Chirality of the trisubstituted nitrogen center – XRD, dynamic NMR, and DFT investigation of 1,2-dihydrobenzo[e][1,2,4]triazine derivatives

Article abstract of DOI:10.1016/j.tet.2017.05.032

Molecular structures of two 1-aryl-2-benzyloxycarbonyl-1,2-dihydrobenzo[e][1,2,4]triazines 1 were established by single crystal XRD and compared to those of 4-benzyloxycarbonyl (2) and 4-benzyl (4) analogues. The structures revealed a highly pyramidalized asymmetric N(1) center stabilized by steric interactions in 1, but not in 2 and 3. Activation parameters for enantiomer interconversion were obtained by DNMR methods in C₆D₅Cl: ΔH^? = 18.1(1) kcal mol^?1, ΔS^? = ?0.6(1) cal mol^?1 K^?1 for Ar = Ph (1a) and ΔH^? = 18.6(4) kcal mol^?1, ΔS^? = 5.2(6) cal mol^?1 K^?1 for Ar = 2-anisyl (1b). DFT computational investigation of the origin of the interconversion barrier on model compounds revealed steric destabilization of the inversion TS.

Full text of DOI:10.1016/j.tet.2017.05.032

Accepted Manuscript
Chirality of the trisubstituted nitrogen center – XRD, dynamic NMR, and DFT
investigation of 1,2-dihydrobenzo[e][1,2,4]triazine derivatives
Piotr Kaszyński, Arkadiusz Kłys, Sławomir Domagała, Krzysztof Woźniak
PII:
S0040-4020(17)30507-0
10.1016/j.tet.2017.05.032
TET 28698
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 March 2017
Revised Date: 27 April 2017
Accepted Date: 8 May 2017
Please cite this article as: Kaszyński P, Kłys A, Domagała Sł, Woźniak K, Chirality of the trisubstituted
nitrogen center – XRD, dynamic NMR, and DFT investigation of 1,2-dihydrobenzo[e][1,2,4]triazine
derivatives, Tetrahedron (2017), doi: 10.1016/j.tet.2017.05.032.
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ACCEPTED MANUSCRIPT
Tetrahedron March 15, 2017
REVISED: April 26, 2017
Piotr Kaszyński
Centre for Molecular and Macromolecular
Studies
Polish Academy of Sciences
Sienkiewicza 112
90363 Łódź, Poland
E-mail: Piotr.kaszynski@mtsu.edu
Chirality of the trisubstituted nitrogen center – XRD, dynamic NMR, and
DFT investigation of 1,2-dihydrobenzo[e][1,2,4]triazine derivatives
Piotr Kaszyński,*1,2,3 Arkadiusz Kłys,2 Sławomir Domagała,4 and Krzysztof Woźniak4
1
Centre for Molecular and Macromolecular Studies, Polish Academy of Sciences,
Sienkiewicza 112, 90363 Łódź, Poland, E-mail: piotrk@cbmm.lodz.pl
Department of Chemistry, University of Łódź, Tamka 12, 91403 Łódź, Poland
Department of Chemistry, Middle Tennessee State University, Murfreesboro, TN 37132, USA
Department of Chemistry, University of Warsaw, Pasteura 5, 02089 Warsaw, Poland
2
3
4
Abstract:
Molecular
structures
of
two
1-aryl-2-benzyloxycarbonyl-1,2-
dihydrobenzo[e][1,2,4]triazines 1 were established by single crystal XRD and compared to those
of 4-benzyloxycarbonyl (2) and 4-benzyl (4) analogues. The structures revealed a highly
pyramidalized asymmetric N(1) center stabilized by steric interactions in 1, but not in 2 and 3.
Activation parameters for enantiomer interconversion were obtained by DNMR methods in
C6D5Cl: ∆H‡ = 18.1(1) kcal mol-1, ∆S‡ = -0.6(1) cal mol-1 K-1 for Ar = Ph (1a) and ∆H‡ = 18.6(4)
kcal mol-1, ∆S‡ = 5.2(6) cal mol-1 K-1 for Ar = 2-anisyl (1b). DFT computational investigation of
the origin of the interconversion barrier on model compounds revealed steric destabilization of
the inversion TS.
Keywords: chirality, dynamic NMR, heterocyclic chemistry, single crystal XRD, DFT
calculations
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Graphical abstract
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Introduction
A typical tricoordinated nitrogen atom is configurationally labile, and, in contrast to
heavier elements such as P and S,1 its inversion is a low energy process.2,3 For this reason amine
nitrogen atoms are not typically considered stable chirality centers in the absence of any other
stereogenic elements in the molecule.4 Substitution of an amine H atom with a heteroatom
possessing a lone pair increases the inversion barrier.5-10 In particular, substituting with an NH2
group enhances configurational stability of the nitrogen center,11 and leads to a complicated
conformational behavior of the resulting hydrazines.12,13 Interaction of the unshared electron
pairs results in a gauche conformation or about 90o torsional angle between the electron pairs in
the global minimum, which is in agreement with the “gauche rule”14 and supported by structural
data15 and computational results.16,17 Consequently, N,N’-substituted hydrazines, irrespective of
the degree of nitrogen pyramidalization, have axially chiral rotamers. Some, e.g. derivatives of I
(Figure 1),18-20 have sizable activation energies to enantiomer interconversion, as evident from
observed patterns in the 1H NMR spectra21,22 and results of dynamic NMR analyses.18,23-25
The rotation around the N–N bond is restricted in cyclic hydrazines, and inversion of the
pyramidal nitrogen atom becomes the main dynamic process responsible for enantiomer
interconversion. The configurational stability of the stereogenic nitrogen center can be enhanced
in several ways:3 a) by increase of pyramidalization of the nitrogen atom through heteroatom
substitution, b) by increase of the s-character of the unshared pair orbital through confining into a
3-membered ring, c) by increase of rigidity of the cyclic system, d) by planarizing the adjacent N
atom, and e) by increase of steric congestion of the substituents. While the first two methods
involve changes in the electronic structure of the nitrogen atom in the ground state, the latter
three destabilize the inversion TS largely through steric interactions. For instance, activation
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energy,
∆
G‡, for nitrogen inversion in pyrazolidine (II, n = 5, R = Me, Figure 1) is measured at
11.1 kcal mol-1.5 Contraction of the heterocyclic ring gradually increases the inversion barrier to
16.2 kcal mol-1 in diazetidine (II, n = 4, R = Me),26 and to about 27 kcal mol-1 in diazirine (II, n
= 3),27,28 due to progressively increasing conformational rigidity of the ring and rehybridization
of the N atoms. Conformational restriction of pyrazolidine (II, n = 5) increases the inversion
barrier by about 8 kcal mol-1 in 2,3-diazanorbornane III (R = Me).29,30 On the other hand,
planarization of the adjacent nitrogen atoms in II, n = 5 through the carbamide functionality in
IV has a modest effect on the configurational stability of the nitrogen center (∆
G‡ = 11.6 kcal
mol-1, R = Bn).31 The preferred orthogonal orientation of the unshared electron pairs prevails also
in cyclic N,N’-diacyl hydrazines (e.g. type I, R = COOEt), in which axially chiral enantiomeric
conformers are separated by significant activation barriers.18,29,32
Figure 1. Selected types of cyclic hydrazines.
The search for derivatives with the configurationally stable trisubstituted nitrogen atom
as the only source of chirality in a molecule represents an interesting area of organic chemistry.
For some monocyclic 1,3,4-oxadiazolidines,33,34 oxaziridines,35,36 and 1,3,4-thiadiazolidines33
activation energies,
been isolated.34-36
∆
G‡, exceed 23 kcal mol-1, and enantiomers of several such derivatives have
Recently, we found evidence of enhanced configurational stability of the pyramidalized
nitrogen atom in 1,2-dihydro[1,2,4]triazines, a class of compounds of the general structure V
(Figure 1) previously not investigated in this context. While working towards
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benzo[
e
][1,2,4]triazinyl radicals,37 we observed an AB diastereotopic pattern of the benzylic
1
hydrogen atoms in the H NMR spectra of derivatives 1 (Figure 2).38 Given the interest in the
asymmetric nitrogen atom, this observation prompted us to carry out detailed studies into the
nature and origin of the inhibited inversion in 1. Herein we report molecular and crystal
structures for 1a and 1b, the first such structures for 1,2-dihydrobenzo[e][1,2,4]triazine, and
investigate activation parameters for their enantiomer interconversion using variable temperature
1H NMR spectroscopy and DFT computational methods. The molecular structure of 1a is
compared to those of its isomer 2a and derivative 3a.
Figure 2. The structures of 1a and 1b with the numbering scheme for the heterocycle.
Results and Discussion
Synthesis: Compounds 1 were obtained along with their isomers 2 by trapping of the anion 4
with benzyl chloroformate followed by chromatographic separation of the resulting isomers
(Scheme 1). Trapping of anion 4a with benzyl bromide provided an analogous mixture of
N-
benzyl derivatives out of which the 4-benzyl isomer 3a was isolated in 43% yield. Synthesis and
characterization details have been described previously.38
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Scheme 1. Synthesis of the 1,2-dihydrobenzo[
derivative 3a.
e][1,2,4]triazines 1, their isomers 2, and benzyl
Crystal and molecular structures: Colorless crystals of 1a and 2a were obtained from
CH2Cl2/cyclohexane, while 1b and 3a from petroleum ether/CH2Cl2 solutions, and their solid-
state structures were determined by low temperature single crystal X-ray diffraction methods.
Molecules of 1a, 2a and 3a crystallize in the triclinic P-1 space group, whereas 1b crystallizes in
the monoclinic P21/c space group. Each crystal structure contains one molecule in the
asymmetric part of the unit cell. Results are shown in Tables 1 and 2 and in Figures 3-5.
Analysis of the molecular structures of derivatives 1a and 1b revealed that the 3-
phenylbenzo[
atom, which is outside the molecular plane by nearly 0.8 Å (Table 2, Figure 3). This distortion
alleviates the unfavorable conjugation of 12 electrons in the heterocycle core, and also avoids
e][1,2,4]triazine system is approximately planar with the exception of the N(2)
π
local interactions of unshared electron pairs in the N(1)–N(2) fragment. As a consequence, the
substituents on the hydrazine fragment adopt a pseudo anti orientation relative to each other, as
shown for 1b in Figure 3. The observed geometry of the N(1)–N(2) fragment, including its bond
length of 1.417 Å, are typical for other hydrazide derivatives,39-42 and the geometry of the 1,2-
dihydro[1,2,4]triazine is reminiscent of that found19,20 for derivatives of type I (Figure 1).
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Table 1. Crystallographic data for investigated derivatives.a
1a
1b
2a
3a
Empirical formula
C27H21N3O2 C28H23N3O3 C27H21N3O2 C26H21N3
•0.04(H2O)
Fw
420.28
P-1
449.49
21/c
419.47
375.46
P-1
space group
P
P-1
a
b
, Å
, Å
7.6165(3)
9.1438(4)
18.8954(3) 9.0784(8)
9.5553(5)
15.8668(3) 10.1684(9) 9.9098(5)
c, Å
16.8190(7) 7.59731(15) 12.7434(11) 11.6678(5)
91.840(3)
102.242(4) 94.2861(16) 85.341(3)
108.813(4) 90 63.899(3)
90
78.137(3)
94.551(4)
98.953(4)
115.869(5)
α
β
, deg
, deg
γ, deg
V
Z
ρ
, Å3
1077.14(8) 2271.37(7) 1033.80(16) 968.45(9)
2
4
2
2
(calcd), g/cm3
1.296
0.083
0.0396
0.0495
0.1243
0.0673
0.1384
1.037
1.314
0.087
0.0720
0.0489
0.1221
0.0650
0.1322
1.029
1.348
0.087
0.0258
0.0413
0.1133
0.0446
0.1172
1.023
1.288
0.077
0.0490
0.0562
0.1400
0.0806
0.1581
1.050
ꢀ
, mm-1
Rint
b (I > 2
Rw c (I > 2
(all data)
Rw (all data)
R
σ
(I))
(I))
σ
R
goodness of fit on F2
a
b
c
Temperature 100 K,
λ
= 0.71073 Å;
R
=
∑
||
Fo| - |Fc||/∑
|Fo|.
Rw = [∑[w(F
o2 -
F
c2)2]/ o2)2]]1/2
∑[w(F
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Table 2. Selected interatomic distances (Å) and angles (o) for investigated derivatives. a
1a
1b
2a
3a
N(1)–N(2)
1.417(1) 1.417(1) 1.4052(9) 1.428(2)
1.426(1) 1.428(1) 1.282(1) 1.290(1)
1.289(2) 1.288(1) 1.4260(9) 1.399(1)
1.439(2) 1.437(1) 1.440(1) 1.436(2)
1.390(1) 1.391(1) 1.3835(9) –
N(2)–C(3)
C(3)–N(4)
N(1)–CPh
N–CO
C(3)–CPh
1.475(2) 1.475(1) 1.480(1) 1.485(2)
C=O
1.202(1) 1.202(1) 1.211(1)
–
N(1) pyramid b
N(2) pyramid b
N(4) pyramid b
N(2)…Benzene c
CPh–N(1)–N(2)–CO
0.411
0.173
–
0.380
0.193
–
0.349
–
0.344
–
0.101
0.755
–
0.140
0.675
–
0.793
126.8
25.4
87.4
0.769
125.8
23.1
79.7
d
COO…NR2
15.0
82.8
–
N(1)Ar…Benzene e
80.1
C(3)Ph…Benzene f
Ring puckering g
5.1
–
5.2
–
45.3
36.2
47.2
37.6
a Numbering according to the chemical structures. b Distance (in Å) of the N atom from the plane
c
defined by its three substituents. Distance (in Å) of the N atom from the plane defined the
d
benzene ring of the heterocycle. Angle between planes defined by the three atoms of each
e
fragment. Angle between planes of the phenyl ring at the N(1) and the benzene ring of the
f
heterocycle. Angle between planes of the phenyl ring at the C(3) and the benzene ring of the
heterocycle. g Angle between N(1)–C(8a)–C(4a)-N(4) and N(1)–N(2)–C(3)-N(4) planes.
The carbonyl group in 1 is partially conjugated with the adjacent nitrogen atom N(2): the
nitrogen center is significantly planarized, and the planes defined by the COO and C(3)N(2)N(1)
fragments form an angle of about 25o (Table 2).
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Figure 3. Thermal ellipsoid diagrams drawn at 50% probability for 1a (shown with
crystallization H2O) and two views of 1b (with and without H atoms for clarity). Oxygen atoms
are marked in red and nitrogen in blue. Pertinent molecular dimensions are listed in Table 2.
In contrast, high degree of pyramidalization of the N(1) atom and nearly orthogonal
orientation of the attached Ph ring prevent effective conjugation with the adjacent aromatic
systems (Figure 3). Thus, as a consequence of the pyramidalization and steric congestion, the
N(1) nitrogen atom can be considered as a stereogenic center of enhanced configurational
stability responsible for the observed diastereotopic splitting of the benzylic hydrogen atoms in
1
the H NMR spectrum of 1. In addition, it possesses a lone pair with a significant s-character
pointing to the center of the chiral cavity formed by three benzene rings and the carbonyl group
as shown in Figure 4 for 1b.
Figure 4. A space-filling model of the experimental structure of 1b showing the N(1) nitrogen
atom.
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A comparison of the 1a and 2a isomers is instructive. In the 4-COOBn isomer 2a and
also in the 4-benzyl derivative 3a the [1,2,4]triazine ring adopts a chevron or “open book”
conformation, characteristic for 8-π electron six-membered heterocyclic 1,4-dienes,43 with a
puckering angle of about 37o (Table 2). Less steric congestion around the amide bond, allows for
a more efficient overlap between the πCO* orbital and the lone pair nN in 2a than in the 1a
isomer. This is evident from the closest to parallel COO and NR2 planes, most planarized
nitrogen atom and, as a consequence of most effective electron density transfer from N to CO,
the shortest N–CO bond and the longest C=O distance in the investigated series (Table 2). The
Ph ring at the N(1) position bisects the puckering angle (the Ph…N(2)-C(3)-C(4a)-C(8a)
interplanar angle is 78.5o for 2a and 63o for 3a), while the Ph ring at the C(3) position adopts a
staggered conformation with respect to the adjacent C(3)=N(2) bond with the torsion angle of
43o and 49o for 2a and 3a, respectively (Figure 5). The N(1) is still significantly pyramidalized in
both compounds, but the planar, dicoordinated N(2) center does not inhibit interconversion of
chiral conformers. Structures of 2a and 3a complement two other structurally characterized
derivatives of 1,4-dhydrobenzo[e][1,2,4]triazine.44,45
Figure 5. Thermal ellipsoid diagrams drawn at 50% probability for two views of 2a and 3a.
Pertinent molecular dimensions are listed in Table 2.
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In three derivatives, 1a, 2a, and 3a, the unit cell contains two molecules related by
inversion symmetry, while the unit cell of the methoxy derivative 1b contains four molecules. In
addition, the unit cell of 1a contains two molecules of water of crystallization modelled with 4%
occupancy. Therefore, statistically every 25-th unit cell is occupied by two water molecules.
Significant intermolecular interactions have been found in the crystal structures of 1b, 2a,
and 3a. For instance, in 1b the C=O… CH3O contact is 0.35 Å shorter than the sum of van der
…
Waals (VDW) radii of O and C atoms resulting in a chain structure. Similar CH2 O=C
interactions in 2a lead to a dimeric structure. In 3a, the benzylic HCH…HCH distance between
neighboring molecules is 0.229 Å inside the H…H VDW separation, which also results in a
dimeric structure.
1
Dynamic NMR measurements: Ambient temperature H NMR spectra of 1a and 1b in C6D5Cl
show the benzylic CH2 protons as the AB pattern with the 2JHH = 12.5 Hz for 1a and the 2JHH
=
12.6 Hz for 1b, indicating their magnetic nonequivalence (Figure 6). With increasing
temperature the rate of inversion also increases and the signals coalesce at Tc = 376 and 341 K
for 1a and 1b, respectively. The calculated free energy of activation, ∆GTc‡, for the process is
18.3 and 16.8 kcal mol-1 for 1a and 1b, respectively.46
Complete line shape analysis performed for a series of spectra shown in Figure 6
followed by standard Arrhenius analysis of the resulting exchange rates kr vs temperature (Figure
7) gave the activation parameters, ∆H‡ and ∆S‡, listed in Table 3.
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Figure 6. Stacked 1H NMR spectra of 1b in C6D5Cl: experimental (left) and simulated (right).
Figure 7. Arrhenius plot of exchange rate kr vs T for 1a and 1b obtained from complete line
shape analysis of spectra in Figure 6. Fitting values are in Table 3. Correlation parameter r2 >
0.996.
Results show that the enthalpy of activation, ∆H‡, to inversion is about 18 kcal mol-1 for
both derivatives with a slightly higher value for the methoxy derivative 1b. The determined
entropy of activation, ∆S‡, is weakly negative for 1a indicating a more organized TS relative to
the GS, in accordance with the theoretical model (vide infra). In contrast, the positive value of
∆S‡ obtained for the methoxy derivative 1b indicates a less organized TS, which may suggest
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solvation effects. As a consequence of the positive ∆S‡ value, the MeO derivative 1b is more
configurationally labile than 1a in spite of higher ∆H‡.
Table 3. Results of analysis of variable temperature 1H NMR spectroscopy measurements for 1a
and 1b in C6D5Cl. a
compound Activation parameters b Thermodynamic parameters at 25 oC
Tc
∆G‡Tc at Tc
/kcal mol-1
lnA
Ea
/kcal mol-1 /kcal mol-1 /cal mol-1 K-1 /kca2l9m8 ol-1
∆H‡
∆S‡
∆G‡
/K
From
From Tc
Arrhenius
18.4±0.1
16.8±0.4
30.87±0.1 18.73±0.1
33.76±0.6 19.2±0.4
18.1±0.1
18.6±0.4
-0.6±0.1
5.2±0.6
18.3±0.1
17.0±0.4
376
341
18.3±0.1
16.8±0.1
1a
1b
b
a Variable temperature NMR spectroscopy data shown in Figure 5. From fitting kinetic data in
Figure 6.
Computational analysis: For a better understanding of factors responsible for configurational
stability of 1 and to the support NMR spectroscopy results, DFT calculations were conducted at
the B3LYP/6-31G(2d,p) level of theory for model derivatives 5–10 (Figure 8).
Analysis of the simplest system, 1-phenyl-1,2-dihydro[1,2,4]triazine (5), revealed a
twisted structure similar to that observed in 1a and 1,2-dihydropyrazines of type I: the N(1) and
N(2) atoms are significantly displaced from the ring plane and the 1-phenyl substituent is bent
away from the ring (angle α N(4)…N(1)-CPh = 133o). The interconversion to the opposite
conformational enantiomer involves inversion of the ring and both nitrogen atoms, as shown in
Figure 9 for 5: the N(1) center essentially planarizes (τ changes from 0.141 Å in 5 to 0.077 Å in
5-TS), while pyramidalization of the N(2) center is little changed in 5-TS. The dihedral angle
θ
(H–N(2)–N(1)-CPh, Figure 8) deceases from 119.3o to 8.3o in 5-TS (Table 4) and the calculated
barrier to inversion in 5, ∆H‡, is only 5.02 kcal mol-1.
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Substitution of the carboxyl group at the N(2) position in derivative 6 increases the
barrier to 12.76 kcal mol-1. In contrast, fusing a benzene ring at the e edge results in reduction of
the barrier by about 2 kcal mol-1 in 8 when compared to 5. Further increase of the inversion
barrier in 5 is achieved by placing a Ph substituent at the C(3) position in 7. The same trend
repeats for the 1,2-dihydrobenzo[e][1,2,4]triazine series 8–10 for which the activation enthalpies
are about 2 kcal mol-1 lower than those in the monocyclic analogous 5–7 (Figure 8).
Figure 8. The structures of compounds investigated by the B3LYP/6-31G(2d,p) method and
activation parameters for inversion (∆H‡ and in parentheses ∆G‡298, kcal mol-1). Numbering in 7
defines structural elements in all derivatives 5-10 used in Table 4.
Analysis of the geometry of the ground and transition state structures for the monocyclic
derivatives revealed that introduction of the COOH group, or fusing a benzene ring to 5 changes
the orientation of the N(1) benzene ring in the TS from nearly parallel (φ = 13.8o) to almost
perpendicular to the heterocyclic ring (φ = 123.3o in 6 and φ = 87.0o in 8; Table 4). Steric strain
of the substituent is also apparent in the GS: the angle N(4)…N(1)-CPh decreases from α = 137.9
in 5 by 11.5o in 6 and by 17.4o in the benzo-fused derivative 8. While the COOH group can avoid
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steric interactions with the ortho hydrogen atoms of the N(1) phenyl group by twisting (ψC(3)–N(2)-
C=O = 167o), the fused benzene ring cannot. This leads to destabilization of the GS in 8 and
decrease in activation energy by about 2 kcal mol-1 relative to 5 (Figure 8). This trend is
observed in all three dihydrobenzo[e][1,2,4]triazines.
Substitution of a Ph group at the C(3) position leads to steric congestion in 7-TS: the
passing of the heterocyclic ring plane by the COOH group during the inversion process is
hindered by the Ph group (nearly co-planar in the GS; ωN(4)–C(3)-
= 13.9o) at the C(3)
CPh-CPh
position. As a consequence, both the COOH and C(3)–Ph groups are twisted in the TS from the
preferred parallel orientation by about ∆ψ = 20o and ∆ω = 35 o, respectively, which, along with
steric interactions, contributes to the increase in the activation enthalpy (Figure 8). Similar
geometrical and thermodynamic effects are observed in 10a, when compared to 9. Interestingly,
the relative orientation of the N(1) and N(2) substituents also changes, and the dihedral angle θX–
increases upon substitution of the Ph at the C(3) position, further demonstrating steric
N(2)–N(1)-CPh
congestion.
Finally, substitution of the MeO group at the ortho position of the N(1)–Ph ring leads to
destabilization of the GS in 10b due to steric interactions, and the calculated enthalpy of
activation, ∆H‡, for the inversion process is lower by about 0.8 kcal mol-1 relative to the 10a
analogue. Overall the calculated free energies of activation, ∆G‡298, for the model derivatives 10a
and 10b are about 1 kcal mol-1 higher than those obtained experimentally for 1a and 1b (Table
3). Nevertheless, these results represent a reasonably good agreement between theory and
experiment, considering gas phase calculations of simplified models.
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Figure 9. DFT optimized geometry of two enantiomeric GS and inversion TS for 5. The
connection of the three structures was verified with IRC calculations.
Table 4. Selected structural parameters for ground states and inversion transition states of
models 5–10. a
compound
α
φ
θ
ψ
ω
N(4)…N(1)-CAr
C(6)–N(1)-CAr-CAr X–N(2)-N(1)-CAr C(3)–N(2)-CX=O N(4)–C(3)-CPh-
CPh
GS 137.9
TS 149.3
4.6
13.8
119.5
8.3
–
–
–
–
5
6
7
GS 126.4
TS 166.6
12.0
123.3
100.8
17.7
167.4
169.0
–
–
GS 135.5
TS 137.0
15.3
106.0
106.1
54.9
161.1
142.5
13.9
49.1
GS 120.5
TS 148.1
9.0
87.0
114.4
74.6
–
–
–
–
8
9
115.3
GS
11.8
64.9
100.8
8.3
173.8
169.0
–
–
174.6
TS
10a
124.9
GS
13.8
67.2
109.8
31.7
167.6
132.5
20.0
42.0
159.1
TS
a For definition of the structural elements see Figure 8.
Geometry optimization of 1a and 1b at the same level of theory reproduced closely the
experimental structures with essentially the same conformational features. Attempts at location
of the transition state geometries for the inversion process in 1a and 1b were unsuccessful. Due
to significant molecular flexibility, only rotational transition states of the ester group were found
using the QST3 algorithm.
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Conclusions
Substituted 1,2-dihydrobenzo[e][1,2,4]triazine derivatives possessing a chiral nitrogen
atom as the key chirality center have been structurally characterized for the first time. The N(1)
nitrogen atom of the [1,2,4]triazine ring is significantly pyramidalized mainly due to interactions
with the adjacent N(2) atom. The configurational stability of this stereocenter is further enhanced
by the presence of the neighboring substituents, and the enthalpy of activation ∆H‡ of the
inversion process is about 18 kcal mol-1. Computational analysis of model compounds indicates
that the observed barrier to inversion results mainly from steric interaction of the substituents.
Thus, substitution of the [1,2,4]triazine ring in positions 2 and 3 appears to destabilize the
inversion TS, while the fused benzene ring and the MeO group on the 1-Ph ring destabilize the
GS, hence lower the barrier to inversion.
The present derivatives 1 are still too labile for separation into enantiomers. Results
suggest however, that 1,2,3-trisubstituted 1,2-dihydro[1,2,4]triazines with a bulky acyl group
(e.g. pivaloyl) at the N(2) position may sufficiently stabilize the configuration of the N(1) center
and permit isolation of enantiomers.
Computational Details
Quantum-mechanical calculations were carried out using the Gaussian 09 suite of programs.47
Geometry optimizations were undertaken at the B3LYP/6-31G(2d,p) level of theory using
default convergence limits. Transition state structures were located using the QST3 method, for
which ground state input structures were obtained by full geometry optimizations of the both
enantiomeric conformers, while the approximate transition state structures were generated using
relaxed scans of the PES with varied X–N(2)–N(1)–CPh dihedral angle. Vibrational frequencies
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were used to characterize the nature of the stationary points and to obtain thermodynamic
parameters. Zero-point energy (ZPE) corrections were scaled by 0.9806.48 Reaction path was
followed for derivative 5 and 6 from the inversion transition state structure in both directions
using the keyword “IRC=(RCFC, LQA, recorrect=never, recalc=-5, maxpoint=300, tight)” and
specifying “forward” or “reverse”.
Experimental Section
Synthesis. Compounds 1–3 were obtained as described before.38
X-Ray data collection. Single-crystal X-ray measurements for 1a, 1b, 2a, and 3a were
performed with a Supernova diffractometer equipped with an Eos detector (1a, 3a), Supernova
Dual diffractometer with an Atlas detector (1b) and a Bruker Apex-II CCD diffractometer (2a).
All measurements were conducted at 100 K using the Mo Kα radiation. The crystals were
positioned at 74 and 50 mm from the Atlas and Eos/Apex-II detector, respectively. A total
number of 1020, 1394, 2925 and 799 frames were collected at 1° intervals with a counting time
of 30s, 50s, 15s and 35s for 1a, 1b, 2a and 3a, respectively. The data were corrected for
Lorentzian and polarization effects. Data reduction and analysis were carried out with the
Crysalis program (Agilent, CrysAlis PRO, Agilent Technologies, Yarnton, England, 2012). The
structures were solved by direct methods and refined using SHELXL-9749 within the Olex2
program.50 The refinement was based on F2 for all reflections except those with very negative F2.
Weighted R factors (wR) and all goodness-of-fit (GooF) values are based on F2. Conventional R
factors are based on F with F set to zero for negative F2. The Fo >2
σ
(Fo2) criterion was used only
2
for calculating the R factors and it is not relevant to the choice of reflections for the refinement.
The R factors based on F2 are about twice as large as those based on F. Scattering factors were
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taken from the International Tables for Crystallography.51 All hydrogen atoms were placed in
idealized positions. A small amount of water ~4% per one molecule of main moiety is present in
the case of 1a. The structures have been deposited at CCDC (1522807-1522810).
1
1
Temperature-dependent H NMR spectroscopy and data analysis. Variable temperature H
NMR spectra of 1a and 1b were recorded at 600 MHz in C6D5Cl at several temperatures
2
typically every 5 K (with 15 min of stabilization). The geminal coupling constant JHH for each
compound was dßetermined at the lowest temperature (301 K, 2JHH = 12.5 Hz for 1a and 2JHH
12.6 Hz for 1b) and assumed to be the same at all investigated temperatures.
=
Experimental activation parameters. To establish activation parameters for the inversion
process with the Arrhenius method, the exchange rate, kr, was established by complete line shape
analysis using the DNMR utility in TopSpin 2.1 software package.52 Thus, sections of the
experimental spectra for the benzylic CH2 group (4.8 – 5.3 ppm) were simulated by variation of
two parameters: line broadening (Lb) and rate of exchange (kr), to obtain correlation >96%.
Alternatively, ∆G‡ value for each derivative was calculated from the coalescence temperature,
Tc. The separation ∆ν between signals of diastereotopic hydrogen atoms was measured at the
lowest temperature (301 K), and the transmission coefficient κ was assumed to be 0.5, since the
reaction involves a degenerate process.53 Details are provided in the ESI.
Acknowledgements
Support for this project was provided by the National Science Center (2014/13/B/ST5/04525).
The authors thank Dr. Emilia Obijalska for preparation of suitable crystals for XRD analysis.
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