Ureidobenzotriazine multiple H-bonding arrays: The importance of geometrical details on the stability of H-bonds

Article abstract of DOI:10.1021/jo7019338

(Chemical Equation Presented) A 3-ureidobenzo-1,2,4-triazine 1-N-oxide (1) was synthesized successfully. The derivative displays an acceptor-donor- acceptor-acceptor (ADAA) hydrogen-bonding motif in CDCl₃ and DMSO-d₆ solution as well as in the solid state. Although moderately strong association of 1 was observed with DAD motifs, nonspecific binding is observed with ureidopyridines featuring a complementary DADD array. Density functional calculations of conformations 1a and 1b together with two complexes revealed the clearly nonplanar geometry of the multiply hydrogen-bonded complex, in which some bonds are significantly longer (3.2 A) than is optimal for H-bonds. As a result, only very small free energies of association were calculated, in line with the experimentally observed absence of specific assembly of the components.

Full text of DOI:10.1021/jo7019338

Ureidobenzotriazine Multiple H-Bonding Arrays: The Importance
of Geometrical Details on the Stability of H-Bonds
G. B. W. L. Ligthart,† Dawei Guo,‡ A. L. Spek,§ Huub Kooijman,§ Han Zuilhof,*,| and
Rint P. Sijbesma*,†
Laboratory of Macromolecular and Organic Chemistry, EindhoVen UniVersity of Technology, P.O. Box
513, 5600 MB, EindhoVen, The Netherlands, The Research Institute of Petroleum Processing, Beijing
100083, People’s Republic of China, BijVoet Center for Biomolecular Research, Crystal and Structural
Chemistry, Utrecht UniVersity, Padualaan 8, 3584 CH, Utrecht, The Netherlands, and Laboratory of
Organic Chemistry, Wageningen UniVersity, Dreijenplein 8, 6703 HB Wageningen, The Netherlands
r.p.sijbesma@tue.nl; han.zuilhof@wur.nl
ReceiVed September 3, 2007
A 3-ureidobenzo-1,2,4-triazine 1-N-oxide (1) was synthesized successfully. The derivative displays an
acceptor-donor-acceptor-acceptor (ADAA) hydrogen-bonding motif in CDCl3 and DMSO-d6 solution
as well as in the solid state. Although moderately strong association of 1 was observed with DAD motifs,
nonspecific binding is observed with ureidopyridines featuring a complementary DADD array. Density
functional calculations of conformations 1a and 1b together with two complexes revealed the clearly
nonplanar geometry of the multiply hydrogen-bonded complex, in which some bonds are significantly
longer (3.2 Å) than is optimal for H-bonds. As a result, only very small free energies of association were
calculated, in line with the experimentally observed absence of specific assembly of the components.
Introduction
decade, a large number of strongly bonded complexes held
together by more than three hydrogen bonds have been
described.13-17 In particular, strongly associating self-comple-
mentary molecules developed by our group have been of
Inspired by the generic storage mechanism of DNA, arrays
of multiple parallel or near-parallel hydrogen bonds have been
commonly used motifs in molecular recognition for the last 20
years,1-5 since strength, specificity, and directionality are
increased compared to single hydrogen bonds. The strength of
multiple hydrogen-bonded complexes has been found to depend
not only on the number of hydrogen bondssand the donor
acidity and acceptor basicity of the individual hydrogen
bonds6-9sbut also strongly on the particular arrangement of
the donor and acceptor functional groups.10-12 During the past
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† Eindhoven University of Technology.
‡ The Research Institute of Petroleum Processing.
§ Utrecht University.
| Wageningen University.
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10.1021/jo7019338 CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/07/2007
J. Org. Chem. 2008, 73, 111-117
111

Ligthart et al.
eminent importance for the development of main-chain su-
pramolecular polymers.18-22 However, the self-complementarity
of these units imposes restrictions to the self-assembly of
copolymers and the construction of supramolecular architectures
consisting of more than one compound. Given our research
interest in multiple hydrogen-bonding units as well as the recent
use of complementary recognition motifs in supramolecular
polymers, there is a clear need for strong complementary binding
motifs. A number of complementary multiple hydrogen-bonding
arrays have been developed, including ones based on oligoa-
mides,17 hydrazides,23 and pairs of heterocyclic building blocks,
such as naphthyridine-ureidopyridine,24 naphthyridine-ure-
idoguanosine,25,26 naphthyridine-ureidopyrimidinone,27 anthy-
ridine with dihydropyridine12 or an azapentacene analog with
dihydropyridine,28 and heterocyclic homodimers combined with
donor-acceptor interactions.29,30 In all these pairs, the individual
components either lack the high synthetic accessibility required
for use in supramolecular polymers or association to the
heterocomplexes is not fully selective.31-36 In this report, a study
into a new complementary hydrogen-bonding module is pre-
sented. The synthetic accessibility and binding capability of
3-ureido-1,2,4-triazine 1-N-oxide 1 and suitability as an accep-
tor-donor-acceptor-acceptor (ADAA) hydrogen-bonding scaf-
fold is reported. N-Oxides of nitrogen heterocycles have a
formally full negative charge on the oxygen atom, and pyridine
N-oxide has been reported to be a stronger hydrogen-bond
acceptor than pyridine.6,37-41 Therefore, strong binding by 1
FIGURE 1. Two conformations of 3-ureido-1,2,4-triazine 1-N-oxide
1 and their corresponding hydrogen-bonding array.
would be expected. Although 1 can be present in two possible
conformations, 1a and 1b, as displayed in Figure 1, the
equilibrium might be shifted toward the ADAA form upon
presenting to a complementary donor-acceptor-donor-donor
(DADD) partner.
We complement these experimental studies by density
functional quantum mechanical calculations to evaluate the
experimentally found binding properties of the compound.
Specifically, detailed geometric effects are studied, to reveal
overall large effects on the hydrogen-bonding strength. This
combination of experimental and theoretical data is then finally
discussed in detail to highlight frequently overlooked aspects
of binding in multiple hydrogen-bonding arrays: linearity of
the array and planarity of the overall donor-acceptor complex.
Results and Discussion
Synthesis and Characterization. Two general methods have
been reported for the synthesis of 1,2,4-triazine N-oxides: by
direct oxidation of the parent triazine with organic peroxides
or by the formation of the triazine N-oxide ring via cyclization.42
3-Aminobenzo-1,2,4-triazine 1-N-oxide (2) is a precursor to
tirapazamine (3-aminobenzo-1,2,4-triazine 1,4-dioxide), which
is a bioreductively activated DNA-damaging agent that selec-
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A
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free guanidine base followed by base-induced cyclization.48,49
The free guanidine base was prepared by passing an aqueous
solution of guanidine hydrochloride through an ion exchange
column (DOWEX 550A OH) and evaporation of the eluate in
vacuo. 3-Aminobenzo-1,2,4-triazine 1-N-oxide (2) was subse-
quently obtained in 96% yield through reaction of o-fluoroni-
trobenzene with free guanidine followed by in situ cyclization
with t-BuOK. Condensation of 2 with n-butyl isocyanate gave
the desired product 1 as bright yellow crystals in 31% yield
(Scheme 1).
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112 J. Org. Chem., Vol. 73, No. 1, 2008

Ureidobenzotriazine Multiple H-Bonding Arrays
SCHEME 1
Compound 1 can potentially exist in two conformers, each
of which is characterized by a different intramolecular H-bond
(structures 1a and 1b). It was anticipated that compound 1 would
feature a ADAA array of hydrogen-bonding sites (conformation
1a), presumably because in both conformers N4 bears a larger
electron density than N2 (NPA charges roughly -0.6 and -0.4,
respectively). To elucidate the conformation in solution, nuclear
Overhauser experiments using selective excitation were per-
formed.50 The presence of conformer 1a in CDCl3 and DMSO-
d6 was confirmed by observation of the intramolecular NOE
contact indicated in Scheme 1. X-ray analysis of the product
showed that the molecule features an intramolecular hydrogen
bond from the urea NH to N4 in the triazine ring to display an
AADA array of hydrogen-bonding sites in the solid state. The
unit cell contains two independent molecules, one of which
exhibits disorder in the butylureido group. The N-N distance
between the nitrogen atoms involved in the intramolecular
hydrogen bond (average distance 2.68 Å) is larger than the C-C
distance between the atoms connected to the central N-H
(average distance 2.58 Å). In addition, the corresponding
C-N-C angles for the two independent molecules are 129.38°
and 129.18°. These data are accurately mimicked by our
calculations, with distances and angles of 2.78 and 2.55 Å and
132.19°, respectively [B3LYP/6-311G(d,p) data]. The molecule
is also not fully planar, since the triazine ring is at an angle of
8.0° and 2.0° with the ureido group for the two nonequivalent
molecules in the unit cell. Specifically, the observed deviations
from linearity in the H-bond array, i.e., the fact that O101, N102
104, and O102 are not on one line (see structure in Figure 2),
,
N
may affect the capability of 1 to form multiple hydrogen-bonded
arrays with complementary molecules.
Binding Studies. Since dimerization of 1 by double hydrogen
bonds was observed in the solid state, dimerization in CDCl3
1
solution was determined by H NMR dilution experiments.
Compound 1 was found to self-associate weakly (Kdim < 5 M-1
in CDCl3 at 25 °C). Association of 1 with compounds 3a,b and
4a,b, featuring DAD and DADD arrays, respectively, was
1
investigated by H NMR titration experiments (Chart 1). For
comparison, association constants of compounds 3 and 4 with
1-N-propylthymine 5 are included in Table 1.
While binding of 1-N-propylthymine 5 to DAD molecules
3a and 3b is moderately strong (845 and 460 M-1, respectively),
compound 1 displays a lower binding constant (106 and 83 M-1
,
respectively). Binding of these molecules may occur to the ADA
part of the ADAA array of conformer 1a or to the ADA array
of conformer 1b (see Figure 1). However, association of 1 with
3a and 3b is not accompanied with a significant shift in the
intramolecular hydrogen bond, as the position of the intramo-
lecular NH resonance does not shift by more than 0.1 ppm upon
presenting the DAD partner. This indicates that no structural
adjustment occurs upon binding and thus that the intramolecular
hydrogen bond to N4 in the triazine ring is maintained.
Moreover, no change in NOE contacts as indicated in Scheme
1 was observed. Binding of pyridylureas 4 to 1a and 1b forming
DADD-ADAA arrays was investigated to determine the
existence of favorable hydrogen bonding with the N-oxide. In
solution, as well as in the solid state, pyridylureas are known
to form a six-membered ring with an intramolecular hydrogen
bond from one of the urea NHs to the nitrogen in the pyridine
ring and double hydrogen bonds between two individual
molecules.52,53 Upon complexation with a complementary
binding motif, these bonds can be broken.53-55 The ability of 5
to bind to 4a and 4b confirms the low energetic penalty for
(50) Stott, K.; Keeler, J.; Van, Q. N.; Shaka, A. J. J. Magn. Reson. 1997,
125, 302-324.
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FIGURE 2. Displacement ellipsoid representation (50% probability
level) of the single-crystal X-ray structure of the hydrogen-bonded dimer
of compound 1. Only the 80% disorder form of one of the two
molecules is shown.
(52) Sudha, L. V.; Sathyanarayana, D. N. J. Mol. Stuct. 1984, 125, 89-
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3779-3780.
J. Org. Chem, Vol. 73, No. 1, 2008 113

Ligthart et al.
CHART 1
TABLE 1. Association Constants and Free Energies of Association
of 1 and 5 with 3 and 4 Determined in CDCl3 at 25 °C
TABLE 2. Energy Differences Between 1a and 1b from Different
Methods and Basis Setsa
1
5
∆E0
entry
method and basis set
B3LYP/6-311G(d,p)
B3LYP/6-311+G(2df,2p)//B3LYP/6-311G(d,p)
LMP2/6-311G(d,p) //B3LYP/6-311G(d,p)
LMP2/6-311+G(d,p)//B3LYP/6-311G(d,p)
(kJ/mol)
-∆G°
(kJ/mol)
-∆G°
Ka (M-1) (kJ/mol)
compd Ka (M-1
3a
)
probe (signal)
1
2
3
4
2.81
4.23
3.77
1.84
106 ( 13 11.5 ( 0.3 3a (NH2) (1.7)a
845d
16.7
15.2
10.0
11.6
3b 83 ( 17 10.9 ( 0.5 3b (NH-amide) (1.8)a 460e
4a
<10
<5b
<5c
4a (NH2)
4b (NH-amide)
57d
4b <10
110d
a At B3LYP/6-311G(d,p) level, ∆H298 ) 2.77 kJ/mol, ∆G298 ) 2.10
kJ/mol.
a CIS values (ppm) given in parentheses. b The fit was obtained for five
data points due to broadening of the NH2 protons. c The fit was obtained
for five data points due to overlap in signals. d Literature data from So¨ntjens
et al.31 e Literature data from Beijer et al.51
TABLE 3. Calculated Binding Abilities of the Hydrogen-Bonded
Complexes under Study [B3LYP/6-311G(d,p); in kJ/mol] and Dipole
Moments of the Complexes
1
dipole
moment
(D)
this process. However, H NMR titrations of 1 with 4 show
very low association constants (<10 M-1). These surprising
results suggest a weak to no ability of the N-oxide to form a
hydrogen bond.
entry
complex
∆Eï
∆H298
∆G298
1
2
3
4
1a‚4a
-69.18
-70.769
-62.40
-56.68
-63.058
-64.16
-55.03
-53.94
-9.79
-10.45
-0.63
4.31
10.53
1a‚dap
1b‚4a
Quantum Mechanical Calculations. Even though the pres-
ence of an AADA array in 1 is indicated in solution and the
crystal structure, formation of quadruply hydrogen-bonded
complexes in solution was not found with seemingly comple-
mentary agents. Two questions might be answered with
computational calculations: (i) is there a large difference in
energy between conformations 1a and 1b, and (ii) what are the
stabilities of hydrogen-bonded complexes of these conformations
and the corresponding partners? Finally, the combination of
experimental and theoretical data can be used to delineate an
explanation for the absence of intermolecular hydrogen-bonding
here and hence provide deeper insight into the phenomenon of
multiple hydrogen bonding.
8.33
1b‚dap
TABLE 4. Calculated Hydrogen-Bond Lengths in 1‚4b Complexes
atom pair 1a‚4a
bond length (Å)
atom pair 1b‚4a
bond length (Å)
O1-N3
2.907
N1-N3
3.131
N1-N4
3.150
N2-N4
3.159
N2-N5
3.195
O1-N5
2.866
O2-N6
3.041
O1-N6
3.131
showed that quantum mechanical techniques could be used to
perform calculations on molecular systems of practical signifi-
cance.60,61 More specifically, density functional B3LYP calcula-
tions recently confirmed the strong homodimerization of
ureidopyrimidinone (UPy) molecules in the keto tautomer and
enol tautomer. For the keto tautomer, experimental hydrogen-
bond distances r(N-N) and r(N-O) are 2.97 and 2.76 Å,14
respectively, while the B3LYP/6-311G(d,p)-computed values
are 3.01 and 2.78 Å, respectively.61 Since in those cases
agreement within experimental error was found for these
parameters, the same methods were used to evaluate differences
in the possible conformations of 1 and stabilities of the
hydrogen-bond complexes of 1 with complementary compounds
4a and 2,6-diaminopyridine.
Geometry Optimization. The calculated energy difference
between 1a and 1b at specific methods and basis sets is
displayed in Table 2. The calculated energy differences between
1a and 1b is only 4.2 kJ/mol at the B3LYP/6-311G(d,p) level
(entry 1). Further stepwise increase of the basis set size up to
B3LYP/6-311+G(2df,2p) (entry 2) shows no changes, suggest-
ing that the basis set at the B3LYP/6-311G(d,p) level is
appropriate. At the B3LYP/6-311G(d,p) level, the free energy
of 1a is slightly lower than that of 1b (∼2.9 kJ/mol), which
means that the equilibrium between the two conformations lies
Previously, extensive theoretical investigations have been
reported on hydrogen-bonded dimers.56 More recently, multiple
hydrogen-bonded systems, including DNA base pairs,57-59 have
also been studied theoretically, in order to rationalize relative
stabilities.10,60-63 Validation of studies of electronic energies
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114 J. Org. Chem., Vol. 73, No. 1, 2008

Ureidobenzotriazine Multiple H-Bonding Arrays
FIGURE 3. Optimized structures of complexes 1a‚4a (a) and 1b‚4a (b).
toward 1a. Furthermore, the energy difference between the two
conformations at the LMP2/6-311G(d,p)//B3LYP/6-311G(d,p)
level is 3.77 kJ/mol, and at LMP2/6-311+G(d,p)//B3LYP/6-
311G(d,p) level, 1a is favored by 1.85 kJ/mol (entries 3 and
4). These data, obtained with several totally different high-level
methods, all suggest that the two conformations of 1 display a
similar stability, with a slightly lower energy of the ADAA array
1a. While the NOE-NMR experiments reveal the presence of
conformer 1a, the small calculated energy differences suggest
that conformations 1a and 1b may both exist in significant
fractions in solution.
Hydrogen-Bonding Abilities of 1 with Complementary
Motifs. The hydrogen-bonding combinations of 1a and 1b with
both 4a and 2,6-diaminopyridine (dap) have been fully opti-
mized to obtain information about the structure and stability of
the corresponding heterodimers. The calculated results are col-
lected in Table 3. Remarkably, the free energies in all complexes
of 1a and 1b are all close to zero, indicating that the hydrogen
bonding in complexes of 1 is weak. This is unlike the situation
reported earlier for the self-complexation of quadruply H-bonded
ureidopyrimidone (UPy), which displays a strong H-bonding
that is also computed. Therefore, the current data strongly
suggest that little complex formation can be expected, as was
indeed experimentally observed. Furthermore, a trend can be
seen in the energy of complex formation in decreasing order:
1a‚dap > 1a‚4a > 1b‚4a > 1b‚dap. This trend was mimicked
when more sophistication was added in the computations, e.g.,
by going from total energies to free energies, i.e., inclusion of
vibrational energy and intrinsic entropy effects.
Two reasons suggest that the low dimer stability should be
attributed to intrinsic effects in the complex: First, the calculated
dipole moments of the complexes (5-13 D) are much bigger
than in UPy dimers (∼0.2 D), which implies significant solvent
stabilization of the dipole in complexes of 1. However, the
overall complexation energies are small, which points to an
intrinsic rather than a solvent effect. Second, although differ-
ences are small, the computed data indicate that complexes of
1a are slightly more stable than that of 1b. Therefore, the lack
of quadruple hydrogen-bond formation is not due to the absence
of an ADAA array in 1. The experimental observation that 1
prefers binding to a DAD array rather than to a DADD array is
therefore due to the nature of the hydrogen-bonded complexes
involved.
To compare the differences in structure, the hydrogen-bond
lengths of heterodimers 1a‚4a and 1b‚4a have been collected
in Table 4. A two- and three-dimensional picture of the
optimized structures of the heterodimers are given in Figure 3.
The computed hydrogen-bonding lengths of complex 1a‚4a are
between 2.91 and 3.20 Å. These lengths are significantly longer
than distances found by both X-ray determination as well as
J. Org. Chem, Vol. 73, No. 1, 2008 115

Ligthart et al.
150 K, Mo KR radiation, graphite monochromator, λ ) 0.71073
Å. Data were collected on a CCD area detector on a rotating anode.
The structure was solved by direct methods (SHELXS86) and
refined on F2 using SHELXL-97-2. The NHBu moiety of one of
the two independent molecules is disordered over two positions.
An 80:20% disorder model was introduced. Positional parameters
of the ordered N-H hydrogen atoms were refined, and all other
hydrogen atoms were included in the refinement on calculated
positions riding on their carrier atoms. The non-H atoms of the
minor disorder component were included in the refinement with a
fixed isotropic displacement parameter, set equal to the equivalent
isotropic displacement parameter of the corresponding atom in the
major disorder component. All other non-hydrogen atoms were
refined with anisotropic displacement parameters. Hydrogen atoms
were refined with a fixed isotropic displacement parameter linked
to the value of the equivalent isotropic displacement parameter of
their carrier atoms. Final wR2 ) 0.1128, w ) 1/[σ2(F2) +
analogous density functional and ab initio methods for strong
multiple hydrogen-bonded motifs, which are between 2.70 and
3.00 Å.
An additional feature indicating weak association of the
individual molecules is the significantly longer distances of the
two middle hydrogen bonds. In this way, a concave molecule
is formed, which is not capable of strong binding to the more
linear pyridylurea 4a. A similar explanation can be given for
weak binding of 1b to 4a. Even though the carbonyl group of
1b is involved in a bifurcated hydrogen bond to the urea of 4a,
hydrogen-bond lengths do not indicate strong binding. Further-
more, geometry optimization clearly shows that the individual
molecules in the heterocomplexes are not planar. In fact, the
angles between the two π-planes are 28.5° and 26.9° for
complex 1a‚4a and 1b‚4a, respectively. These findings suggest
that the electronic fine structure of 1 prevents the formation of
ADAA‚DADD motifs.
In addition, upon formation of the hydrogen-bond dimer, the
structures of 1a and 4a need to be deformed with respect to
their (planar) structure prior to hydrogen bonding, and this
deformation energy amounts to almost 9 kJ/mol. Although this
is not a major component, this deformation energy is almost
zero in the case of, e.g., UPy-Upy dimers, which also
contributes to the weaker hydrogen-bond formation.
(0.0613P)2 + 0.2843P], where P ) (max(Fo ,0) + 2Fc2)/3, R1 )
2
0.0409 (for 4205 I > 2σ(I)), S ) 1.032, 373 refined parameters,
-0.23 < ∆F < 0.22 e Å-3. Full details have been deposited with
the CCDC (deposition number 651332).
Binding Experiments. For the 1H NMR titrations, CDCl3
(Cambridge Isotope Laboratories) was dried and deacidified over
activated alumina (type I) and stored on 4 Å molecular sieves.
DMSO-d6 was dried over 4 Å molecular sieves. At least eight data
points in the 20-80% saturation range were measured using
temperature control at 25 °C unless stated otherwise. The association
constants were evaluated by nonlinear least-squares computer fitting
of the concentration dependence of the chemical shifts of NH
protons to a 1:1 binding isotherm by ignoring dimerization of the
individual components using standard methods.64
Conclusions
We have shown that 3-butylureidobenzo-1,2,4-triazine 1-N-
oxide (1), which is readily available by condensation of an
isocyanate with 3-aminobenzo-1,2,4-triazine 1-N-oxide (2),
displays an ADAA hydrogen-bonding motif. Although signifi-
cant binding to a complementary DAD array is observed in
chloroform solution, very weak association is found for seem-
ingly complementary DADD arrays. Theoretical analysis of
conformations 1a (with an ADAA array) and 1b (with an ADA
array) by DFT and local MP2 calculations indicates that this is
not due to a higher stability of the ADA array, as no significant
differences in free energy are found. The theoretically calculated
small free energies of association of 1 with a ureidopyridine
and diaminopyridine (0-9 kJ/mol) are in line with the experi-
mental data that little or no complex formation can be expected.
Geometry optimization of the multiply hydrogen-bonded com-
plexes by DFT calculations show that these are clearly non-
planar, with several long (3.2 Å), and correspondingly weak,
hydrogen bonds. In other words, the hydrogen-bonding mono-
mers have to deform themselves a bit to form the multiply
hydrogen-bonded complex (cost: 9 kJ/mol), while the resulting
hydrogen bonds are still long and therefore not very strong.
Apparently, the formal full negative charge on the N-oxide
oxygen atomswhich could have been expected to yield strong
hydrogen bondssdoes not compensate for these effects. This
example of the benzotriazine moiety points to the value of a
combined experimental and theoretical approach in the develop-
ment of novel multiply hydrogen-bonded systems.
Computational Methods. The molecular geometries of 1a and
1b and hydrogen-bonded complexes have been fully optimized
using density functional theory (DFT) with the B3LYP functional
as implemented in Gaussian 0365 and the basis sets indicated in
the text. To obtain the single point energies, 1a and 1b have also
been calculated with 6-311+G(d,p), 6-311+G(2d,2p), and 6-311+G-
(2df,2p) basis sets.
Synthesis. 2,4-Diamino-6-(3,4,5-tris(dodecyloxy)phenyl)-s-tri-
azine (3a) was synthesized according to Beijer et al.13 2,6-Bis-
(hexanoylamino)pyridine (3b) was synthesized according to Bern-
stein et al.66 Hexanoic acid (6-aminopyridin-2-yl)amide (4a) and
hexanoic acid [6-(3-butylureido)pyridin-2-yl]amide (4b) were syn-
thesized according to So¨ntjens et al.31
3-Butylureido-1,2,4-benzotriazine 1-N-Oxide (1). To a mixture
of 3-amino-1,2,4-benzotriazine 1-N-oxide (2) (0.26 g, 1.6 mmol)
in dry pyridine (4 mL) was added n-butyl isocyanate (1.58 g, 16.0
mmol) dropwise. The suspension was stirred at 110 °C for 16 h.
The pyridine was evaporated in vacuo before chloroform was added,
and the solution was washed with 1 M HCl, water, and brine and
(64) Schneider, H.-J.; Yatsimirsky, A. Principles and Methods in
Supramolecular Chemistry; J. Wiley & Sons Ltd.: Chichester, 2000.
(65) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. J. A.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A.
D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian
03, Revision C02; Gaussian, Inc.: Wallingford CT, 2004.
Experimental Procedures
Single-crystal X-ray structure determination for compound
1: C12H15N5O2, Mr ) 261.29, yellow block-shaped crystal (0.2 ×
0.3 × 0.3 mm), monoclinic, space group P21/c (no. 14) with a )
10.9174(10) Å, b ) 19.4699(10) Å, c ) 12.785(3) Å, â ) 110.518-
(10)°, V ) 2545.0(7) Å3, Z ) 8, Dx ) 1.364 g cm-3, F(000) )
1104, Mo KR ) 0.098 mm-1, 69 404 reflections measured, 5814
independent reflections, Rint) 0.0529, 1.00° < θ < 27.48°, T )
(66) Bernstein, J.; Stearns, B.; Dexter, M.; Lott, W. A. J. Am. Chem.
Soc. 1947, 69, 1147-50.
116 J. Org. Chem., Vol. 73, No. 1, 2008

Ureidobenzotriazine Multiple H-Bonding Arrays
dried. The product could be obtained as yellow block crystals by
crystallization from chloroform (0.13 g, 31%). 1H NMR (CDCl3):
δ ) 8.91 (br, 1H, NH), 8.40 (dd, 1H, J ) 8.0. 0.7 Hz), 7.92 (dt,
1H, J ) 7.1, 0.8 Hz), 7.80 (dd, 1H, J ) 8.3, 0.7 Hz), 7.61 (dt, 1H,
J ) 7.0, 0.8 Hz), 7.30 (br, 1H, NH), 3.48 (q, 2H, J ) 6 Hz), 1.70
(m, 2H), 1.53 (m, 2H), 1.04 (t, 3H, J ) 7 Hz) ppm. 13C NMR
(CDCl3): δ ) 154.9, 152.9, 145.9, 136.3, 132.2, 127.8, 126.7,
120.4, 39.9, 31.6, 30.1, 13.6. ppm. ESI-MS: (m/z) calcd 261.29,
observed 262.19 (M + H+), 284.17 (M + Na+), 545.35 (2M +
Na+), 806.51 (3M + Na+), 1067.70 (4M + Na+). FTR-IR (ATR):
ν ) 3251, 3096, 2931, 2869, 1678, 1579, 1518, 1490, 1419, 1357,
1303, 1280, 1198, 1135, 1050, 962, 840 cm-1. Anal. Calcd for
C12H15N5O2: C, 55.16; H, 5.79; N, 26.80. Found: C, 54.97; H,
5.53; N, 27.06.
3-Amino-1,2,4-benzotriazine 1-N-Oxide (2). Synthesis was
according to a modified literature procedure:48 Guanidine hydro-
chloride (5.74 g, 60.0 mmol) was passed through an ion exchange
column (120 g, DOWEX 550A OH) and the eluate was evaporated
in vacuo to yield the free guanidine base as a colorless oil (3.50 g,
59.0 mmol). To the guanidine were added THF (60 mL) and
o-fluoronitrobenzene (0.70 g, 5.0 mmol), and the mixture was stirred
at 70 °C for 4 h. KO-t-Bu (0.60 g, 5.3 mmol) was subsequently
added to the orange mixture followed by an additional 2 h of stirring
at 70 °C. Upon addition of ethyl acetate (40 mL) to the cooled
mixture, more yellow precipitate was formed which was isolated
by filtration. The crude product was dissolved in hot ethyl acetate
and washed with water. The resulting solid was washed with acetone
and dried in vacuo to obtain the pure title compound (0.78 g, 96%).
Spectroscopic data of the compound corresponded to those reported
previously.67
Supporting Information Available: General procedures, table
of atomic coordinates of the calculated geometries of complexes
1a‚4 and 1b‚4, copies of 1H NMR and 13C NMR spectra of
compounds 1-5, copies of 15N NMR and FTIR spectra of
compounds 1 and 2, and crystallographic data of 1 (CIF). This
material is available free of charge via the Internet at http:
//pubs.acs.org.
JO7019338
(67) Fuchs, T.; Chowdhury, G.; Barnes, C. L.; Gates, K. S. J. Org. Chem.
2001, 66, 107-114.
J. Org. Chem, Vol. 73, No. 1, 2008 117