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The Structure of N-Benzylazoles from Pyrrole to Carbazole: Geometries and Energies
Dionisia Sanz, Rosa M. Claramunt, Christian Roussel, Ibon Alkorta, José Elguero
To cite this version:
Dionisia Sanz, Rosa M. Claramunt, Christian Roussel, Ibon Alkorta, José Elguero. The Structure of N-Benzylazoles from Pyrrole to Carbazole: Geometries and Energies. Indian Journal of Heterocyclic Chemistry, 2018, 28 (1), pp.1-10. �hal-02093199�
The Structure of N-Benzylazoles from Pyrrole to Carbazole: Geometries and Energies
Dionisia Sanz1*, Rosa M. Claramunt1, Christian Roussel2, Ibon Alkorta3, José Elguero3
1Departamento de Química Orgánica y Bio-Orgánica, Facultad de Ciencias, UNED, Paseo Senda del Rey, 9, E-28040 Madrid, Spain
2Aix-Marseille Université, CentraleMarseille, CNRS, Institut des Sciences Moléculaires de Marseille UMR 7313, 13397 Marseille, France 3Instituto de Química Médica, Centro de Química Orgánica “Lora-Tamayo”, CSIC, Juan de la
Cierva, 3, E-28006 Madrid, Spain
(Dedicated to Prof. S.P. Singh on his 80th Birthday)
ABSTRACT The complete series of 18 parents N-benzylazoles (10 azoles and 8 benzazoles) have been calculated at the B3LYP/6-311++G(d,p) level. The geometries have been compared with the X-ray structures reported in the literature for six derivatives (1H-imidazole, 1H-1,2,3-triazole, 1H-1,2,3,4-tetrazole, 1H-benzimidazole, 1H-benzotriazole, and 9H-carbazole). Only one minimum has been found for the 18 molecules, but several transition states connecting them have been located. The calculated geometries agree well with those reported by X-ray crystallography.
INTRODUCTION
following one: Small rings (three- and four-membered rings),
phosphorus analogues), six-membered rings (azines and their oxygen, sulfur, and phosphorus analogues), and larger rings (seven-, eight-, and nine-membered rings).[1-3] Although this not covers all heterocycles, it shows the importance of azoles, between one-third and one-fourth of all heterocycles.[4]
KEY WORDS N-Benzylazoles,N-Benzylbenzazoles, X-Ray geometries, DFT calculations, Enantiomerization.
Systematic exploration of the whole family of azoles (including azoles and benzazoles) is almost impossible because there are several thousands of them, thus, some restriction must be applied. We have restricted the present study to parent compounds (no C-substituents) bearing on the nitrogen atom a benzyl group. The resulting 18 derivatives were calculated to determine their minimum energy conformations (rotations about two single bonds) and geometries. Furthermore, the transition states (TSs) connecting the minima have been calculated. Note that even in the case of a unique minimum, there are several TSs in the path from one minimum to an identical minimum.
A total of 17 N-benzylazoles are known; only 1-benzyl- 1H-pentazole (10) has never been reported. Some of these compounds have been described in many papers, their interest lies mainly as synthetic intermediates,[5] although some interesting biological properties have been reported.[6]
A commentary is necessary here. For comparative purposes, it is useful to the number the N atom bearing the benzyl group, N1; but, this is not the IUPAC numbering rule; according to it, the N atoms must have the lowest numbers, this lead to N4 for 5 and N2 for 7,9,12, 15, and 17.
Finally, carbazole is an accepted exception and the N atom is numbered N9. When, in general, for the 18 compounds, ! !"#"$"%"&
(clockwise),Scheme 1.
COMPUTATIONAL DETAILS
The geometry of the molecules has been fully optimized with the hybrid HF/DFT B3LYP computational method and the B3LYP/6-311++G(d,p) level.[7-10] Frequency calculations have been carried out at the same computational level to
verify that the structures obtained correspond to energetic minima (0) or to TSs (1). All the calculations have been carried out with the Gaussian-09 package.[11]
RESULTS AND DISCUSSION X-ray structures
A search in the Cambridge Structural Database[12] of N-benzylazoles afforded six hits that are represented in Figure 1.
The refcodes, from EYIRIN to NUPSIG, are also reported.[12]
Calculated structures
Figure 2 summarizes the information concerning the optimized geometries (absolute minima).
To analyze these results, we have reported in Table 1 the four angles, the nature of the substituents at positions (P) 2, 3, 4, and 5 (P2-P5) assuming that the N-benzyl is at position 1 and the absence-presence matrix[20,21] of the three possible substituents at positions 2, 3, 4, and 5, C, N, and B (benzene). The CH substituents have been removed since they are used as reference to calculate the intercepts.[22,23]
The results of the statistical analyses of Table 1are given inTable 2.
Since the N atom has priority over the CH or the benzene, when there is an atom at N5, there is always an atom at N2
$ %'< #=&
N3/N4, and B2/B5 are not independent (there is not B4 because otherwise the matrix will be singular).
>
? K'Z \1=76,
\2?#_ `1?`2?!#j{ \2 deviates (pyrrole =20.4,
Scheme 1: The 18 studied compounds
1H-Imidazole(2) 1H-1,2,3-Triazole(6) 1H-1,2,3,4-Tetrazole(8)
EYIRIN[13] and EYIRIN01[14] NILKOI[15] ZECWOV[16]
\1?&j<j\2=56.4 \1?~%<#\2=31.9 \1?~j<\2=82.1
`1?!#j<!`2=127.2 `1?!#_<`2=129.0 `1?!#!<&`2=130.5
?
1H-Benzimidazole(13) 1H-Benzotriazole(16) 9H-Carbazole(18)(two-independent mol)
RUFBAW[16] and RUFBAW01[17] YAXJEO[18] NUPXIG[19]
>Z\1?j<_\2=20.6
>_!Z\1?$<\2=64.3
\1?$<&\2=67.4 \1?&<#\2=27.0
\1?_<#\2=54.4
>Z`1?!#<!`2=126.6
>_!Z`1?!#j<$`2=126.7
`1?!#_<~`2=129.1 `1?!#%<&`2=126.5
`1?!#%<`2=126.8 Figure 1: X-ray geometries of N-benzylazoles. Two torsion angles are necessary to describe the conformation of these
1 = X–N–Csp3–Cipso2 = Cortho–Cipso–Csp3
!"#1#2 describe the orientation of the N-Csp3 substituent with regard to the
$" %&'+ "4;<;>;? #1@#2 in theory, but they can
"'%%'H%% '%%%
values) either in the case of polymorphism (13) (different space groups) or when there are two-independent molecules in the unit cell (18)
1H-Pyrrole(1) 1H-Imidazole(2) 1H-Pyrazole(3)
\1?j<%\2=20.4 \1?j%<~\2=40.5 \1?<\2=53.8
`1?`2=125.5 `1?!#j<`2=126.9 `1?!!<`2=127.9
Figure 2: Calculated geometries of N-benzylazoles. Figure 1 shows identical comments
1H-1,2,4-triazole(4) 4H-1,2,4-triazole(5) 1H-1,2,3-Triazole(6)
\1?~j<\#?j_<! \1?j%<\2=41.7 \1?jj<\2=56.6
`1?!#!<_`2=129.5 `1?`2=128.2 `1?!#_<!`2=129.4
2H-1,2,3-triazole(7) 1H-1,2,3,4-Tetrazole(8) 2H-1,2,3,4-Tetrazole(9)
\1?~~<\2=89.8 \1?j~<~\2=59.0 \1?<~\2=79.0
`1?`2=122.2 `1?!#!<%`2=131.1 `1?!##<j`2=123.6
1H-Pentazole(10) 1H-Indole(11) 1H-Isoindole(12)
\1?~~<~\2=89.9 \1?&<%\2=23.7 \1?#<!\2=30.2
`1?`2=124.1 `1?!#&<j`2=126.1 `1?`2=124.5
1H-Benzimidazole(13) 1H-Indazole(14) 2H-Indazole(15)
\1?_<&\2=32.8 \1?$<$\2=43.4 \1?~_<\2=56.1
`1?!#j<`2=127.4 `1?!#_<!`2=128.4 `1?!!<_`2=126.7
1H-Benzotriazole(16) 2H-Benzotriazole(17) 9H-Carbazole(18)
\1?j<&\2=48.4 \1?~~<%\2=89.8 \1?~&<!\2=13.4
`1?!#_<!`2=130.1 `1?`2=121.1 `1?`2=125.6
Figure 2: Continued
Table 1: Geometrical parameters, substituent descriptors, and presence-absence matrix. Rxx corresponds to crystal structures of N-benzylazoles (xx)
No \1 \2 `1 `2 P2 P5 P3 P4 N2 B2 N5 B5 N3 B3 N4 B4
1 76.4 20.4 125.5 125.5 C C C C 0 0 0 0 0 0 0 0
2 64.8 40.5 126.7 126.9 C C N C 0 0 0 0 1 0 0 0
3 77.7 53.8 119.9 127.9 N C C C 1 0 0 0 0 0 0 0
4 86.9 60.1 121.0 129.5 N C C N 1 0 0 0 0 0 1 0
5 64.9 41.7 128.2 128.2 C C N N 0 0 0 0 1 0 1 0
6 66.9 56.6 120.1 129.4 N C N C 1 0 0 0 1 0 0 0
7 88.7 89.8 122.2 122.2 N N C C 1 0 1 0 0 0 0 0
8 68.8 59.0 121.4 131.1 N C N N 1 0 0 0 1 0 1 0
9 77.8 79.0 122.6 123.6 N N N C 1 0 1 0 1 0 0 0
10 88.8 89.9 124.1 124.1 N N N N 1 0 1 0 1 0 1 0
11 75.4 23.7 125.6 126.1 C B C B 0 0 0 1 0 0 0 1
12 72.1 30.2 124.5 124.5 C C B B 0 0 0 0 0 1 0 1
13 70.5 32.8 126.7 127.4 C B N B 0 0 0 1 1 0 0 1
14 73.3 43.4 120.1 128.4 N B C B 1 0 0 1 0 0 0 1
15 80.9 56.1 119.0 126.7 N C B B 1 0 0 0 0 1 0 1
16 69.5 48.4 120.1 130.1 N B N B 1 0 0 1 1 0 0 1
17 88.4 89.8 121.1 121.1 N N B B 1 0 1 0 0 1 0 1
18 85.1 13.4 125.6 125.6 B B B B 0 1 0 1 0 1 0 1
R2 56.6 56.4 126.1 127.2 C C N C 0 0 0 0 1 0 0 0
R6 84.2 31.9 120.9 129.0 N C N C 1 0 0 0 1 0 0 0
R8 86.7 82.1 121.5 130.5 N C N N 1 0 0 0 1 0 1 0
R13 76.0 20.6 127.1 125.6 C B N B 0 0 0 1 1 0 0 1
R130 73.7 64.3 126.3 126.7 C B N B 0 0 1 1 0 0 0 1
R16 73.5 67.4 120.8 129.1 N B N B 1 0 0 1 1 0 0 1
R18a 75.2 27.0 124.5 126.5 B B B B 0 1 0 1 0 1 0 1
R18b 70.2 54.4 124.9 126.8 B B B B 0 1 0 1 0 1 0 1
Table 2: Statistical analysis of Table 1 data. This table does not use the IUPAC correct numbering but that of pyrrole, theN-benzyl group is always N1
Angles \1 \2 `1 `2 `1`2
Intercept 75±2 33±3 126±0.2 126±0.2 No intercept
N2 2.9±2.0 21.3±3.2 –6.1±0.2 2.5±0.2 –8.5±0.2a
B2 10.2±4.0 –13.0±6.6 0.8±0.4 0.7±0.4 -
N5 12.0±2.3 31.7±3.7 2.4±0.2 –6.1±0.2 8.5±0.3
B5 - –6.2±3.6 - 0.5±0.2 –0.3±0.2
N3 –10.0±1.9 - 0.6±0.2 1.4±0.2 –0.6±0.2
B3 - - –1.0±0.2 –1.1±0.2 0.3±0.2
N4 4.8±2.2 6.2±3.5 1.4±0.2 1.2±0.2 -
R2 0.868 0.960 0.993 0.994 0.993
RMS error 3.6º 5.7º 0.3º 0.3º 0.5º
a`1`2 = – (8.7±0.2) N2–N5 – (0.7±0.2) N3–N4. n=18. R2=0.993, RMS residual=0.5°
Comp. Azole Minimum TS1A TS1B Lower TS2 TS3
1 Pyrrole 0.0 6.4 - 6.4 4.0 0.1
\1 76 0 - 87 87
\2 20 90 - 90 180
2 Imidazole 0.0 5.2 6.7 5.2 4.2 1.8
\1 65 0 180 86 80
\2 40 90 90 79 20
3 Pyrazole 0.0 14.8 3.2 3.2 3.8 3.1
\1 78 0 180 73 80
\2 54 90 90 56 16
4 1,2,4-triazole 0.0 13.9 1.1 1.1 2.9 2.9
\1 87 0 180 78 79
\2 60 90 90 17 15
5 1,3,4-triazole 0.0 3.2 - 3.2 2.4 0.4
\1 65 0 - 88 88
\2 42 90 - 90 0
6 1,2,3-triazole 0.0 14.9 4.4 4.4 6.7 6.7
\1 67 0 180 79 79
\2 57 91 0 48 48
7 1,2,5-triazole 0.0 10.0 - 10.0 0.0 3.7
\1 88 0 - 88 89
\2 90 91 - 90 0
8 1,2,3,4-tetrazole 0.0 13.0 1.6 1.6 5.2 5.2
\1 69 0 180 77 77
\2 59 90 90 37 37
9 1,2,3,5-tetrazole 0.0 9.3 10.2 9.3 0.7 5.0
\1 78 0 180 82 87
\2 79 91 90 72 10
10 Pentazole 0.0 8.3 - 8.3 0.0 4.7
\1 89 0 - 89 89
\2 90 90 - 90 0
11 Indole 0.0 4.3 20.7 4.3 5.3 0.9
\1 75 0 180 87 81
\2 24 90 90 84 21
12 Isoindole 0.0 5.4 - 5.4 3.5 0.2
\1 72 0 - 88 88
\2 30 90 - 90 0
13 Benzimidazole 0.0 3.2 17.5 3.2 4.9 2.3
\1 71 0 180 87 75
\2 33 90 91 90 40
14 1H-indazole 0.0 13.1 14.8 13.1 4.2 3.8
\1 73 0 180 76 79
\2 43 90 91 64 37
15 2H-indazole 0.0 2.5 14.3 2.5 3.9 3.8
\1 81 0 180 73 77
\2 56 90 91 46 26
16 1H-benzotriazole 0.0 13.3 12.9 12.9 6.1 6.1
\1 70 0 180 82 82
\2 48 90 91 52 52
Table 3: Energetic and geometric data of minima and TSs
(Contd...)
Figure 3: Representation of the potential energy (kJ/mol)
%%<%%12 angles (°).
Red: High-energy parts
Comp. Azole Minimum TS1A TS1B Lower TS2 TS3
17 2H-benzotriazole 0.0 9.8 - 9.8 0.0 4.3
\1 88 0 - 88 89
\2 90 90 - 90 0
18 Carbazole 0.0 19.3 - 19.3 7.3 0.0
\1 85 0 - 89 90
\2 13 90 - 90 0
Table 3: (Continued)
?$$$'< #?!_<#
\1, correspond to carbazole where if there is a benzene at position 2,3 there is another at positions 4,5, thus the 10.2°
value correspond to two fused benzenes.
`1 `2 angles (N2 = N5), it is useful `1`2 difference because for “symmetrical”
molecules1,5,7,10,12,17, and 18, it must be 0. In this case, we should use N2–N5 and N3–N4 as independent variables. Thus, it should be possible to use a multiple model where the difference of presence-absence values for N atoms is used. The result, bottom of Table 2, is equivalent but only with two-independent terms instead {!Kipso bond position depends almost only on the presence/absence of N atoms at positions 2 and 5. It is noteworthy that a fused benzene ring has no effect, i.e., a CH and a fused benzene ring are equivalent (case of compounds11 and 13).
Comparing in Table 1 the calculated values [Figure 2]
and the experimental crystallographic values [Figure 1], it `1 `2 are very similar; on
\1 \2 are, in general,
<
where less energy is required: To distort a C-C-C angle 10°, 4 kJ·mol!while for ethane a twist of 10°, <1 kJ/mol.[24]
TSs
A 3D representation of the energy surface of compound 5 is represented in Figure 3.
N-benzylazoles have four minima (three in the case of “symmetrical” compounds 1,5,7,10,12,17, and 18).
Two corresponds to 360° rotations (180° for “symmetrical”
compounds) about N-Csp3\1 angle) and 180° about Cipso- Csp3 \2 angle). Remember that there is a TS relating the (degenerate isomerization). These isomerizations [Figure 4]
do not exchange the N-benzylic protons, HA and HB, that are in most conformations diastereotopic and, consequently, anisochronous. Note that, the TSs have been optimized (only one imaginary frequency), both angles are different from the minimum.
The enantiomerization process exchanges HA and HB making them enantiotopic and isochronous [Figure 5]. For instance, in the case of imidazole 2\1?j%<~\2 = 40.5°; its \1?j%<~\2 = –40.5° (295.2° and 319.5°).
We have reported in Table 3 all the energies (in italics, kJ/mol) and torsion angles of the minima and TSs and in Figures 6 and 7 a normalized view of TS1, TS1A, and TS1B. Table 4: Statistical analysis of Table 3 data. The
lower values correspond to the lower values of columns TS1A+TS1 and TS1B+TS1. This table does not use the
IUPAC correct numbering but that of pyrrole, the N-benzyl group is always N1
TS1A+TS1 TS1B+TS1 Lower values
N2 10.9±1.4 - 3.4±1.4
B2 20.6±4.8 11.6±4.7 17.5±3.9
N5 - 6.3±2.3 5.5±2.2
N3 - 2.8±1.7 -
B3 –4.4±3.1 –7.3±3.3 –4.9±2.6
N4 - - -
B4 3.0±2.1 15.1±2.2 6.7±1.8
R2 0.886 0.905 0.882
RMS error 4.1 kJ/mol 4.0 kJ/mol 3.3 kJ/mol
In some cases, compounds 6,8, and 16, only one TS has been found.
A multivariate analysis of Table 3 values using the presence-absence data of Table 1 lead to the following results [Table 4].
The TS1 barrier is both a TS1A and a TS1B barrier, thus there are 18 values for all columns of Table 4. For barriers of the 1A class, the most important effects are N2 and B2 while for barriers of the 1B class; the most important effects are B2 and B4. Finally, the set of lower barriers is mainly sensitive to the steric effects of a fused benzene ring at positions 23/45, resulting in the highest value of carbazole, 19.3 kJ/mol.
CONCLUSIONS
The main conclusions of the present work are:
well with the experimental X-ray geometries in what
angles are concerned but not concerning torsion angles (conformation).
'
the benzyl group depends only on the presence/absence of N atoms at positions 2/5.
'
depends on several substituent effects and, in any case, the models are not very good.
enantiomerization process and depend essentially on the presence of fused benzene rings at positions 2,3 and 4,5.
These barriers are too low to observe experimentally anisochrony in the1H NMR of the benzyl sp3 protons.
ACKNOWLEDGMENTS
This work was supported by Ministerio de Economía, Industria y Competitividad of Spain (CTQ2014-56833-R Figure 5: Enantiomerization process through TS1A (N3 to the back) and TS1B (N3 to the front) that exchange HA and HB
\H%^_$'_^H-imidazole (2)
Figure 4: Rotations through TS2 and TS3 that do not exchange HA and HB\H%^_$'_^H-imidazole (2)
11 Indole TS1A 11 Indole TS1B 12 Isoindole TS1
13 Benzimidazole TS1A 13 Benzimidazole TS1B 141H-Indazole TS1A
141H-Indazole TS1B 152H-Indazole TS1A 152H-Indazole TS1B
161H-Benzotriazole TS1A 161H-Benzotriazole TS1B 172H-Benzotriazole TS1
18 Carbazole TS1
Figure 6: TS1, TS1A, and TS1B of N-benzylazoles
Figure 7: TS1, TS1A, and TS1B of N-benzylazoles
1 Pyrrole TS1 2 Imidazole TS1A 2 Imidazole TS1B 3 Pyrazole TS1A
3 Pyrazole TS1B 41,2,4-Triazole TS1A 41,2,4-Triazole TS1B 51,3,4-Triazole TS1
61,2,3-Triazole TS1A 61,2,3-Triazole TS1B 71,2,5-Triazole TS1 81,2,3,4-Tetrazole TS1A
81,2,3,4-Tetrazole TS1B 91,2,3,5-Tetrazole TS1A 91,2,3,5-Tetrazole TS1B 10Pentazole TS1
and CTQ2015-63997-C2-2-P) and Comunidad Autónoma de Madrid (S2013/MIT2841, Fotocarbon).
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Accepted: 20 Feb 2018
