The Structure of N-Benzylazoles from to Carbazole: Geometries and Energies Dionisia Sanz, Rosa M. Claramunt, Christian Roussel, Ibon Alkorta, José Elguero

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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￿

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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 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-, 1H-1,2,3-triazole, 1H-1,2,3,4-, 1H-, 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.

KEY WORDS N-Benzylazoles, N-Benzylbenzazoles, X-Ray geometries, DFT calculations, Enantiomerization.

INTRODUCTION 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 following one: Small rings (three- and four-membered rings), not covers all heterocycles, it shows the importance of azoles, between one-third and one-fourth of all heterocycles.[4] Systematic exploration of the whole family of azoles verify that the structures obtained correspond to energetic (including azoles and benzazoles) is almost impossible minima (0) or to TSs (1). All the calculations have been because there are several thousands of them, thus, some carried out with the Gaussian-09 package.[11] restriction must be applied. We have restricted the present study to parent compounds (no C-substituents) bearing RESULTS AND DISCUSSION on the atom a benzyl group. The resulting 18 derivatives were calculated to determine their minimum X-ray structures energy conformations (rotations about two single bonds) and geometries. Furthermore, the transition states (TSs) A search in the Cambridge Structural Database[12] of connecting the minima have been calculated. Note that even N-benzylazoles afforded six hits that are represented in Figure 1. in the case of a unique minimum, there are several TSs in the The refcodes, from EYIRIN to NUPSIG, are also reported.[12] path from one minimum to an identical minimum. Calculated structures A total of 17 N-benzylazoles are known; only 1-benzyl- 1H-pentazole (10) has never been reported. Some of these Figure 2 summarizes the information concerning the compounds have been described in many papers, their optimized geometries (absolute minima). interest lies mainly as synthetic intermediates,[5] although To analyze these results, we have reported in Table 1 some interesting biological properties have been reported.[6] the four angles, the nature of the substituents at positions A commentary is necessary here. For comparative (P) 2, 3, 4, and 5 (P2-P5) assuming that the N-benzyl is at purposes, it is useful to the number the N atom bearing the position 1 and the absence-presence matrix[20,21] of the three benzyl group, N1; but, this is not the IUPAC numbering possible substituents at positions 2, 3, 4, and 5, C, N, and B rule; according to it, the N atoms must have the lowest (benzene). The CH substituents have been removed since numbers, this lead to N4 for 5 and N2 for 7, 9, 12, 15, and 17. they are used as reference to calculate the intercepts.[22,23] Finally, carbazole is an accepted exception and the N atom The results of the statistical analyses of Table 1 are given is numbered N9. When, in general, for the 18 compounds, in Table 2. ! !"#"$"%"& Since the N atom has priority over the CH or the benzene, (clockwise), Scheme 1. when there is an atom at N5, there is always an atom at N2 COMPUTATIONAL DETAILS $%'<#=& N3/N4, and B2/B5 are not independent (there is not B4 The geometry of the molecules has been fully optimized because otherwise the matrix will be singular). with the hybrid HF/DFT B3LYP computational method and > [7-10] the B3LYP/6-311++G(d,p) level. Frequency calculations ? K'Z 1=76, have been carried out at the same computational level to 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

1?!#j

? 1H-Benzimidazole (13) 1H-Benzotriazole (16) 9H-Carbazole (18) (two-independent mol) RUFBAW[16] and RUFBAW01[17] YAXJEO[18] NUPXIG[19]

‚ƒ„ >†Z1?j<_2=20.6 1?$<&2=67.4 1?&<#2=27.0

‚ƒ„ >†_!Z1?$<2=64.3 1?_<#2=54.4

‚ƒ„ >†Z1?!#

‚ƒ„ >†_!Z1?!#j<$2=126.7 1?!#%<€2=126.8 Figure 1: X-ray geometries of N-benzylazoles. Two torsion angles are necessary to describe the conformation of these 3 3 1 = X–N–Csp –Cipso2 = Cortho–Cipso–Csp 3 !"12 describe the orientation of the N-Csp substituent with regard to the $"%O'P"4;<;>;?1@2 in theory, but they can "'%%'[%%'%%% 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- (3)

2 1?j<%2=20.4 1?j%<~ =40.5 1?<2=53.8 1 1 1?2=125.5  ?!#j<2=126.9  ?!!€<€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?!#!<_2=129.5 1?2=128.2 1?!#_

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?!##

1H-Pentazole (10) 1H- (11) 1H- (12)

1?~~<~2=89.9 1?&<%2=23.7 1?#

1?2=124.1 1?!#&

1H-Benzimidazole (13) 1H- (14) 2H-Indazole (15)

1?_<&2=32.8 1?$<$2=43.4 1?~_<€2=56.1 2 1?!#j< =127.4 1?!#_

1H-Benzotriazole (16) 2H-Benzotriazole (17) 9H-Carbazole (18)

1 1?j€<&2=48.4  ?~~<%2=89.8 1?~&

1?!#_

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 100000 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 10000101 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 NB 00110001 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, the N-benzyl group is always N1

Angles 1 2 1 2 12 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 2 1M2 = – (8.7±0.2) N2–N5 – (0.7±0.2) N3–N4. n=18. R =0.993, RMS residual=0.5° Table 3: Energetic and geometric data of minima and TSs

Comp. 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 (Contd...) Table 3: (Continued)

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 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 Figure 3: Representation of the potential energy (kJ/mol) B2 20.6±4.8 11.6±4.7 17.5±3.9 %%<%%12 angles (°). N5 - 6.3±2.3 5.5±2.2 Red: High-energy parts N3 - 2.8±1.7 -   are, in general, B3 –4.4±3.1 –7.3±3.3 –4.9±2.6 1 2 < N4 -- - where less energy is required: To distort a C-C-C angle 10°, B4 3.0±2.1 15.1±2.2 6.7±1.8 4 kJ·mol%!while for ethane a twist of 10°, <1 kJ/mol.[24] R2 0.886 0.905 0.882 RMS error 4.1 kJ/mol 4.0 kJ/mol 3.3 kJ/mol TSs A 3D representation of the energy surface of compound 5 ?$$/$'<Š #?!_<# is represented in Figure 3.  , correspond to carbazole where if there is a benzene at 1 N-benzylazoles have four minima (three in the case position 2,3 there is another at positions 4,5, thus the 10.2° of “symmetrical” compounds 1, 5, 7, 10, 12, 17, and 18). value correspond to two fused benzenes. Two corresponds to 360° rotations (180° for “symmetrical” compounds) about N-Csp3 angle) and 180° about C - Œ12 angles (N2 = N5), it is useful 1 ipso Csp3 angle). Remember that there is a TS relating the 12 difference because for “symmetrical” 2 molecules 1, 5, 7, 10, 12, 17, and 18, it must be 0. In this case, we should use N2–N5 and N3–N4 as independent (degenerate isomerization). These isomerizations [Figure 4] variables. Thus, it should be possible to use a multiple do not exchange the N-benzylic protons, HA and HB, that model where the difference of presence-absence values are in most conformations diastereotopic and, consequently, for N atoms is used. The result, bottom of Table 2, is anisochronous. Note that, the TSs have been optimized equivalent but only with two-independent terms instead (only one imaginary frequency), both angles are different from the minimum. {!MKipso bond position depends almost only on the presence/absence of N atoms at positions 2 and The enantiomerization process exchanges HA and HB 5. It is noteworthy that a fused benzene ring has no effect, making them enantiotopic and isochronous [Figure 5]. For i.e., a CH and a fused benzene ring are equivalent (case of instance, in the case of imidazole 21?j%<~ 2 = 40.5°; its compounds 11 and 13). 1?Mj%<~ 2 = –40.5° (295.2° and 319.5°). Comparing in Table 1 the calculated values [Figure 2] We have reported in Table 3 all the energies (in italics, and the experimental crystallographic values [Figure 1], it kJ/mol) and torsion angles of the minima and TSs and in

1 2 are very similar; on Figures 6 and 7 a normalized view of TS1, TS1A, and TS1B. Figure 4: Rotations through TS2 and TS3 that do not exchange HA and HB\[%^_$'_^H-imidazole (2)

Figure 5: Enantiomerization process through TS1A (N3 to the back) and TS1B (N3 to the front) that exchange HA and HB \[%^_$'_^H-imidazole (2)

In some cases, compounds 6, 8, and 16, only one TS has angles are concerned but not concerning torsion angles been found. (conformation). A multivariate analysis of Table 3 values using the # ' presence-absence data of Table 1 lead to the following the benzyl group depends only on the presence/absence results [Table 4]. of N atoms at positions 2/5. # ' The TS1 barrier is both a TS1A and a TS1B barrier, thus there are 18 values for all columns of Table 4. For barriers depends on several substituent effects and, in any case, of the 1A class, the most important effects are N2 and B2 the models are not very good. while for barriers of the 1B class; the most important effects # Š are B2 and B4. Finally, the set of lower barriers is mainly enantiomerization process and depend essentially on the sensitive to the steric effects of a fused benzene ring at presence of fused benzene rings at positions 2,3 and 4,5. positions 23/45, resulting in the highest value of carbazole, 19.3 kJ/mol. # These barriers are too low to observe experimentally anisochrony in the1H NMR of the benzyl sp3 protons. CONCLUSIONS ACKNOWLEDGMENTS The main conclusions of the present work are: # This work was supported by Ministerio de Economía, well with the experimental X-ray geometries in what Industria y Competitividad of Spain (CTQ2014-56833-R 11 Indole TS1A 11 Indole TS1B 12 Isoindole TS1

13 Benzimidazole TS1A 13 Benzimidazole TS1B 14 1H-Indazole TS1A

14 1H-Indazole TS1B 15 2H-Indazole TS1A 15 2H-Indazole TS1B

16 1H-Benzotriazole TS1A 16 1H-Benzotriazole TS1B 17 2H-Benzotriazole TS1

18 Carbazole TS1

Figure 6: TS1, TS1A, and TS1B of N-benzylazoles

1A 1 Pyrrole TS1 2 Imidazole TS 2 Imidazole TS1B 3 Pyrazole TS1A

3 Pyrazole TS1B 4 1,2,4-Triazole TS1A 4 1,2,4-Triazole TS1B 5 1,3,4-Triazole TS1

6 1,2,3-Triazole TS1A 6 1,2,3-Triazole TS1B 7 1,2,5-Triazole TS1 8 1,2,3,4-Tetrazole TS1A

8 1,2,3,4-Tetrazole TS1B 9 1,2,3,5-Tetrazole TS1A 9 1,2,3,5-Tetrazole TS1B 10 Pentazole TS1

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Accepted: 20 Feb 2018