[A010]
Quantum Chemical Estimation of Reactivity of 2,3,4,5-Tetrahydro-1,5-benzodiazepin-2(1H)-ones in Electrophilic Aromatic Substitution.
Ausra Vektarienea * and Gytis Vektarisb
aInstitute of
Biochemistry, Mokslininkų 12, LT-2600, Vilnius, Lithuania, Tel.: +370 5 2729195; Fax:+370 5
2729196, E-mail: avekt@bchi.lt
bVilnius University
Research Institute of Theoretical Physics and Astronomy, A. Goštauto
12, Vilnius 2600, Lithuania, Tel.: +370 5 2620953, Fax: +370 5
2125361, +370 5 2124694, E-mail: vektaris@itpa.lt
*Corresponding author, E-mail: avekt@bchi.lt.
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Abstract
B3LYP and AM1 calculation study was employed to estimate the regioselectivity of an electrophilic aromatic substitution in functionalized 2,3,4,5-Tetrahydro-1,5-benzodiazepin-2(1H)-ones. Charge density, frontier molecular orbital study, energetics of s-complex intermediates of electrophilic substitution reactions in the 2,3,4,5-Tetrahydro-1,5-benzodiazepin-2(1H)-ones yield information on different reactivity of aromatic sites.
Introduction
Recent years increasing interest has been directed towards
synthesis of functionalized tetrahydro-1,5-(or 1,4)-benzodiazepinones due to
their unique biological activity [1-2].
Among the diversity of synthetic attempts literature provides data closely
connected to functionalization reactions of substituted 2,3,4,5-tetrahydro-
1,5(or 1,4)-benzodiazepinones by direct electophilic substitution of aromatic
ring. In most cases described reactions demonstrate different activity of
particular benzene carbons towards attacking electrophiles [3-8].
Otherwise literature provides no data concerning quantum chemical estimation of
reactivity 2,3,4,5-tetrahydro- 1,5-benzodiazepinones. Therefore it was
interesting to predict most reactive benzene sites of 2,3,4,5-tetrahydro-
1,5-benzodiazepinones using results of quantum chemical calculations.
Results and discussion
In this context we concentrate our efforts on the experimental data obtained by Janciene and Puodziunaite referred in literature [9-11] and presented in scheme 1. Described results pointing out
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yielded products with different orientation of entering
electrophilic nitro group in the electrophilic aromatic substitution [9-11].
5-Acetyl-7-bromo-2,3,4,5-tetrahydro- 1,5-benzodiazepinone 1 and analogous
C-3 and C-4 methyl substituted 1,5-benzodiazepinones 2 and 3 were
nitrated exceptionally at position 9 [9].
Reaction of 5N-formyl-benzodiazepinone bearing C-4 methyl substitute 4
with nitration agent lead to the mixture of isomeric 8- and 9- mononitro
benzodiazepinones in a ratio 1:1,2. While 
nitration of
5N-formylbenzodiazepinone 5 with C-3 methyl substitute and
5N-trifluoroacetylbenzodiazepinone 6 and its C-3 methylated analogue 7
in the same fashion afforded the mixture of 8- and 9-mononitro products in a
ratio of 1:4 to 1:3 ratio [10-11].
In order to get more insight into nature of the observed regiochemistry it was
interesting to have quantum chemical estimation of molecular parameters and
compare calculated results with experimental data obtained from [9-11]
. Quantum chemical calculations were caried
out to study geometry
and electronic structure of substituted 7-bromo-2,3,4,5-tetrahydro-
1,5-benzodiazepinones 1-7. Also energies of electrophilic aromatic
substitution reaction: p-localization energies of s-complexes and heat of formation of s-complex obtained from AM1 calculations. Full
geometry optimization of starting compounds 1-7 was performed by DFT
calculations at the B3LYP/STO-4G level using GAMESS program package
[12].
Optimized structures 1-7 are shown in figures 1-
7
accordingly. The an
alysis of obtained conformations for optimized
structures 1-7 shows that the benzene ring together with N-1 and N-5
nitrogens causes planar conformation for all optimized structures. While
remaining diazepine skeleton for tetrahydro-1,5-benzodiazepinones 1-4 and
6 adopts chair conformation with the C-3 or C-4 methyl in pseudo
axial-positions. Optimized structures of tetrahydro-1,5-benzodiazepinones
5 and 7 bearing formyl and trifluorocetyl groups at N-5 and methyl
at C-3 gets twist conformations which are lowest in energy. The planar
conformation of benzene and nitrogens N-1, N-5 on diazepine demonstrate that
2pz orbitals of benzene and
2pz lone electron pair orbitals of nitrogens
create single system of delocalized p- molecular orbitals. It suggests that differences
in electronegativity of nitrogens could make high impact on electron density of
benzene nucleus. Otherwise in electrophilic aromatic substitution reactions,
electrophiles attack the electron rich p -cloud of an
aromatic system, forming an intermediate s-complex.
Therefore the examination of 2pz atomic orbitals electron
population densities in two highest bonding p-molecular
orbitals HOMO, HOMO-1 [13],
and estimation of total pz electron population density for
particular atoms was of our interest. The computational results
presented 
in table 1
indicate that for all derivatives pz
electron population density in HOMO-1 is mostly located
at C-9 carbon and less located at C-8 carbon atom. The similar tendencies
observed for parameters of total pz electron population
densities for C-9 and C-8 respectively. This calculation result predicts no more
than common tendency of the nitration direction. Likewise, in experiments [9-11]
the nitration process of all studied compounds took place predominantly at C-9
position. The pz electron population densities in HOMO
calculated for all derivatives shows C-8 position to be dominating. This
estimation suggests that substitution at C-8 is also possible. Differences
observed in pz electron population densities did not seem
significant enough to explain the regiochemistry of reaction. Therefore for
further investigation we used several
approaches [14-16]
to evaluate difference in the reactivity between 8 and 9 positions of aromatic
moiety for the molecules 1-7. The isolated molecule approach seeks
correlation between rates of attack of an electrophilic reagent and the mostly
negatively charged - high electron densities centers. The localization energy
method employs the change in p-energy between the aromatic molecule and benzene
s-complex cation to be
compared. The Mulliken, Lowdin charges, and also net atomic charge densities
restrained electrostatic potential charges (ESP charges) at a B3LYP/ STO-4G
level were calculated and compared with observed experimental reactivity [9-11]
towards position 8 and 9. The results of calculated Mulliken charges (Table 1,
were results are presented only for C-8 and C-9 atoms) indicate that for all
derivatives the aromatic charges decrease in the following succession: C-7 >
C-9 > C-8 > C-6 suggesting that 9 position is possible for elecrophilic
attack when C-7 is occupied. Lowdin and ESP charges presented in table 1
are better descriptors for predicting of most reactive sites of aromatic
nucleus towards attacking electrophiles. Calculation results indicate the high
differences in charge distribution of derivatives 1-3 between
benzene carbons at 8 and 9 positions. The increase of negative charge density on
C-9 (-0.0305) (arithmetical mean values of Lowdin charge from table 1 are
presented in text) comparing to C-8 (+0.0008) imply that position 9 should be
the most susceptible to electrophilic attack than position 8 correlate with
observed reactivity. The smaller difference of charge distribution of carbons
C-8 (-0.0062) and C-9 (-0.0276) in compounds 5-7 concur experimental
results of nitration process leading to the mixture of 8- and 9- mononitro
products in rate 1:4 to 1:3. The almost equal charge parameters for C-8
(-0.0127) and C-9 (-0.0256) in compound 4 guess both positions to be
attractive for electrophiles while nitration reaction leads formation both
isomers in ratio 1:1. Observed behavior for distribution of ESP charges for
1-7 represent the same tendencies as it was observed for Lowdin charges.
It is worth to notice that substitutes in tetrahydro-1,5-benzodiazepinone
skeleton yielded differences in ESP charge density on N-1 and N-5 atoms of
1-7. In order to further quantify the differences in reactivity
between position 8 and 9 the p-localization energies
for s - complex and NO2+ (the
attacking electrophile) according to the definition given for electrophilic
aromatic substitution in literature [16,
17] also heat of formation (Hf) of s -
complexes were calculated using AM1 method and presented in table 2.
Obtained energies were compared with experimentaly observed regioselectivity [9-11].
Calculated differences of p-localization energies for
s-complex (DL+) for
NO2+ substitution of N-acetylderivatives
1-3, at position C-9 is favored to form s-complexes over substitution at position 8 by ~ 5.65 ÷ 8.35
kcal/mol. This result predicts that experimental exceptional reactivity of C-9
position for N-acyl 1,5-benzodiazepinones 1-3 is in agreement with theory
since substitution at C-8 was not detected. In the case of nitration of N-formyl
derivative 4 p-localization energies differ only
by 0.16 kcal/mol that correlates with the experiment showing that two mononitro
compounds were formed in almost equal ratio. The DL+ for compounds 5-7 is in the
range of 1.51 ÷ 4.89 kcal/mol. The smaller DL+ values for compounds 5-7 in
comparison with those for 1-3 yielded satisfying correlation with
experiments which confirmed the formation of both possible nitro isomers, though
the substitution at C-9 is favored (9-nitro isomers predominate in the crude
nitration mixtures). Conclusions
The calculations evidently point to the suitability of localization energy to predict the reactivity of differently substituted tetrahydro-1,5-benzodiazepinones in the electrophilic aromatic substitution. Investigation of Lowdin charges also useful for estimation of reactivity. The conformational and configurational properties of differently substituted tetrahydro-1,5-benzodiazepinone skeleton affected differences in ESP charge density on N-1 and N-5 atoms and successive differentiation of charge distribution on particular benzene nucleus. Presumably, this may explain the distinct contribution of heterocycle skeleton for the stability of s-complex and subsequently for the orientation of entering electrophile by substitution reaction of aromatic moiety.
References