Structure investigation of bridgehead aziridine: Synthesis, theoretical, and crystallographic study of 2,4,6-triphenyl-1,3-diazabicyclo[3.1.0]hex-3-ene

Article abstract of DOI:10.1002/hlca.200690021

A one-pot three-component procedure to efficiently create the 1,3-diazabicyclo[3.1.0]hex-3-ene system is reported. The molecular structure of 2,4,6-triphenyl-1,3-diazabicyclo[3.1.0]hex-3-ene (3) was studied by X-ray diffraction and compared to ab initio a

Full text of DOI:10.1002/hlca.200690021

190
Helvetica Chimica Acta – Vol. 89 (2006)
Structure Investigation of Bridgehead Aziridine: Synthesis, Theoretical, and
Crystallographic Study of 2,4,6-Triphenyl-1,3-diazabicyclo[3.1.0]hex-3-ene
by Giuseppe Bruno*, Francesco Nicolò, and Archimede Rotondo
Dipartimento di Chimica Inorganica, Chimica Analitica e Chimica Fisica, Università degli Studi di
Messina, Salita Sperone 31, I-98166 Vill. S. Agata, Messina
(e-mail: gbruno@unime.it)
and Francesco Risitano*, Giovanni Grassi, and Francesco Foti
Dipartimento di Chimica Organica e Biologica, Università degli Studi di Messina, Salita Sperone 31,
I-98166 Vill. S. Agata, Messina
(e-mail: frisitan@isengard.unime.it)
A one-pot three-component procedure to efficiently create the 1,3-diazabicyclo[3.1.0]hex-3-ene sys-
tem is reported. The molecular structure of 2,4,6-triphenyl-1,3-diazabicyclo[3.1.0]hex-3-ene (3) was stud-
ied by X-ray diffraction and compared to ab initio and density-functional-theory (DFT) calculations
restricted to the core moiety. Geometry optimizations for structural isomers and tautomeric forms of
this aziridine fragment, taken as simplified models, were carried out at high calculation levels. Moreover,
the same methods were utilized to evaluate the proton affinity of two crucial aziridine tautomers.
Introduction. – Functionalized bridgehead aziridines are an important class of com-
pounds because of their occurrence in nature as well as their pharmacological activities
[1–9]. Consequently, there is a rising interest in setting up effective synthetic method-
ologies and also in studying structural and electronic properties of these derivatives. In
the present paper, we report a straightforward procedure for the diastereoselective syn-
thesis of the 1,3-diazabicyclo[3.1.0]hex-3-ene system [10]. This is based on a one-pot
multi-component mechanism [11] involving a-halogeno ketones such as 1 and alde-
hydes such as 2 in the presence of AcOH/AcONH4 [12] (Scheme). We carried out a
study of the structural characteristics of the new derivative 2,4,6-triphenyl-1,3-diazabi-
cyclo[3.1.0]hex-3-ene (3) by using the X-ray diffraction technique. The structural data
of 3 were compared with a series of molecular geometries of all diastereoisomers of 3
which were optimized by using ab initio and density-functional-theory (DFT) calcula-
tions carried out either with compound 3 or with its tautomer 2,4,6-triphenyl-1,3-diaza-
bicyclo[3.1.0]hex-2-ene (3T). These calculations were with the intermediate level of
basis set [6-311+G(2d,p) and 6-31+G(d,p)] and gave results in good agreement
with the experimental geometry obtained by the diffraction data. The B3LYP hybrid
method appears to be very suitable to the best-fitting of the geometrical parameters
obtained by diffraction data.
We also performed several ab initio and DFT calculations in the gas phase of sim-
plified models related to the core molecular skeleton of 3 and thoroughly discussed the
relative stability of all 22 possible isomers and tautomers. We found a wide range (49
© 2006 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 89 (2006)
191
Scheme. Synthesis of Compound 3 in its ‘exo’ form
kcal/mol) for their relative thermodynamic energies with respect to the isomer R5
which was assessed to be the most stable one at any level of calculation.
One of the most important chemical processes is the protonation reaction. It does
not only play an important role in general chemistry but is also of highest physiological
relevance. Therefore, a secure computational prediction of proton affinities (PA) is of
utmost importance. Since many of the pharmacologically active compounds are of such
a large size that treatment on a reasonable ab initio level is still excluded, we limited
these studies to simplified models. Thus, the proton affinity of both N-atoms
PA(N(1)) and PA(N(4)) of the tautomers R0 and R0T was determined by a wide vari-
ety of computational methods which allowed us to evaluate the relative importance of
adding extra diffuse and polarization functions for the PA calculations; zero-point cor-
rections was also applied at the HF/6-31+G(d,p) level.
Experimental. – Synthesis. In a typical experiment, phenacyl chloride (1) and benzaldehyde (2) were
treated with an excess of AcOH/AcONH4 in EtOH for 1 h under reflux. After workup, 3 was isolated in
90% yield.
Only the formation of the ‘exo’ form 3 was observed in contrast to previous synthetic procedures
which led to diastereoisomer mixtures [13–15]. Thus, our reaction is practically simple, starting from
inexpensive and easily available products, and diastereoselective (Scheme).
X-Ray Crystallographic Study of 3. A summary of crystal and intensity data as well as refinement
details is presented in Table 1. Crystallographic data were collected, at r.t., on a Siemens-P4 diffracto-
meter, by using the MoKa radiation. Cell constants were determined by using 70 reflections. Intensity
data were corrected for Lorentz and polarization effects. y-Scan absorption correction was applied
[16]. The structure was solved by using the package SIR-97 [17] and subsequently refined on the F2 values
by the full-matrix least-squares programs SHELXL-97 [18]. Non-H-atoms were refined anisotropically.
H-Atoms were located from Fourier difference maps and then fixed in idealized positions with an iso-
tropic value determined by the ‘riding-model’ technique. Atom scattering factors and anomalous disper-
sion corrections for all the atoms were taken from the international crystallographic tables [19]. Geomet-
rical calculations were performed by PARST97 software[20]. The molecular plots were produced by the
ORTEP program [21]. The absolute configuration for structure 3 is unknown since the scarce anomalous
scattering did not allow an exact Flack parameter [22] determination.
Ab initio and DFT Calculations. The experimental structure model of 3 (Fig. 2) was used as input for
the GAUSSIAN 98 [23] program. The diastereoisomers of 3 as well as those of the tautomer 3T were
made up by GaussView, therefore they were optimized by the HF/6-31+G(d,p), B3LYP/6-31+G(d,
p), and B3LYP/6-311+G(2d,p) functionals. All the optimized geometries were confirmed to be station-
ary points by the absence of imaginary frequencies in the computed IR spectra. Frequency calculations
were carried out at the HF/6-31+G(d,p) level to characterize stationary points and to estimate the zero-
point-energy corrections in computing the proton affinity (PA) of R0 and R0T and the relative-energy
order of the simplified isomers.

192
Helvetica Chimica Acta – Vol. 89 (2006)
Table 1. Crystal Data and Structure Refinement for 3
Empirical formula
Mr
Temperature
Wavelength
Crystal system
Space group
Unit cell dimensions
C22H18N2
310.38
298(2) K
0.71073 Å
Monoclinic
P21
a=9.1360(10) Å Absorption correction
b=5.4923(6) Å Max. and min.
c=16.7284(18) Å transmission
q range for data collection 2.23–26.008
Index ranges
À1ꢀhꢀ11, À6ꢀkꢀ1,
À20ꢀlꢀ20
Reflections
2550/2161 (Rint =0.0183)
collected/unique
Completeness to q=268 98.6%
y scan
0.993 and 0.945
a=908
Refinement method
full-matrix least-squares on F2
b=94.004(7)8
g=908
Data, restraints,
parameters
Goodness-of-fit on F2
2161, 1, 219
Volume
Z
Calc. density
837.34(16) Å3
2
1.059
Final R indices (I>2s(I)) R1 =0.0405, wR2 =0.0814
1.231 Mg/m3
R indices (all data)
Extinction coefficient
Largest diff. peak and
hole
R1 =0.0669, wR2 =0.0928
0.023(4)
Absorption coefficient 0.072 mmÀ1
F(000)
Crystal size
328
0.110 and À0.113 e·ÅÀ3
0.44×0.38×0.10
mm3
Ab initio calculations of all 22 potential isomers shown in Fig. 1, taken as models for the core moiety
of 3, were carried out with the GAUSSIAN 98 package. Geometry optimization was reached by using
B3LYP/6-311++G(2df,2p), HF/6-311++G(2df,2p), MP2(FU)/6-31+G(d,p), and HF/6-31+G(d,p).
These same calculation levels were employed for the PA evaluation of the N(1) and N(4) atoms of the
two tautomers R0 and R0T. PAs at the HF/6-311++G(2df,2p) and MP2(FU)/6-311++G(2df,2p) levels
were obtained by the SPE (single-point-energy) difference between protonated and unprotonated forms.
SPEs were computed on the structures obtained by B3LYP/6-311++G(2df,2p) optimization.
Results and Discussion. – X-Ray Crystal Structure of ‘exo’-2,4,6-Triphenyl-1,3-di-
azabicyclo[3.1.0]hex-3-ene (3). As expected, the bridgehead aziridine moiety of 3
exhibits a ‘Tuareg’-saddle conformation with three Ph residues attached to C(6),
C(5), and C(3)1) (Fig. 2). The orientation of the Ph group at C(6), as demonstrated
by the dihedral angles about N(1)ÀC(6) and C(6)ÀC(7), is in an anti–anti conformation
with respect to the fused rings, which, on their turn are considerably bent to each other,
the angle between the mean planes being 73.9(2)8. Significant bond distances and
angles of the aziridine moiety are: N(1)ÀC(6) 1.472(3) Å, N(1)ÀC(2) 1.483(3) Å,
N(1)ÀC(5) 1.490(3) Å, C(2)ÀN(1)ÀC(6) 61.3(1)8, and N(1)ÀC(2)ÀC(6) 59.0(1)8,
N(1)ÀC(6)ÀC(2) 59.7(1)8. These distances and angles are all comparable with the cor-
responding data reported for 2-(4-bromophenyl)-1,3-diazabicyclo[3.1.0]hexane [24]
and parent aziridine compounds reported in the CSD [25]. The entire molecular geom-
etry of 3 was optimized by ab initio and DFT methods. Structural parameters, obtained
at the B3LYP level, employing the two basis sets 6-311+G(2d,p) and 6-31+G(d,p), are
1
)
Arbitrary numbering, see Fig. 2.

Helvetica Chimica Acta – Vol. 89 (2006)
193
Fig. 1. Structures of the studied 22 isomers of the core aziridine skeleton of 3
in good agreement with those obtained from diffraction data (Table 2). Both these lev-
els reproduced exactly the X-ray data, whereas the HF/6-31+G(d,p) optimization gave
definitely different parameters. Therefore, once again the good agreement of B3LYP
calculations with data obtained by X-ray diffraction is evidenced . The expected differ-
ences concern just the dihedral angles defining the orientation of the Ph rings with
respect to the aziridine core. These are due to the particular solid-state interactions
responsible of the molecular packing, while in the gas phase, the low rotational barriers
drive molecules to the lower individual conformational energy. The interesting intra-
molecular H-bond involving a Ph CÀH H-atom and N(1) (C(12)···N(1) 2.913(4) Å,
C(12)ÀH(12)···N(1) 102.38) has to be mentioned. The molecular packing of 3 (Fig.
3) is mainly determined by Van der Waals interactions and few weak H-bonds involving
both the N(1) and N(4) atoms.
Ab initio Calculations. We optimized the geometry of compound 3 and also of its
three diastereoisomers and all four diastereoisomers of the tautomer 3T by ab initio
and DFT methods employing the basis set 6-31+G(d,p). The geometry of these
eight diastereoisomers with their stereodescriptors for C(2), C(5), and C(6)1), their
absolute and relative stability energies within each group of diastereoisomers and

194
Helvetica Chimica Acta – Vol. 89 (2006)
Fig. 2. Crystal structure of 3, with 30% of anisotropic ellipsoid probability. Arbitrary atom numbering.
the relative stability energies between equivalent tautomers are reported in Fig. 4. In
agreement with the stereoselectivity of the reaction [12], compound 3 (denoted by 3
(2R,5S,6R) in Fig. 4) appears to be the most stable of the diastereoisomers. The energy
difference between the two most stable diastereoisomers of 3 is only 0.51 kcal/mol, the
most stable is that obtained under thermodynamic control. The four diastereoisomeric
tautomers 3T are systematically ca. 2.5 kcal/mol more stable than the corresponding 3,
as evidenced in Fig. 4.
Among all cyclic and open isomers and tautomers of the aziridine core moiety of
compound 3, 22 structures were taken as models (Fig. 1) and their relative energies
computed at various levels of calculation (Table 3). At every level of calculation, iso-
mer R5e is the most stable and R12 the least stable one. Between these two isomers,
we calculated at the B3LYP/6-311++G(2df,2p) level an energy gap of 49.40 kcal/
mol. At this same level, the energy gap between the isomers R0 and R0T is just 2.20
kcal/mol. Table 3 shows that the ranking of the relative isomer stability at different cal-
culation levels is roughly the same. However, when electronic corrections are not con-
sidered (HF methods), isomer R10, characterized by charge separation, evidences
anomalies becoming the least stable isomer.
Although the absolute energies in considering the zero-point corrections are obvi-
ously less than the corresponding energies computed at the HF/6-31+G(d,p) level, the
relative ranking order remains unchanged.
The proton affinities of the N(1) and N(4) atoms1), i.e., PA(N(1)) and PA(N4)) of
the tautomers R0 and R0T were calculated at several levels. The structure parameters

Helvetica Chimica Acta – Vol. 89 (2006)
195
Fig. 3. Crystal packing of 3 along the b crystallographic axis
of R0 and R0T together with those of the corresponding mono- and diprotonated forms
were optimized and reported in Table 4. We assume that exploitation of the large basis
set 6-311++G(2df,2p) combined with the hybrid density-functional theory B3LYP
would be the more appropriate for both geometric and PAs evaluation. As already
stated for the protonation of saturated alkylamines [26], whatever kind of N-protona-
tion triggers a significant stretching of the close NÀC bond distances and a shortening
of the next CÀC (or CÀN) ones.
When N(4) of R0T is protonated, a major change affects the N(1)ÀC(5) bond dis-
tance, i.e., N(1)ÀC(5) shrinks from 1.4288 to 1.3566 Å (D=0.072 Å). Other changes to
be mentioned involve the bond angles N(4)ÀC(5)ÀN(1) of all protonated species. Thus
the bond angle of 109.278 in R0 and 119.178 in R0T, typical for sp3 and sp2 of C(5),
respectively, decreases by 7.87 and 7.568, respectively, on protonation at N(1) and
N(4). The only structural parameters not really affected by protonation are the
C(2)ÀC(3) and C(2)ÀC(6) bond lengths. Bond distances and angles of the tautomer
R0 computed at every B3LYP level are in good agreement with the corresponding val-
ues recorded at the B3LYP/6-31G(d) level for the similar l-azabicyclo[3.1.0]hexane
[27]. In Table 5, the PA(N(1)) and PA(N(4)) of R0 and R0T are reported. To get a bet-

196
Helvetica Chimica Acta – Vol. 89 (2006)
Table 2. Selected Structure Parameters (bond lengths [Å] and angles [8]) Obtained from the X-Ray Crystal
Structure and from ab initio and DFT Gas-Phase Calculations of 3. Arbitrary atom numbering1).
X-Ray
B3LYP/6-311+G(2d,p) B3LYP/6-31+G(d,p) HF/6-31+G(d,p)
Bond lengths:
N(1)ÀC(6)
N(1)ÀC(2)
N(1)ÀC(5)
N(4)ÀC(3)
N(4)ÀC(5)
C(13)ÀC(3)
C(6)ÀC(7)
C(6)ÀC(2)
C(3)ÀC(2)
C(5)ÀC(19)
1.472(3)
1.4642
1.4676
1.4875
1.2793
1.4971
1.4717
1.4883
1.5053
1.4971
1.5231
1.4653
1.4698
1.4904
1.2869
1.4707
1.4742
1.4924
1.5094
1.5011
1.5260
1.4413
1.4436
1.4686
1.2594
1.4585
1.4802
1.4958
1.4880
1.4994
1.5226
1.483(3)
1.490(3)
1.282(3)
1.481(3)
1.479(3)
1.486(3)
1.506(3)
1.490(3)
1.510(3)
Angles:
C(6)ÀN(1)ÀC(2)
C(6)ÀN(1)ÀC(5)
C(2)ÀN(1)ÀC(5)
C(3)ÀN(4)ÀC(5)
N(1)ÀC(6)ÀC(7)
N(1)ÀC(6)ÀC(2)
C(7)ÀC(6)ÀC(2)
N(4)ÀC(3)ÀC(13)
N(4)ÀC(3)ÀC(2)
C(13)ÀC(3)ÀC(2)
N(1)ÀC(2)ÀC(3)
N(1)ÀC(2)ÀC(6)
C(3)ÀC(2)ÀC(6)
N(4)ÀC(5)ÀN(1)
N(4)ÀC(5)ÀC(19)
N(1)ÀC(5)ÀC(19)
61.3(1)
112.8(2)
103.9(2)
107.6(2)
117.4(2)
59.7(1)
120.8(2)
123.1(2)
114.0(2)
122.9(2)
105.2(2)
59.0(1)
61.79
113.80
104.54
108.96
118.50
59.22
122.39
123.55
112.78
123.67
105.41
59.00
61.90
113.93
104.63
108.75
118.40
59.20
122.46
123.54
112.80
123.65
105.37
58.91
62.10
114.84
105.66
109.41
118.42
59.03
122.50
123.81
112.58
123.61
104.71
58.87
112.6(2)
108.8(2)
109.7(2)
111.1(2)
113.93
108.21
111.28
112.11
113.94
108.34
111.21
112.02
113.54
107.54
111.42
112.21
C(18)ÀC(13)ÀC(3)ÀN(4)
À6.6(4)
À10.48
À10.34
À12.95
ter insight into the protonation effect, we used the ab initio Hartree-Fock (HF), second-
order Möller-Plesset (MP2), and density-functional theory (DFT) methods with
medium and large basis sets. Zero-point-energy corrections at the HF/6-31+G(d,p)
level exhibits an overestimated value of ca. 3.8% in PA with respect to the correspond-
ing uncorrected one.
The R0 model shows a similar PA for both N atoms at every calculation level: at the
highest calculation level PA(N(1)) is 225.65 and PA(N(4)) 225.47 kcal/mol. On the
other hand, a relevant PA difference between the N(1) and N(4) positions is recorded
for the R0T tautomer: at the same highest calculation level this difference is 8.97 kcal/
mol, the PA(N(4)) (229.10 kcal/mol) always being the highest one. In these tautomers,
the PA(N(1)) are mutually comparable and anyway higher than those calculated for 2-
ethenylaziridine and 1-ethenylaziridine [28] (216.56 and 215.96 kcal/mol, resp.). For the

Helvetica Chimica Acta – Vol. 89 (2006)
197
Fig. 4. Optimized geometries of the diastereoisomers of 3 and 3T, and absolute and relative stability
energies computed at the B3LYP/6-31+G(d,p) level. au=arbitrary unit. DE in kcal/mol. Arbitrary
atom numbering1).
isomer R0T, structural changes undergone by protonation are consistent with an
increased availability of electron density around N(4), which explains why PA(N(4))
is always higher than PA(N(1)). In R0, the sp3-hybridized C(5) atom hampers the par-

198
Table 3. Absolute and Relative Energy of Several Isomers Reported in Fig. 1. a.u.=arbitrary unit. DE in kcal/mol.
E(a.u.)a) E(a.u.)b) E(a.u.)c) E(a.u.)d) E(a.u.)e)
DE DE DE DE DE
0.00
Helvetica Chimica Acta – Vol. 89 (2006)
R5e À265.63095 0.00 À263.94333
R5a À265.63010 0.53 À263.94256
R5d À265.61933 7.29 À263.93176
0.00 À264.78736
0.48 À264.78645
7.26 À264.77645
0.00 À263.87667
0.57 À263.87599
6.85 À263.86495
0.00 À263.77063
0.43 À263.76981
7.35 À263.75864
0.51
7.52
R5c À265.60566 15.87 À263.92353 12.42 À264.76293 15.33 À263.85754 12.00 À263.75223 11.55
R5b À265.60527 16.11 À263.92533 11.29 À264.76093 16.58 À263.85880 11.21 À263.75410 10.37
R2d À265.59862 20.29 À263.91499 17.78 À264.74913 23.99 À263.84722 18.48 À263.74005 19.19
R2
R5
À265.59802 20.66 À263.91553 17.44 À264.74690 25.39 À263.84789 18.06 À263.74074 18.76
À265.59783 20.78 À263.91900 15.27 À264.75672 19.23 À263.85247 15.19 À263.74677 14.97
R2a À265.59348 23.51 À263.90658 23.10 À264.74492 26.63 À263.84042 22.75 À263.73328 23.44
R2c À265.59036 25.47 À263.91078 20.42 À264.74512 26.51 À263.84444 20.22 À263.73752 20.78
R2b À265.58939 26.08 À263.91081 20.41 À264.74255 28.12 À263.84348 20.83 À263.73680 21.23
R13a À265.58563 28.44 À263.90728 22.62 À264.73632 32.03 À263.83952 23.31 À263.73303 23.59
R13c À265.58305 30.06 À263.89703 29.05 À264.72854 36.97 À263.82954 29.57 À263.72401 29.25
R13 À265.57842 32.96 À263.89665 29.29 À264.72964 36.22 À263.83033 29.08 À263.72354 29.55
R13b À265.57130 37.43 À263.88456 36.88 À264.70998 48.55 À263.81395 39.36 À263.70978 38.18
R12b À265.56346 42.35 À263.87806 40.96 À264.70486 51.77 À263.81020 41.71 À263.70777 39.44
R0T À265.56008 44.47 À263.87836 40.77 À264.72131 41.45 À263.81226 40.42 À263.70491 41.24
R12a À265.55735 46.18 À263.87255 44.41 À264.69850 55.76 À263.80367 45.81 À263.70121 43.56
R0
À265.55658 46.67 À263.87484 42.98 À264.71796 43.55 À263.80891 42.52 À263.70150 43.38
R12c À265.55244 49.26 À263.86704 47.87 À264.69418 58.47 À263.79868 48.94 À263.69653 46.50
R10 À265.55243 49.27 À263.84396 62.35 À264.70062 54.43 À263.77655 62.83 À263.67202 61.88
R12 À265.55223 49.40 À263.86698 47.91 À264.69454 58.24 À263.79957 48.38 À263.69691 46.26
a) B3LYP/6-311++G(2df,2p). b) HF/6-311++G(2df,2p). c) MP2(FU)/6-31+G(d,p).d) HF/6-31+G(d,p). e) HF/
6-31+G(d,p), zero-point-energy corrected.
tial delocalization of the N(1) nonbonding (n) orbital, thus resulting in a high s-charac-
ter over the N(1)ÀC(5)ÀN(4) moiety.
Conclusions. – We reported the structure characterization of 2,4,6-triphenyl-1,3-
diazabicyclo[3.1.0]hex-3-ene (3), which we chose as a model for the generation of
focused chemical libraries. Compound 3 is part of a class scarcely represented in the
crystallographic database (CSD). Therefore, the stabilities of related isomers and the
PAs of the aziridine models R0 and R0T were evaluated with the hybrid B3LYP calcu-
lation method which seems always the best performing one, especially with extended
basis sets. Beyond the confirmation of the structure considerations already drawn for
the protonation of alkylamines, we established in this paper the PA differences due
to allowed or hampered conjugation between two N-atoms in similar tautomeric sys-
tems like R0 and R0T.
X-Ray measurements were performed at CISDRX (Centro Interdipartimentale di Servizi per la Dif-
frattometria a Raggi-X), University of Messina, which is kindly acknowledged. CCDC-258949 contains
the supplementary crystallographic data for this paper. These data can be obtained free of charge from
the Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif.

Helvetica Chimica Acta – Vol. 89 (2006)
199
Table 4. Results of the B3LYP/6-311++G(2df,2p) Geometry Optimization of Free and Protonated
Tautomers R0 and RT. Arbitrary atom numbering1).
R0
Protonated R0
R0T
Protonated ROT
HÀN(1)+ HÀN(4)+ HÀN(1)+/
HÀN(1)+ HÀN(4)+ HÀN(1)+/
HÀN(4)+
HÀN(4)+
Bond Lengths [A]:
N(1)ÀC(2)
N(1)ÀC(6)
N(1)ÀC(5)
N(1)ÀH
1.4784
1.4612
1.4801
–
1.4897
1.4905
1.2698
1.4687
–
1.4989
1.4891
1.5281
1.0146
1.4837
1.5038
1.2649
1.4325
–
1.4888
1.4430
1.4543
–
1.5139
1.4516
1.2873
1.5000
1.0149
1.5141
1.4963
1.4898
1.0215
1.4930
1.4785
1.2798
1.4775
1.0233
1.4868
1.4892
1.4288
–
1.4770
1.5257
1.4761
1.2670
–
1.5095
1.5059
1.4877
1.0164
1.4743
1.5293
1.4648
1.2466
–
1.4996
1.5157
1.3566
–
1.4739
1.5245
1.4851
1.2964
1.0131
1.5501
1.5616
1.4125
1.0231
1.4644
1.5255
1.4886
1.2734
1.0236
C(2)ÀC(6)
C(2)ÀC(3)
C(3)ÀN(4)
N(4)ÀC(5)
N(4)ÀH
Bond angles [8]:
C(2)ÀN(1)ÀC(6) 60.89
C(2)ÀC(6)ÀN(1) 60.12
C(5)ÀN(1)ÀC(6) 113.67
C(3)ÀC(2)ÀN(1) 104.54
C(6)ÀC(2)ÀC(3) 113.31
C(2)ÀC(3)ÀN(4) 114.51
C(3)ÀN(4)ÀC(5) 107.54
N(4)ÀC(5)ÀN(1) 109.27
59.55
60.55
62.15
60.41
59.46
60.86
59.51
60.16
58.54
60.85
58.52
60.20
56.15
61.53
118.82
101.70
115.61
114.75
111.57
105.62
115.46
105.84
112.00
110.94
111.80
104.09
120.18
102.65
115.79
111.46
115.16
101.40
110.59
106.19
118.43
104.96
107.31
119.17
115.85
103.65
118.43
106.16
111.44
114.04
114.25
107.05
121.09
100.49
111.95
115.06
116.89
104.01
119.02
102.27
114.95
111.61
Table 5. Absolute Energy [a.u.] and Proton Affinity [kcal/mol] of the N Atoms of the Tautomers R0 and
R0T
E [a.u.]
HÀN(1)+
HÀN(4)+
PA(N(1))
PA(N(4))
R0
B3LYP/6-311++G(2df,2p)
//MP2/6-311++G(2df,2p)
//HF/6-311++G(2df,2p)
B3LYP/6-31+G(d,p)
MP2(FU)/6-31+G(d,p)
HF/6-31+G(d,p)
À265.55658
À265.04237
À263.87484
À265.48741
À264.71796
À263.80891
À263.70150
À265.91618
À265.39288
À264.24160
À265.84447
À265.07308
À264.17544
À264.05328
À265.91589
À265.39446
À264.24226
À265.85544
À265.07189
À264.17583
À264.05413
225.65
219.95
230.14
224.06
222.84
230.00
220.74
225.47
220.94
230.56
230.94
222.09
230.24
221.28
HF/6-31+G(d,p)ZPEc
R0T
B3LYP/6-311++G(2df,2p)
//MP2/6-311++G(2df,2p)
//HF/6-311++G(2df,2p)
B3LYP/6-31+G(d,p)
MP2(FU)/6-31+G(d,p)
HF/6-31+G(d,p)
À265.56008
À265.04573
À263.87836
À265.49102
À264.72130
À263.81226
À263.70491
À265.91088
À265.39043
À264.23829
À265.84208
À265.07038
À264.17210
À264.05055
À265.92518
À265.40244
À264.25299
À265.85544
À265.08029
À264.18610
À264.06443
220.13
216.30
225.86
220.29
219.68
225.80
216.89
229.10
223.84
235.08
228.68
225.27
234.59
225.60
HF/6-31+G(d,p)ZPEc

200
Helvetica Chimica Acta – Vol. 89 (2006)
REFERENCES
[1] T. J. Hodgkinson, M. Shipman, Tetrahedron 2001, 57 4467.
[2] A. Regueiro-Ren, R. M. Borzilleri, X. Zheng, S.-H. Kim, J. A. Johnson, C. R. Fairchild, F. Y. F. Lee,
B. H. Long, G. D. Vite, Org. Lett. 2001, 3, 2693.
[3] R. S. Coleman, Curr. Opin. Drug Discovery Dev. 2001, 4, 435.
[4] R. W. Brockman, S. C. Shaddix, M. Williame, R. F. Struck, Cancer Treat. Rep. 1976, 60, 1317.
[5] M. Tomasz, R. Lipman, B. F. McGuinness, K. Nakanishi, J. Am. Chem. Soc. 1988, 110, 5892.
[6] G. Subramaniam, M. M. Paz, S. Kumar, A. Das, Y. Palom, C. C. Clement, D. J. Patel, M. Tomasz,
Biochemistry 2001, 40, 10473.
[7] M. Shibuya, H. Terauchi, Tetrahedron Lett. 1987, 28, 2619.
[8] K. Ando, T. Yamada, M. Shibuya, Heterocycles 1989, 29, 2209.
[9] T. J. Hodgkinson, L. R. Kelland, M. Shipman, J. Vile, Tetrahedron 1998, 54, 6029.
[10] H. W. Heine, R. H. Weese, R. A. Cooper, A. J. Durbetaki, J. Org. Chem. 1967, 32, 2708.
[11] L. Weber, K. Illgen, M. Almstetter, Synlett 1999, 3, 366.
[12] F. Risitano, G. Grassi, F. Foti, S. Moraci, Synlett 2005, 10, 1633.
[13] S. L. Dax, J. J. McNally, M. A. Youngman, Curr. Med. Chem. 1999, 6, 255.
[14] A. Padwa, S. Clough, E. Glazer, J. Am. Chem. Soc. 1970, 92, 1778; A. Padwa, E. Glazer, J. Am.
Chem. Soc. 1972, 94, 7788.
[15] J. Xu, P. Jiao, J. Chem. Soc., Perkin Trans. 1 2002, 12, 1491, and ref. cit. therein.
[16] A. C. T. North, D. C. Phillips, F. S. Mathews, Acta Crystallogr., Sect. A 1968, 24, 351.
[17] A. Altomare, G. L. Cascarano, C. Giacovazzo, A. Guagliardi, M. C. Burla, G. Polidori, M. Camalli,
J. Appl. Crystallogr. 1999, 32, 115.
[18] G. M. Sheldrick, ‘SHELXL97, Program for Crystal Structure Refinement’, University of Göttingen,
Germany, 1997.
[19] J. A. Ibers, W. C. Hamilton, ‘International Tables for X-ray Crystallography’, Vol. IV, Kynoch Press,
Birmingham, UK, 1974.
[20] M. Nardelli, Comput. Chem. 1983, 7, 95.
[21] C. K. Johnson, ‘ORTEP, Report ORNL 3794’, Oak Ridge National Laboratory, Oak Ridge, TN,
1971.
[22] H. D. Flack, Acta Crystallogr., Sect. A 1983, 39, 876.
[23] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. M. Scuseria, A. Robb, J. R. Cheeseman, V. G. Zakr-
zewski, J. A. Montgomery, R. E. Stratmann, J. C. Burant, S. Dapprich, J. M. Millam, A. D. Daniels,
K. N. Kudin, M. C. Strain, O. Farkas, J. Tomasi, V. Barone, M. Cossi, R. Cammi, B. Mennucci, C.
Pomelli, C. Adamo, S. Clifford, J. Ochterski, G. A. Petersson, P. Y. Ayala, Q. Cui, K. Morokuma,
D. K. Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. Cioslowski, J. V. Ortiz, B. B. Ste-
fanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. Gomperts, R. L. Martin, D. J. Fox, T.
Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayakkara, C. Gonzalez, M. Challacombe, P. M. W.
Gill, B. G. Johnson, W. Chen, M. W. Wong, J. L. Andres, M. Head-Gordon, E. S. Replogle, J. A.
Pople, ‘GAUSSIAN98, Revision A.7’, Gaussian Inc., Pittsburgh, PA, 1998.
[24] S. A. Hiller, Y. Y. Bleidelis, A. A. Kemme, A. V. Eremeyev, J. Chem. Soc., Chem. Commun. 1975, 4,
130.
[25] F. Allen, C. M. Bird, R. S. Rowland, P. R. Raithby, Acta Crystallogr., Sect. B 1997, 53, 696.
[26] H. Ishida, Z. Naturforsch., A 2000, 55, 769.
[27] A. Rauk, D. Yang, D. Tsankov, H. Wieser, Y. Koltypin, A. Gedanken, G.V. Shustov, J. Am. Chem.
Soc. 1995, 117, 4160.
[28] M. J. Elrod, Int. J. Mass Spectrom. 2003, 228, 91.
Received October 6, 2005