Synthesis and thermochemical study of quinoxaline-N-oxides: Enthalpies of dissociation of the N-O bond

Article abstract of DOI:10.1002/poc.1932

The synthesis of three new quinoxaline mono-N-oxides derivatives, namely, 2-tert-butoxycarbonyl-3-methylquinoxaline-N-oxide, 2-phenylcarbamoyl-3- ethylquinoxaline-N-oxide, and 2-carbamoyl-3-methylquinoxaline-N-oxide, from their corresponding 1,4-di-N-oxid

Full text of DOI:10.1002/poc.1932

Research Article
Received: 11 March 2011,
Revised: 1 August 2011,
Accepted: 23 August 2011,
Published online in Wiley Online Library: 2 October 2011
(wileyonlinelibrary.com) DOI: 10.1002/poc.1932
Synthesis and thermochemical study of
quinoxaline-N-oxides: enthalpies of
dissociation of the N–O bond
Miguel L. F. Viveirosa, Vera L. S. Freitasa, Nuno Valea, José R. B. Gomesa,b,
Paula Gomesa and Maria D. M. C. Ribeiro da Silvaa*
The synthesis of three new quinoxaline mono-N-oxides derivatives, namely, 2-tert-butoxycarbonyl-3-methylquinoxaline-
N-oxide, 2-phenylcarbamoyl-3-ethylquinoxaline-N-oxide, and 2-carbamoyl-3-methylquinoxaline-N-oxide, from their
corresponding 1,4-di-N-oxides is reported. Samples of these compounds were used for a thermochemical study,
which allowed derivation of their gaseous standard molar enthalpies of formation, ΔfHmo ðgÞ, from their enthalpies
of formation in the condensed phase, ΔfHmo ðcrÞ, determined by static bomb combustion calorimetry, and from their
enthalpies of sublimation, ΔgcrHmo , determined by Calvet microcalorimetry. Finally, combining the ΔfHo ðgÞ for the
quinoxaline-N-oxides derived in this work with literature values for the corresponding 1,4-di-N-oxidems and atomic
oxygen, the bond dissociation enthalpies for cleavage of the first NꢀO bond in the di-N-oxides, DH1(N–O), were
obtained and compared with existing data. Copyright © 2011 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this paper
Keywords: dissociation enthalpy N–O bond; quinoxaline mono-N-oxides derivatives; synthesis; thermochemistry
the three compounds were determined from high temperature
Calvet microcalorimetry measurements. Combining the standard
INTRODUCTION
molar enthalpies of formation in the crystalline phase with the
enthalpies of sublimation of each compound, the corresponding
standard (po = 0.1 MPa) molar enthalpies of formation in the
gas phase at T = 298.15 K were obtained. The latter results
were used to obtain the experimental values for the first
NꢀO bond dissociation enthalpy in the parent di-N-oxide
quinoxalines based on their standard molar enthalpies of
formation in the gas phase that were previously reported in
the literature.[11,12]
The interest in a large range of compounds with the N-oxide
functional group has been expanded significantly over the past
two decades because of their remarkable success in a broad
variety of applications as oxidizing agents. Some of these
compounds, particularly the quinoxaline derivatives, assumed
relevant importance because of their selective biological activi-
ties[1–6] related with inherent pharmacological and toxicological
properties.[7,8] Energetic studies on compounds containing
terminal NꢀO bonds in different molecular environments have
been developed in our research group,[9–18] with the main goal
of evaluating the influence of the chemical vicinity on that
bond. In this context, computational and experimental studies
have been extensively developed for quinoxaline 1,4-di-N-
oxides.[9–20] More recently, with the possibility of synthesizing
very pure samples of two quinoxaline derivatives containing
only a single dative N–O bond, the first experimental thermo-
chemical study for quinoxaline-N-oxide derivatives has been
reported.[13] The present work reports the experimental
study of the energetics of three new quinoxaline mono-N-oxide
derivatives whose structures are represented in Scheme 1,
that is, 2-tert-butoxycarbonyl-3-methylquinoxaline-N-oxide (4.1),
2-phenylcarbamoyl-3-methylquinoxaline-N-oxide (4.2), and 2-
carbamoyl-3-methylquinoxaline-N-oxide (4.3). Their syntheses
have been performed from the corresponding 1,4-di-N-oxides
(compounds 3.1–3.3, Scheme 1) by selective reduction.
EXPERIMENTAL
Synthesis and purification
The quinoxaline di-N-dioxides (3.1–3.3, Scheme 1) were prepared
from benzofuroxan (1) and the appropriate b-ketoester/amide (2)
following the method described by Robertson and Kasubick.[21] Briefly,
* Correspondence to: M. D. M. C. Ribeiro da Silva, Centro de Investigação em
Química, Departamento de Química e Bioquímica, Faculdade de Ciências,
Universidade do Porto, R. do Campo Alegre, 687, P-4169-007 Porto, Portugal.
E-mail: mdsilva@fc.up.pt
a M. L. F. Viveiros, V. L. S. Freitas, N. Vale, J. R. B. Gomes, P. Gomes, M. D. M. C. R. Silva
Centro de Investigação em Química, Departamento de Química e Bioquímica,
Faculdade de Ciências, Universidade do Porto, R. do Campo Alegre, 687
P-4169-007 Porto, Portugal
The standard (po = 0.1 MPa) massic energies of combustion in
oxygen of the three compounds were measured with a high
precision static bomb calorimeter, from which the values of the
standard molar enthalpies of formation in the crystalline phase
at T = 298.15 K were derived. The enthalpies of sublimation of
b J. R. B. Gomes
CICECO, Departamento de Quıímica, Universidade de Aveiro, Campus
Universitário de Santiago, 3810-193 Aveiro, Portugal
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THERMOCHEMICAL STUDY OF QUINOXALINE-N-OXIDES
the combustion experiments to that calculated from the mass of
the sample; the average ratios and the respective uncertainties (twice
the standard deviation of the means) were 0.9997 ꢂ 0.0005 for 4.1,
1.0006 ꢂ 0.0002 for 4.2, and 1.0012 ꢂ 0.0007 for 4.3.
The specific densities of the different samples were assumed to be
1.0 gꢃcmꢀ3, estimated from the mass and volume of pellets of each
compound.
The relative atomic masses used for the elements were those
recommended by the IUPAC Commission in 2007.[23]
Static bomb combustion calorimetry
The energies of combustion of compounds 4.1–4.3 were measured
using a static bomb calorimeter, whose bomb with an internal volume
0.290 dm3 has a twin valve system as previously reported.[24–26]
The energy equivalent of the calorimeter e(calor) was determined
using benzoic acid ([CAS 65-85-0], Standard Reference Material (SRM
39j) supplied by the National Institute of Standards and Technology),
having
a massic energy of combustion, under bomb conditions,
of –(26434 ꢂ 3) Jꢃgꢀ1. The energy equivalent of the calorimeter e(calor) =
(15546.3 ꢂ 1.3) JꢃKꢀ1 (the uncertainty quoted is the standard deviation
of the mean), corresponding to an average mass of 2900.0 g of
water added to the calorimeter, was determined from eight calibration
experiments made under oxygen at p = 3.04 MPa and using 1.00 cm3 of
water added to the bomb.
For the combustion experiments, the crystalline samples were burnt in
pellet form. Because the yields on the synthesis of the compounds were
low, we decided to decrease the amount of compound used in each
experiment and used n-hexadecane (CAS 544-76-3, ≥ 99%, Aldrich
Chemical Co. (Milwaukee, Wisconsin, USA)) as an auxiliary of the combus-
tion measurements to achieve the adequate rise in temperature during
the combustion. The measured standard massic energy of combustion
of the sample of n-hexadecane used for the studies of compounds
4.1 and 4.2 was ꢀ Δcuo(l)= (47,150.4 ꢂ 2.4) Jꢃgꢀ1, while that for 4.3
Scheme 1. Synthetic route (in black) to quinoxaline mono-N-oxides
4.1–4.3 via regioselective monodeoxygenation of 3.1–3.3 with trimethyl
phosphite (A); smaller structures in grey (including nonregioselective
reduction of 3 with phosphorus trichloride, (B), are included to provide
pictorial support to the Discussion section
was ꢀ Δcuo(l)= (47,193.3 ꢂ 3.3) Jꢃgꢀ1
.
benzofuroxan (1, 1 mmol) was suspended in propan-2-ol and the
appropriate b-ketoester/amide (2, 0.7 mmol) was added. The reaction
was allowed to proceed at 60 ꢁC for about 30 (3.2, 3.3) to 150 (3.1)
min on a thermostated water bath, then a catalytic amount of calcium
hydroxide (0.05 mmol) was added portion-wise periodically. Di-N-oxides
3.2 and 3.3 readily precipitated from the reaction mixture and were
simply isolated by suction filtration followed by thorough washing
of the solid with ice-cold propan-2-ol. In turn, di-N-oxide 3.1 was
significantly soluble in the reaction medium and had to be isolated by
adsorption liquid chromatography on silica, using dichloromethane/
methanol 40 : 1 (v/v) as eluant. All the di-N-oxides 3.1–3.3 were obtained
as tan solids in 54% (3.1) to quantitative (3.2, 3.3) yields.
The 3 compounds were then selectively monodeoxygenated with
trimethyl phosphite, as described by Dirlam and McFarland.[22] In brief,
the di-N-oxides (0.05 mmol) were suspended in either propan-2-ol
(3.1) or methanol (3.2, 3.3), then trimethyl phosphite (0.03 mmol) was
added and the mixture refluxed for 2 h. The N-oxides, 4.1–4.3, were
precipitated from the reaction mixture upon cooling to room tempera-
ture and were isolated by suction filtration followed by thorough
washing with ice-cold methanol. N-Oxides 4.1 and 4.3 were additionally
submitted to purification by column chromatography on silica, using
dichloromethane/methanol mixtures as eluants. After a final step of
recrystallization from methanol for all 4 compounds, they were obtained
as pale tan solids in 10 (4.3) to 50% (4.1, 4.2) yields. The structures and
composition of 4.1–4.3 were confirmed by electrospray ionization–ion
trap mass spectrometry (ESI–IT MS), proton (1H-) and carbon-13 (13 C-)
nuclear magnetic resonance (NMR) and elemental analysis. All analytical
and spectral data, and spectral traces and compound melting temperatures,
are provided in the Supplementary Material.
All the samples were ignited at T = (298.150 ꢂ 0.001) K in oxygen at
p = 3.04 MPa with 1.00 cm3 of deionized water previously added to the
bomb. The electrical energy for ignition ΔU(ign.) was determined from
the change in potential difference across a 1400 mF capacitor when
discharged through the platinum ignition wire. For the cotton thread
fuse, with empirical formula CH1.686O0.843, the massic energy of combus-
tion is Δcuo = ꢀ16,240 Jꢃg–1 [27]
.
The corrections for nitric acid formation,
ΔU(HNO3), were based on the value ꢀ59.7 kJꢃmol–1 [28]
,
for the molar
energy of formation of 0.1 molꢃdm–3 HNO3(aq) from N2(g), O2(g), and
H2O(l). An estimated pressure coefficient of specific energy: (@u/@p)T
=
ꢀ0.2 Jꢃg–1. MPa–1 at T = 298.15 K, a typical value for most organic com-
pounds,[29] was assumed. The mass of compound, m(cpd), used in each
experiment was determined from the total mass of carbon dioxide, m
(CO2, total), produced after an allowance for that formed from the
combustion of the cotton thread fuse and the n-hexadecane. For each
compound, the standard massic energy of combustion, Δcuo, was
calculated using the procedure given by Hubbard et al.[30]
Calvet microcalorimetry
The standard molar enthalpies of sublimation of compounds 4.1–4.3
were measured by Calvet High Temperature Microcalorimetry, using
the ‘vacuum-sublimation drop microcalorimetric method’.[31] Samples
of about 3–5 mg contained in a thin glass capillary tube were dropped
at room temperature into a hot reaction vessel in a high temperature
Calvet microcalorimeter (SETARAM HT 1000D (Lyon, France)) held at
T = 390 K, T = 443 K, and T = 458 K for compounds 4.1, 4.2, and 4.3, re-
spectively, and then removed from the hot zone by vacuum sublimation.
The observed enthalpies of sublimation were corrected to T = 298.15 K,
using ΔT298:15 KHmo (g), estimated by a group method of enthalpic contribu-
tions based on Eqn 1 using data from Stull et al.[32]
Prior to the calorimetric measurements, the compounds were dried
under high-vacuum conditions. The composition of both compounds
were confirmed by the ratio of the mass of carbon dioxide recovered in
J. Phys. Org. Chem. 2012, 25 420–426
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M. L. F. VIVEIROS ET AL.
where R1 = OC(CH3)3, R2 = OCH2CH3, R3 = CH3CH2CH3, R4 = C(CH3)4, and
x = 1 in the case of 4.1; R1 = NHPh, R2 = CH3, R4 = NH2Ph, and x = 2
in the case of 4.2; and R1 = NH2, R2 = CH3, R3 = CH3CH3, R4 = CH3NH2,
and x = 1 in the case of 4.3. The microcalorimeter was calibrated in situ
for the working temperatures with naphthalene, ΔgcrHmo (naphthalene, cr) =
(72.60 ꢂ 0.60) kJꢃmol–1[33] using the same procedure for the calibration
experiments.
Table 1. Typical combustion experiments at T = 298.15 K
4.1
4.2
4.3
m(CO2, total)/ g
m(cpd)/ g
m(fuse)/ g
1.47614
0.34504
0.00292
0.21053
1.27472
14.81
1.31360
0.31149
0.00311
0.16827
1.09678
14.37
1.21882
0.38088
0.00258
0.12556
1.00229
14.14
m (n-hexadecane) / g
ΔTad/ K
RESULTS
ef / (JꢃK-1)
Target compounds were successfully obtained following the
synthetic route A to target structures 4 depicted in Scheme 1.
Compounds 4.1 and 4.2 were obtained in acceptable global
yields (~50%), whereas compound 4.3 was synthesized in a very
low yield (~10%) mainly because of the very low solubility of its
dioxygenated precursor 3.3 in low molecular weight alcohols,
which is suitable for carrying out the reduction step with
trimethyl phosphate.[22] In any case, the compounds were isolated
at high chemical purity after recrystallization with methanol, as
shown by the analytical and structural data provided in the
Supporting Material. The establishment of the structure of the
final products as 4 mono-oxygenated isomers is discussed in
the Discussion section.
The results for a typical combustion experiment for each of
the compounds studied are given in Table 1: Δm(H2O) is the
difference between the mass of water added to the calorimeter
and 2900.0 g, the mass assigned for e(calor), ΔTad is the calorim-
eter temperature rise corrected for the heat exchange and the
work of stirring, ΔUP is the correction to the standard state
and the remaining terms are as previously defined.[30] The
samples were ignited at T = (298.150 ꢂ 0.001) K and the internal
energy for the isothermal bomb process, ΔU(IBP), was calculated
using Eqn (2).
Δm(H2O)/ g
ΔU(IBP) / J
0.7
19,839.76
1.7
17,074.49
ꢀ3.4
15,581.86
ΔU(fuse)/ J
ΔU(HNO3)/ J
47.42
25.34
50.51
23.70
41.90
38.21
ΔU(n-hexadecane)/ J 9926.61
7933.92
0.54
8.56
29,077.27
5925.38
0.61
9.19
25,133.60
ΔU(ign.)/ J
ΔUΣ/ J
0.54
8.93
ꢀΔcuꢁ/ (Jꢃg-1)
28,491.98
m(CO2, total) is the total mass of CO2 formed in the experiment;
m (cpd) is the mass of compound burnt in the experiment; m
(fuse) is the mass of fuse (cotton) used in the experiment;
ΔTad is the corrected temperature rise; ef is the energy
equivalent of contents in the final state; Δm(H2O) is the
deviation of the mass of water added to the calorimeter from
2900.0 g; ΔU(IBP) is the energy change for the isothermal
combustion reaction under actual bomb conditions; ΔU(fuse)
is the energy of combustion of the fuse (cotton); ΔU(HNO3) is
the energy correction for the nitric acid formation; ΔU(ign.) is
the electrical energy for the ignition; ΔUΣ is the energy
correction to the standard state; Δcuꢁ is the standard massic
energy of combustion.
ꢀ
ꢁ
ΔUðIBPÞ ¼ ꢀ eðcalorÞ þ cpðH2O; lÞꢃΔmðH2OÞ þ ef ΔTad
þΔUðignÞ
(2)
Table 2. Individual values of the massic energy of combus-
tion, Δcuꢁ, at T = 298.15 K. All values in Jꢃg–1
For the combustion reaction of each compound yielding N2
(g), CO2 (g) and H2O (l), the individual values of Δcuo, together
with the mean values, hΔcuoi, and their standard deviations are
given in Table 2. Because the quantity available for experimental
work involving compound 4.3 was very small, only five
experiments were possible. In the case of 4.2, the quantity of
the compound synthesized was also small and, more impor-
tantly, it was seen to degrade during storage. In fact, because
of the low yields from the syntheses, the quantities for
each compound were small thus preventing a large number
of experiments, and hence, preventing the reduction of the
uncertainties associated with each of the experimental results.
4.1
4.2
4.3
28,466.35
28,480.01
28,491.98
28,492.19
28,418.07
28,420.99
29,114.81
29,077.27
29,068.70
29,061.74
29,127.09
29,140.90
ꢀΔcuꢁ
25,100.51
25,171.11
25,133.60
25,106.57
25,147.72
—
28,461.6 ꢂ 6.9
29,098.4 ꢂ 13.6
25,131.9 ꢂ 13.0
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THERMOCHEMICAL STUDY OF QUINOXALINE-N-OXIDES
Table 3. Derived standard (pꢁ = 0.1 MPa) molar values in the
condensed phases at T = 298.15 K. All values in kJꢃmolꢀ1
Table 5. Derived standard (pꢁ = 0.1 MPa) standard molar
enthalpies in the condensed and gaseous phases, at
T= 298.15 K, and enthalpies of sublimation. All values in kJꢃmolꢀ1
Compound
ꢀΔcUmo (cr)
ꢀΔcHom(cr)
Δf Hom(cr)
Compound
ΔfHom ðcrÞ
ΔgcrHom
ΔfHom ðgÞ
4.1
4.2
4.3
7408.3 ꢂ 6.1
7412.0 ꢂ 6.1 ꢀ383.7 ꢂ 6.1
8127.1 ꢂ 10.3 8129.0 ꢂ 10.3 ꢀ25.0 ꢂ10.4
4.1
4.2
4.3
ꢀ383.7 ꢂ 6.1
ꢀ25.0 ꢂ10.4
ꢀ111.9 ꢂ 7.5
140.8 ꢂ 3.1 ꢀ242.9 ꢂ 6.8
5106.8 ꢂ 7.4
5106.2 ꢂ 7.4 ꢀ111.9 ꢂ 7.5
145.1 ꢂ 2.3
138.0 ꢂ 0.6
120 ꢂ 11
26.1 ꢂ 7.5
Table 3 presents the derived standard molar values for the
energies, ΔcUmo (cr), and enthalpies, ΔcHom(cr), of the combustion
reaction for the compounds and the standard molar enthalpies
of formation, ΔfHom (cr), in the crystalline phase at T = 298.15 K.
The latter were derived from the values of ΔcHom (cr)
and from the standard molar enthalpies of formation at
T = 298.15 K of H2O (l) (ꢀ(285.830 ꢂ 0.042) kJ.mol–1) and CO2 (g)
(ꢀ(393.51 ꢂ 0.13) kJ.mol–1).[34]
of methyl 3-methyl-2-quinoxalinecarboxylate 1,4-dioxide (struc-
ture 3 where R = OCH3) with phosphorous trichloride yields a
mixture that, according to 1H-NMR analysis, is composed
of 57% methyl 3-methyl-2-quinoxinecarboxylate 1-oxide, 16%
methyl 2-methyl-3-quinoxaline carboxylate 1-oxide and 27%
methyl 3-methyl-2-quinoxalinecarboxylate. Detection of such
mixtures by 1H-NMR is straightforward because the presence/
absence of an N–O bond significantly affects the chemical
shifts of neighboring protons, namely, those of the aromatic
proton H-8 and of vicinal protons in the C-2 substituent (see
Scheme 1 for atom numbering). Thus, the d value for the methyl
substituent differs between each of the two possible monodeox-
ygenation products and also between these and the fully
deoxygenated quinoxaline.[22] Also, the latter usually presents
all aromatic protons (H-5 to H-8) clustered in an unresolved
multiplet at ~7.7–8.0 ppm, whereas peaks from protons H-5
and H-8 shift to higher d values in monodeoxygenated deriva-
tives, appearing at ~8.5 and ~8.2 ppm, respectively.[22] The
same authors have also unequivocally shown that the selective
monodeoxygenation of compounds like 3 with trimethyl phos-
phite occurred on the nitrogen farthest apart from the methyl
group, as the subsequent reaction of the sole monodeoxygena-
tion product obtained with acetic anhydride/acetic acid gives
the corresponding 3-acetoxymethylquinoxaline 5 (Scheme 1).
The formation of 5 can only take place if the remaining N–O
bond is on the nitrogen closest to the methyl group.[22]
According to Rossini[35] and Olofsson,[36] the uncertainties
associated with the standard molar energies and enthalpies
of combustion are twice the overall standard deviation of
the mean and include the uncertainties in calibration and in
the values of the auxiliary quantities used.
Results of the Calvet microcalorimetric measurements yielding the
standard molar enthalpies of sublimation, ΔgcrHmo , at T = 298.15 K,
for compounds 4.1–4.3, are registered in Table 4, with the
uncertainties being twice the standard deviation of the mean.
In this table are also shown the molar enthalpies of sublimation,
Δgc;rT; 298:15 KHm and the estimated corrections to T = 298.15 K,
ΔT298:15 KHom (g) for each compound. Finally, the standard molar
enthalpies of formation, Δf HomðgÞ, derived for each compound
in both the crystalline and gaseous phases are summarized
in Table 5.
DISCUSSION
The identification of final compounds as pure isomers 4 was
made on the basis of previous research by Dirlam and
McFarland[22] and of NMR data obtained as follows. Reduction
of compounds 3 was carried out using trimethyl phosphite
(Scheme 1, A), which according to Dirlam and McFarland, allows
for selective monodeoxygenation of the nitrogen farthest from
the 3-methyl group in quinoxaline di-N-oxides like 3 (R ¼ H),
having electron withdrawing substituents in carbon 2 (e.g., 3
where R = CH3 or OCH3; 3-methyl-2-trifluoromethylquinoxaline-
1,4-dioxide).[22] These authors demonstrated, by 1H-NMR, that
while monodeoxygenation of structures such as 3 with trimethyl
phosphite is regioselective, other reducing agents such as phos-
phorous trichloride or sodium dithionite lead to a mixture of
the two possible monodeoxygenation products plus the fully
deoxygenated quinoxaline (Scheme 1, B). For instance, reduction
A
simple inspection of the 1H-NMR spectra of our
monodeoxygenation products (Supporting Material) clearly shows
that the compounds are pure isomers. This is further reinforced by
the very sharp melting point intervals observed, which are strong
indicators of high purity, and by the fact that no peak duplication
was observed in the corresponding 13 C-NMR spectra, as would
be expected if mixtures had been obtained. Furthermore,
the multiplicity pattern obtained for the aromatic protons 5-H to
8-H in 4.1–4.3 corresponds to three multiplets of 1:1:2 relative
intensities, as previously observed by Abadelah et al. for analogous
amino acid and ester quinoxaline-4-oxides, whereas their 1-oxide
isomers exhibited two multiplets with 1:3 relative intensities.[37]
Chemical shifts observed both in the proton and carbon-13 NMR
spectra of 4.1–4.3 were also in agreement with previously
reported data on similar quinoxaline-4-oxides.[37–39]
Table 4. Microcalorimetric standard (pº = 0.1 MPa) molar enthalpies of sublimation, at T = 298.15 K
Δgc;rT;298:15 KHm
kJꢃmolꢀ1
ΔgcrHomðT¼298:15KÞ
kJꢃmolꢀ1
ΔT298:15KHomðgÞ
Compound
No. of experiments
T / K
kJꢃmolꢀ1
4.1
4.2
4.3
6
6
6
390
443
458
160.5 ꢂ 3.1
195.0 ꢂ 2.3
177.6 ꢂ 0.6
19.7
49.9
39.6
140.8 ꢂ 3.1
145.1 ꢂ 2.3
138.0 ꢂ 0.6
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M. L. F. VIVEIROS ET AL.
Therefore, in view of all the above, we can unequivocally
identify our final products as 4.1–4.3.
compared with the phenylcarbamoyl substituent. For a better
understanding of the quality of the results above, we will now
take into account previously reported N–O bond dissociation
enthalpies for some other quinoxaline derivatives. Previously,
some of us were able to obtain reasonable quantities of highly
pure samples of the compounds quinoxaline-N,N′-dioxide,
pyrazine-N,N′-dioxide and 2,3-dimethylquinoxaline-N,N′-dioxide,
The experimental standard molar enthalpies of formation
reported in this work were used to derive the values for the first
N–O bond dissociation enthalpies, DH1(N–O), in the parent di-N-
oxide quinoxalines (compounds 3), that is, the energy associated
with the following gaseous reaction:
using the standard molar enthalpies of formation in the
gas phase previously reported in the literature for compounds
3.1, 3.2, and 3.3[11,12] and for atomic oxygen, Δf HomðgÞ =
(249.18 ꢂ 0.10 kJꢃmol–1).[34] The DH1(N–O) values determined for
compounds 3.1, 3.2, and 3.3 are given in Table 6 and are also com-
pared with those reported in literature for 3-methoxycarbonyl-
2-methylquinoxaline-N,N’-dioxide, 3.4 (Scheme 1, R = OCH3), and
3-ethoxycarbonyl-2-methylquinoxaline-N,N’-dioxide, 3.5 (Scheme
1, R = OCH2CH3).[13]
which allowed the determination of their Δf HomðgÞ by isoperibol
static bomb calorimetry and Calvet microcalorimetry.[19,40] The
mean values reported for the cleavage of both dative N!O
bonds, DHM(N–O), in the 1,4-di-N-oxides listed above are
255.8 ꢂ 2.0 kJꢃmol–1,[19] 254.0 ꢂ 2.3 kJꢃmol–1,[19] and 260.9 ꢂ 2.7
kJꢃmol–1,[40] respectively, for quinoxaline-N,N′-dioxide, pirazine-
N,N′-dioxide and 2,3-dimethylquinoxaline-N,N′-dioxide. These
values were calculated as half of the enthalpy associated with
the following chemical process:
As can be seen, the DH1(N–O) values derived from the exper-
imental enthalpies of formation span a range of 40 ꢂ 17 kJꢃmol–1;
the less positive value, corresponding to a more labile bond, is
found for 3.1, 242.4 ꢂ 9.0 kJꢃmol–1, while the most positive value
is found for compound 3.2, 282 ꢂ 14 kJꢃmol–1. The latter may
be considered only as qualitative because of the larger
uncertainties associated with the experimental Δf HomðgÞ deter-
mined before for compounds 3.2 and 4.2. The value derived
for compound 3.3, 255.6 ꢂ 7.4 kJꢃmol–1, is within the associated
uncertainty identical to those reported before for compounds
3.4 and 3.5 (Table 6).[13] First, it is possible to conclude that the
tert-butoxycarbonyl, the phenylcarbamoyl, and the carbamoyl
groups have a larger destabilization effect than the methyl
group and hence the dative N!O bonds adjacent to the former
groups are cleaved first (Scheme 1). Then, from the numerical
data reported above for DH1(N–O), it can be concluded that
the tert-butoxycarbonyl group causes a larger destabilization
X1; 4 ꢀ di ꢀ N ꢀ oxideðgÞ ! XðgÞ þ 2OðgÞ
(4)
where X is quinoxaline or pyrazine or derivatives of these com-
pounds obtained by replacing H with other chemical groups,
whose gaseous enthalpies of formation are also reported in
literature.[9] In the case of the dimethyl derivative of quinoxaline,
the Becke, three-parameter, Lee–Yang–Parr (B3LYP)/6-311 +
G(2 d,2p), DHM(N–O) = 260.8 kJꢃmol–1, and B3LYP/6-311 + G
(2 d,2p)//B3LYP/6-31 G(d), DHM(N–O) = 260.6 kJꢃmol–1, calculated
values were found to be in excellent agreement with the exper-
imental result providing further support for the quality of the
DHM(N–O) derived for these 1,4-di-N-oxides.[40] The DHM(N–O)
obtained for 2,3-dimethylquinoxaline 1,4-di-N-oxide clearly sug-
gests that the DH1(N–O) for cleavage of a N!O bond in an adja-
cent position to the methyl groups in 2,3-dimethylquinoxaline
1,4-di-N-oxide, that is, methyl groups attached to positions 2 or
3 of the ring, is ≤ 260.9 ꢂ 2.7 kJꢃmol–1. In principle, this limiting
Table 6. Derived standard (pº = 0.1 MPa) molar enthalpies of formation, ΔfHom ðgÞ, and enthalpies of N–O bond dissociation, DH1
(N–O), at T = 298.15 K. The uncertainties are twice the overall standard deviation of the mean. All values in kJꢃmol–1
R
1,4-di-N-oxides
ΔfHom ðgÞ
mono-N-oxide
ΔfHom ðgÞ
DH1(N–O)
OC(CH3)3
NHPh
NH2
OCH3
OCH2CH3
3.1
3.2
3.3
3.4
3.5
ꢀ236.1 ꢂ 5.9[12]
4.1
4.2
4.3
4.4
4.5
ꢀ242.9 ꢂ 6.81
242.4 ꢂ 9.0
282 ꢂ 14
87.5 ꢂ 9.5[11]
120 ꢂ 111
19.7 ꢂ 5.5[11]
26.1 ꢂ 7.51
255.6 ꢂ7.4
253.6 ꢂ 6.2[13]
253 ꢂ 9[13]
ꢀ148.7 ꢂ 3.2[19]
ꢀ178.0 ꢂ 4.3[40]
ꢀ144.3 ꢂ 5.3[13]
ꢀ174 ꢂ 8[13]
1This work.
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Copyright © 2011 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2012, 25 420–426

THERMOCHEMICAL STUDY OF QUINOXALINE-N-OXIDES
value can be used with enhanced confidence because the DH1
(N–O) calculated for 2,3-dimethylquinoxaline-N,N′-dioxide using
the same density functional theory approach and basis sets
was ~252 kJꢃmol–1.[40] The 260.9 ꢂ 2.7 kJꢃmol–1 value was also
found to be valid for the DH1(N–O) values calculated for 3.5
and also for 3-benzyl-2-methyl-quinoxaline 1,4-di-N-oxide.[40]
Therefore, the DH1(N–O) for compound 3.2 is probably not
accurate and must be used with caution. In the cases of com-
pounds 3.1 and 3.3, the DH1(N–O) values seem to be accurate
even though they are associated with large uncertainties. Why
is that so? On one hand, the DH1(N–O) values derived for these
compounds, respectively, 242.4 ꢂ 9.0 kJꢃmol–1 and 255.6 ꢂ 7.4
kJꢃmol–1, are lower than the 260.9 ꢂ 2.7 kJꢃmol–1 value intro-
duced above and, on the other hand, these values are in quite
good agreement with either the experimentally derived DH1
(N–O) results for 3.4 and 3.5 (DH1(N–O) = ~253 kJꢃmol–1, c.f.
Table 6) and the B3LYP/6-311 + G(2 d,2p)//B3LYP/6-31 G(d) calcu-
lated data for 3.1 and 3.3 (DH1(N–O) = ~242–245 kJꢃmol–1).[11–13]
SUPPLEMENTARY MATERIAL
Analytical and structural data on compounds 4.1, 4.2 and 4.3
(melting points, elemental analyses, MS/NMR data and spectra).
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Experimental thermochemical work involving static bomb
calorimetry and Calvet microcalorimetry has been performed
for three quinoxaline derivatives containing a single dative
N!O bond, namely 2-tert-butoxycarbonyl-3-methylquinoxa-
line-N-oxide, 2-phenylcarbamoyl-3-methylquinoxaline-N-oxide,
and 2-carbamoyl-3-methylquinoxaline-N-oxide. The two calori-
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combustion and the enthalpies of sublimation from which their
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(crystalline and gaseous states) were derived at T = 298.15 K.
The gas phase standard molar enthalpies of formation for
the mono-N-oxides were combined with existing literature
values for the corresponding di-N-oxides and for atomic
oxygen allowing the determination of the first standard molar
enthalpies of dissociation of the N!O bond next to an electron-
withdrawing group in the quinoxaline di-N-oxides. The values
obtained for 2-tert-butoxycarbonyl-3-methylquinoxaline-N-
oxide and 2-carbamoyl-3-methylquinoxaline-N-oxide were
242.4 ꢂ 9.0 kJꢃmol–1 and 255.6 ꢂ 7.4 kJꢃmol–1, respectively. These
results are in good agreement with the same quantities calcu-
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are also in agreement with the experimental values reported
for 3-methoxycarbonyl-2-methylquinoxaline-N,N′-dioxide and
3-ethoxycarbonyl-2-methylquinoxaline-N,N′-dioxide compounds,
the only two experimental DH1(N–O) values existing in the litera-
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compound studied here, 2-phenylcarbamoyl-3-methylquinoxaline-
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too high compared with the values determined for the other
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N′-dioxide based on previous experimental work performed for
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Acknowledgements
Thanks are due to Fundação para a Ciência e Tecnologia (FCT),
Lisbon, Portugal, for financial support to Centro de Investigação
em Química - UP and CICECO. V. L. S. Freitas thanks the FCT
and European Social Fund for the award of a Ph. D. Research
Grant SFRH/BD/41672/2007.
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J. Phys. Org. Chem. 2012, 25 420–426