to release nitric oxide from the
compounds, no data was provided to support the contention.
A second study reported by the same group examined the
biological activity of a group of compounds variously
substituted at the nitric-oxide bearing carbon (Fig. 5) [17].
Again, all of the compounds showed antiplatelet activity in
vitro, with micromolar IC50 values (9-63 µM) in the Born
assay. All compounds showed weak activity in in vivo assays
of inhibition of thrombus formation, with reduction in
sensitivity to laser-induced thrombus formation following
C-Nitroso Compounds Current Topics in Medicinal Chemistry, 2005, Vol. 5, No. 7 699

O
ON NO2 NO2
ON NO2
NO
R1 R2
(CH2) n
21a: R1, R 2 = alkyl 22a: n = 1 23
21b: R1, R2 = benzyl 22b: n = 2
22c: n = 4

Fig. (4). Pseudonitroles with antithrombotic and vasodilating activities [16].

O
H3 C NO
X X
NO
O O
R1 R2 ON
(CH2) n (CH2 )n
24a: R1, R2 , = alkyl, X = CN 25a: X = CH3 , n = 1, 25b: n = 2 26a: n = 1
2 4b: R 1, = alkyl, R 2 = H, X = OCOCH 3 25c: X = COCH3, n = 1, 25d: n = 2 26b: n = 2
2 4c: R1, R2 = alkyl, X = OCOC6 H4 -4-NO2 25e: X = CO2Et, n = 1, 26g: n = 2

Fig. (5). Biologically active CNOs variously substituted at the nitric-oxide bearing carbon [17].

oral administration (rats, 60 mg kg-1) ranging from 5 to 21%
in arterioles and 1 to 15% in venules. As before, no
correlation was observed between activities in in vitro and in
vivo assays.
A third study considered the biological activities of a
series of compounds variously substituted at the position
once removed from nitric-oxide bearing carbon (Fig. 3
above, Table 7) [18]. Again, all compounds tested showed
micromolar in vitro antiplatelet activities. This group of
compounds, however, showed significantly lower activities
in in vivo assays; while some compounds showed reduction
in laser sensitivity of as much as 18%, fully half of the
compounds tested produced no significant reduction. Again,
no correlation was observed between activities in the two
assays. Furthermore, a number of comparisons within
homologous series of compounds seem difficult to reconcile.
Thus, for example, the methyl, ethyl, butyl and cyclohexyl
esters of 3-nitro-2-methyl-2-nitrosopropanoic acid show
sharply different activities, varying by 10-fold in activity in

Table 7. Biological Activity of C-Nitroso Compounds R1R2C(NO)CH2X [18]

X R1 R2 IC50 (µM) Inhibition of thrombus; arterioles (%) Inhibition of thrombus; venules (%)

NO2 Ph H 2.1 10 5

NO2 p-ClPh H 10.5 7 5

NO2 p-CH3O-Ph H 19.5 8 7

NO2 C3H7 H 18.0 n.s. n.s.

NO2 C5H11 H 9.4 11 n.s.

NO2 C7H15 H 15.0 7 4

NO2 Bn H 8.7 n.s. n.s.

NO2 (CH2)2Ph H 9.6 n.s. n.s.

NO2 COOCH3 CH3 38.0 n.s. n.s.

NO2 COOEt CH3 24.0 13 9

NO2 COOBu CH3 4.2 4 n.s.

NO2 COOCyclhex CH3 10.0 18 9

COCH3 CH3 CH3 62.5 n.s. n.s.

COOH CH3 CH3 39.0 n.s. n.s.

OCOCH3 CH3 CH3 46.0 n.s. n.s.

n.s. not significant.

700 Current Topics in Medicinal Chemistry, 2005, Vol. 5, No. 7
the Born assay and producing reductions in sensitivity to
laser-induced thrombus formation ranging from no
significant reduction to 20%, the most active compound
tested. No rationale is offered for these discrepancies, but
they presumably reflect pharmacological differences (uptake,
distribution, clearance) rather than differences in NO-related
chemistry.
In all cases the presumed active agent is nitric oxide. To
evaluate the validity of this hypothesis, the decomposition of
several species were evaluated. Because of low aqueous
solubilities of most compounds, decomposition studies were
conducted as suspensions in phosphate buffer, in ethanol,
and in ethanol/buffer mixtures. All decompositions were
induced thermally at 37 °C, and the production of both NO
and N2O were determined by head-space analysis. While
significant decomposition of C-nitroso compound was
observed, only small amounts (<10%) of NO were observed.
In almost all cases, at least trace amounts of N2O,
presumably arising from loss of HNO, were observed. No
attempt was made to correlate the level of NO or N2O
production with biological activity. Thus, while the results of
these studies are intriguing, a more complete description of
the mechanism of activity awaits more detailed study.
5.2. Furoxans
A comprehensive review regarding the synthesis of
furoxans has recently appeared, and the reader is directed to
this excellent source [99].
Considerably more work has been reported on the
biological activity of furoxans. Some of the earliest reports
of biological activity came from Ghosh and Whitehouse,
who reported in the late 1960s that a series of benzofurazans
and benzofuroxans inhibited both RNA and protein synthesis
in sheep lymphocytes [100, 101]. Although the effect could
conceivably have arisen from released oxides of nitrogen, no
clear mechanism for the activity has been established, and at
least some reports suggest that the biological activity of
these compounds involves inhibition of nucleoside transport.
In 1974 – still before the identification of nitric oxide as the
EDRF – Ghosh reported the vasodilatory properties of
furazanobenzofuroxan, furazanobenzothiadiazole and their
N-oxides (Fig. 6) [102]. All of the compounds showed
X N
N N
N N
O O
N N
O O
X = S, O
Fig. (6). Vasodilators furazanobenzofuraoxan, furazanobenzothiadiazole and their N-oxides [102].
O O
H3C S H3C
R R
N N
O O
Fig. (7). Inhibitors of platelet aggregation:4-methyl-3-(arylsulfonyl)furoxans [103, 104].
Gooden et al.
significant activity in rabbit ear artery and cat spinal artery
assays. Unaware of the potent vasodilatory activity of nitric
oxide, the authors rationalized their findings by comparison
of the structure to that of glycerol trinitrate.
In 1992, Calvino and co-workers reported the platelet
aggregation inhibitory effect of a series of 4-methyl-3-
(arylsulfonyl)furoxans (Fig. 7), with IC50 values ranging
from 1 to 100 µM [103]. The authors correlated the activity
to an increase in intracellular cGMP concentrations and
noted the possibility that this effect could be mediated by
nitric oxide. No efforts were made, however, to determine
the nature or extent of NO release. Ghigo and co-workers
also considered the biological activity of the same class of
compounds, noting their activity as inhibitors of platelet
aggregation [104]. Although the authors carefully describe
the effect of the furoxan on arachadonic acid, intracellular
calcium levels and cGMP, they ultimately argued away from
an NO-mediated effect, concluding rather that the effect was
likely mediated by direct inhibition of guanylate cyclase.
Contemporaneously, Feelisch and co-workers unambiguo-
usly determined that the furoxans are nitric oxide pro-drugs,
demonstrating that furoxans, but not furazans, activate
guanylate cyclase in a process activated by low molecular
weight thiols [105]. Careful analysis of the inorganic
products of furoxan decomposition showed the formation of
nitrite, nitrate and nitrosothiol in addition to nitric oxide.
With the mechanism of action now firmly established, a
number of studies on the biological activities of furoxans
appeared in relatively short order. Gasco and co-workers
have reported on the activity of several classes of furoxans
[106]. Thus, for example, 4-phenyl-3-furoxancarbonitrile
was reported as an especially potent agent for the activation
of soluble guanylate cyclase, the inhibition of platelets and
the relaxation of precontracted rat aortal strips [107].
Biological activities are significantly diminished in the
presence of hemoglobin, a scavenger of nitric oxide. The
same group reported on the activity of a series of water
soluble furoxans that incorporate a heteroatom (O or S) at
the 3- or 4-position: such compounds are formally imidate
derivatives. Generally, the incorporation of electron-
withdrawing substituents adjacent to the N-O moiety
enhances the biological activity of this group of compounds.
O
X N X N
N N
N N
O O
O
N N
N
O
O O O O
S H3C S
R
N N N N O
O O
C-Nitroso Compounds
Significantly, the incorporation of an ionizable basic moiety
at the 3-position facilitated non-thiol mediated NO release,
in some cases to 95%. This group also considered the
biological activity of benzofuroxans in light of the NO-
donating activity of furoxans. Simple benzofuroxans fail to
liberate significant quantities of nitric oxide, either in the
presence or absence of thiols. In contrast, benzodifuroxan
and benzotrifuroxan both act as potent vasodilators and
release significant quantities of nitric oxide. Both
compounds also act as potent activators of soluble guanylate
cyclase, even at µM concentrations. Again, release of
nitrogen oxides was dependent on thiol cofactor; in the
presence of cysteine formation of NO, NO2- and N2O are all
observed.
Furoxans have been examined as orally available sources
of nitric oxide for cardiac care. Unlike glyceryl trinitrate
(GTN), these compounds are predicted to lack tolerance
issues. The cardiovascular and haemodynamic effects of 4-
hydroxymethylfuroxan-3-carboxamide were considered in
both pigs and dogs by Bohn and co-workers in 1995 [107].
Similar to other NO donors (molsidomine, pirsidomine),
CAS 1609 provided a significant reduction in preload,
systolic blood pressure, left ventricular work and myocardial
oxygen consumption. Additionally, intravenous administrat-
ion of the compound to dogs with induced acute heart failure
significantly reduced mortality. Although the biological
effects are consistent with NO release, no efforts were made
to identify or quantitate released nitric oxide. Significantly,
feeding studies over a five-day period demonstrated no
induction of tolerance.
A few additional furoxans have been reported, and all
show typical NO-induced behavior. In particular, the furoxan
moiety has been appended to a variety of pharmacophores,
including dihydropyridines, antiimflamatories, proton-pump
inhibitors, adrenoreceptor antagonists, histamine antagonists,
and β-blockers in a search for dual-functionality compounds.
Despite the many promising attributes of the furoxans, all
show significant mutagenic activity and none have
progressed in clinical trials.
SR
R R
R R
HN N N
O O
O O
RSH
R R
N N
O
O RSH
SR
RSH R
R
N N
O
O
Scheme 20. Thiol-mediated mechanism of NO release from furoxans [105].
Current Topics in Medicinal Chemistry, 2005, Vol. 5, No. 7 701
The mechanism of release of nitric oxide from the furoxans
is complex and likely varies as a function of both furoxan
structure and reaction conditions. The original thiol-
mediated mechanism proposed by Feelisch et al. [105]
(Scheme 20) is general and sufficient to rationalize the
release of both NO and HNO from all furoxans. Gasco and
co-workers have considered NO release from furoxans
extensively. In particular, this group noted the thiol-
independent release of NO from several imidate furoxans.
The mechanism of this release was rationalized in terms of
the increased nucleophilicity of the heteroatom-bearing
carbon and, increasing the propensity for hydrolytic release.
This same group reported on the NO release from nitrile-
substituted furoxans; these compound release NO via an
alternative pathway that yields unique organic products
(Scheme 21) [109].
5.3. 1, 2-Diazetine 1, 2-Dioxides
The diazetine dioxides have been examined to a limited
extent as NO donors. In general, these compounds activate
guanylate cyclase, inhibit platelet activation, and show
vasodilatory activity. In one instance, intraperitoneal
injection provided significant (to 30%) decrease in systolic
arterial blood pressure in hereditary hypertensive rats.
The mechanism of nitric oxide release from diazetine
dioxides is unclear. Differences between rates of NO release
and the onset and extent of vasodilation strongly suggested
that simple extrusion of nitric oxide could not fully account
for the activity of these compounds. Although a thiol-
dependent mechanism has been proposed [96] no correlation
is observed between thiol concentration and rates of NO
release. This observation may reflect trapping of nitrogen
oxide products by thiol at high thiol concentration. The
organic products isolated from the decomposition were 1, 2-
hydroxylamino oxime 27 and hydroxy oxime 28. Based on
these observations, a thiol-dependent release pathway was
proposed (Scheme 22).
SR
RS R
N R N
O
NO
RSNO NO
[O]
NO
SR R SR
R
N R N R
O O
N
O
702 Current Topics in Medicinal Chemistry, 2005, Vol. 5, No. 7 Gooden et al.

Ph C
SPh

N N
O
O
N N
C C Ph SR
Ph Ph SPh N
RS
Ph C N
N N N N SPh NH2
O O O
O O O
N
N
RSNO
OH

O NO

Ph N
SPh

N
O NH

Scheme 21. Thiol-mediated mechanism of NOrelease from nitrile-substituted furoxans [109].

X
O
R N
N RS
R O X R O RSH R OH
O SR
RS N N
R N
N NH
N R OH
R O
X R O
O 27
R N RSSR, X
N -X
R O

RS OH
O SR O
O R N
R N R N R N
NO
NO
OH
R
R R R
28
RSSR NO

-RSNO
Scheme 22. Thiol-mediated mechanism of NO release from 1, 2-diazetine 1, 2-dioxides [96].

CONCLUSION
Many C-nitroso compounds show biological activity that
is attributable to nitric oxide release. Substitution of the
nitrogen-bearing carbon facilitates tremendous control over
the rate of NO release and the redox form of nitrogen
released. On the other hand, many C-nitroso species pose
significant challenges for pharmacological development,
especially toxicological issues. Nonetheless, the flexibility of
this class is well suited for development, and the C-nitroso
compounds clearly should receive significant consideration
as biological agents.
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