¹⁵N NMR spectra, tautomerism and diastereomerism of 4,5-dihydro-1H-1,2,3-triazoles

Abstract

Despite the great number of 4,5-dihydro-1H-1,2,3-triazoles synthesized, ¹⁵N NMR data of these heterocycles are extremely rare. The aim of this paper is to present such data and examples of their application. The compounds investigated have been synthesized according to the given references or procedures. Their ¹⁵N NMR spectra were measured at natural abundance. For some compounds, the chemical shift assignments were confirmed with the help of ¹⁵N labelled material. The influences on ¹⁵N chemical shifts of substitution pattern, solvent and concentration were investigated. Additionally, some lanthanide induced shift (LIS) investigations were performed. ¹³C labelled compounds were employed as tools to provide the assignment of tautomeric structures.

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Introduction

¹⁵N NMR spectroscopy is a powerful tool for the characterization of nitrogen containing compounds because ¹⁵N chemical shifts strongly depend on structural and electronic features which hence result in a broad shift range of approximately 900 ppm, i.e. −400 to +500 ppm relative to nitromethane as external reference.^1–3 Despite and sometimes through the influence of solvents as well as concentration, pH value and temperature of the solutions on ¹⁵N shifts, many problems, including for example tautomerism^2–4 or positions of protonation of heterocycles,^3,5 could be solved with the help of ¹⁵N NMR spectroscopy.

The number (more than 3300) of 4,5-dihydro-1H-1,2,3-triazoles that are registered by Chemical Abstracts attests to the importance of this class of heterocycles for many areas ranging from organic syntheses to pharmaceutical research.⁶ Nevertheless, ¹⁵N NMR data of these heterocyclic compounds are surprisingly rare. To the best of our knowledge, only a handful have been published in previous papers from our group.^7–9 The primary goal of the present study is to fill this gap and to utilize such data for the elucidation of the structures of tautomers and diastereomers.

The dihydro-1,2,3-triazoles investigated have been synthesized according to procedures reported in the literature or described in the Experimental section. In most cases, they were prepared by 1,3 dipolar cycloaddition of an azide to an alkene. Their ¹⁵N NMR spectra were measured at natural abundance (0.37% ¹⁵N) except for some cases (compare Fig. 1) in which the shift assignment had to be confirmed with the help of ¹⁵N labelling.

Fig. 1 ¹⁵N and ¹³C labelled compounds.

Experimental

The known dihydrotriazoles 1–32, 34, 36–38, 40, 41, 44, 46–53, 55–60 and 62 were prepared according to the procedures given in the references listed in Table 3. The compounds 33, 35, 39, 42, 43 and 45 were obtained by 1,3 dipolar cycloaddition of the corresponding azides to norbornene (molar ratio azide ∶ norbornene ca. 1 ∶ 2) under the reaction conditions specified in Table 1. The physical and spectroscopic data of these new compounds are summarized in Table 2. Chemical shifts are given in ppm and J values are given in Hz.

Table 1 Synthesis of new 4,5-dihydro-1H-1,2,3-triazoles from azides and norbornene at room temperature

Compound	Solvent	Time/d	Yield (%)	Ref. azide
a The azide was prepared similarly to the described procedure using the appropriate p-substituted aniline.
33	Et2O	10	95	10
35	Et2O	3	87	11^a, 12
39	CHCl3	3	47	11^a, 13
42	CHCl3	3.5	58	11^a, 14
43	CHCl3	3.5	48	11^a, 15
45	Et2O	2	100	12

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Table 2 Data of new 4,5-dihydro-1H-1,2,3-triazoles (3a,4,5,6,7,7a-hexahydro-4,7-methano-1H-benzotriazoles)

Compound	33	35	39	42	43	45
a May be exchanged.
δ ^1H (ppm)	(in CDCl3)	(in CDCl3)	(in CDCl3)	(in CDCl3)	(in CDCl3)	(in DMSO-d6)
3a-H	4.34 (d, J 10)	4.52 (d, J 9.4)	4.57 (d, J 9.7)	4.64 (d, J 9)	4.67 (d, J 8.8)	4.51 (d, J 9.4)
4-H	2.61^a (broad s)	2.62 (broad s)	2.61 (broad s)	2.65 (broad s)	2.63 (broad s)
5-H/6-H	1.15–1.70 (m)	1.20–1.85 (m)	1.20–1.80 (m)	1.20–1.80 (m)	0.9–1.9 (m)
7-H	2.30^a (broad s)	2.74 (broad s)	2.78 (broad s)	2.80 (broad s)	2.85 (broad s)
7a-H	3.19 (d, J 10)	3.72 (d, J 9.4)	3.69 (d, J 9.7)	3.73 (d, J 9)	3.70 (d, J 8.8)	3.78 (d, J 9.4)
8-H	1.12 (s)	1.16 (s)	1.15 (s)	1.15 (s)	[in 0.9–1.9 (m)]
Other hydrogens	0.93 (t, 4′-H)	6.79 (m, arom.)	6.80–7.40	7.30 (m, arom.)	7.32 (m, arom.)	6.75 (m, arom.)
	3.53 (t, 1′-H)	7.23 (m, arom.)	(m, arom.)	7.95 (m, arom.)	7.62 (m, arom.)	7.10 (m, arom.)
	1.15–1.70
	(m, 2′-H/3′-H)
δ ^13C (ppm)	(in CDCl3)	(in CDCl3)	(in CDCl3)	(in CDCl3)	(in CDCl3)	(in DMSO-d6)
C-3a	85.3	84.7	85.9	86.4	86.9	84.8
C-4/C-7	40.8, 41.3	39.6, 40.6, 40.8 (C-1′)	39.5, 40.9	39.2, 40.4	39.5, 40.5
C-5/C-6	24.8, 25.7	24.3, 24.9	24.4, 25.0	24.2, 24.8	24.2, 24.9	24.1, 24.8
C-7a	62.8	60.6	60.1	59.0	58.9	60.1
C-8	30.7, 32.3 (C-2′)	31.5	31.7	31.4	31.5
Other carbons	13.7 (C-4′) 20.0 (C-3′) 48.0 (C-1′)	113.4, 115.1, 130.9, 146.2 (arom.)	114.7, 115.6, 136.4, 157.8 (arom.)	25.6 (COMe) 112.5, 129.6, 130.1, 143.3 (arom.), 195.5 (CO)	103.5 (CN) 113.4, 118.7, 133.1, 143.0 (arom.)	115.4, 115.8, 132.5, 152.5 (arom.)
Melting point /°C	(colorless oil)	123 (ether–petroleum ether)	100.5–101 (ether–petroleum ether)	144–145	140–140.5 (petroleum ether–ether–methanol)	156–160 (THF)
Analysis
Formula	C11H19N3	C15H20N4	C13H14FN3	C15H17N3O	C14H14N4	C13H15N3O
Found (calc.) (%)
C	68.19 (68.35)	70.15 (70.28)	67.56 (67.51)	70.39 (70.57)	70.64 (70.57)	67.84 (68.10)
H	9.86 (9.91)	7.88 (7.80)	6.10 (6.10)	6.70 (6.71)	5.93 (5.92)	6.65 (6.59)
N	22.00 (21.74)	21.90 (21.86)	18.20 (18.17)	16.30 (16.46)	23.60 (23.51)	18.20 (18.33)
IR/cm^−1	(in CCl4)	(in CCl4)	(in CCl4)	(in CCl4)	(in CCl4)	(KBr)
	1450, 1460, 1470, 2880, 2960	1095, 1260, 1330, 1475, 1510, 2960	1225, 1490, 1505, 2960	1265, 1365, 1495, 1595, 1675 (CO), 2960	1370, 1495, 1510, 1600, 2220 (CN), 2960	1125, 1140, 1230, 1360, 1440, 1460, 1510, 2960

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Table 3 ¹⁵N chemical shifts and synthesis references for compounds of Schemes 1–5

Compound	^15N Chemical shifts				Reference for preparation
	N-1	N-2	N-3	Other nitrogen
a In CD3OD. b The chemical shifts have been reported in ref. 7. c The chemical shifts have been reported in ref. 8. d In DMSO-d6. e In DMSO-d6 at 363 K. f Doublet with ^1JNH = 100.5 Hz. g No assignment of meso and rac compounds, the chemical shifts have been reported in ref. 9.
1	−195.5	54.6	−31.4		22, 23
2	−194.6	53.3	−28.4		22, 24
3	−182.8	35.0	−29.3		25
4	−182.7	33.3	−42.0		26
5	−174.4	35.7	−34.4		27
6	−178.8	34.7	−29.9		28
7	−195.5	52.8	−56.2	−127.1 (CN)	29
8	−175.4	34.6	−30.4		28
9	−168.3	32.7	−17.6	−12.7 (NO2)	30, 31
10	−182.5	37.6	−50.7	−286.4 (NEt2)	32
11	−182.6	34.1	−46.8		26
12	−177.1	36.3	−48.4		33
13	−176.9	35.8	−46.8		33
14	−177.6	44.4	−5.3		34
15	−179.5	43.5	−8.2		34
16	−172.5	52.4	−12.1		35
17	−172.4	52.0	−10.4		35
18	−148.4	43.7	32.2		36
19	−163.1	44.0	32.8		36
20 ^a ^, ^b	−169.1	39.6	30.4		37
21 ^b	−173.1	42.8	27.4		37
22	−179.7	32.4	−6.9		35
23	−172.9	36.4	3.5	−160.4 (NMe)	38
24	−183.1	34.6	5.4	−161.2 (NMe)	38
25 ^c	−140.2	36.5	−18.8		8
26	−167.7	18.3	−36.3		39
27	−159.3	12.4	−11.4		39
28	−184.0	48.0	−25.8		40
29	−188.3	47.6	−36.1		41
30	−166.9	47.0	−36.5		42
31	−201.2	38.2	−17.4		43
32	−162.9	33.3	2.5		44
33	−190.1	47.9	−39.0		see Exp.
34	−168.7	38.5	−25.4		45
35	−176.9	33.5	−35.4	−339.5 (NMe2)	see Exp.
36	−176.5	33.5	−31.2		46
37	−175.0	33.5	−29.3		46
38	−173.9	33.5	−27.5		41, 46, 47
39	−176.0	33.1	−26.7		see Exp.
40	−174.9	32.6	−24.0		41
41	−175.0	32.2	−23.8		44, 46
42	−170.9	32.2	−17.0		see Exp.
43	−170.8	31.6	−14.5	−127.5 (CN)	see Exp.
44	−169.7	31.7	−12.1	−12.5 (NO2)	41, 46
45 ^d	−175.7	33.9	−28.7		see Exp.
46	−172.6	33.8	−26.8	−324.7 (pyrrolidino)	48
47	−137.9	38.1	5.6	−318.1 (pyrrolidino)	31
48	−175.9	33.9	−23.7	−329.3 (morpholino)	48, 49
49 ^d	−178.5	34.2	−37.1	−197.6 (imide-N)	44, 50
50	−193.7	46.2	−53.6	−198.3 (imide-N)	44
51 ^e	−189.4^f	34.6	−40.9		19
52 ^e	−193.4^f	37.0	−37.6		(19)
53	−200.1	36.0	−46.2		19
54	−183.2	40.0	−41.9		see Exp.
55	−170.0	41.4	−11.9	−12.4 (NO2)	51
				−321.0 (NMe)
56	−172.1	34.3	−15.9		28
57	−168.9	35.0	−12.0		52
58	−159.4	62.3	−12.1		53
59	−161.3	58.4	−5.4		53
60	−152.7	59.4	−11.2		53
61	−194.1	51.0	−32.9		see Exp.
62 ^g	−170.5	36.5	−26.8		9
	−170.5	36.5	−27.3

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Compound 54: Butyl azide¹⁰ (600 mg, solution in Et₂O, 64%, 3.88 mmol) and 2,3,4,5-tetraphenylcyclopentadienone (850 mg, 2.21 mmol) were dissolved in benzene (10 ml). The mixture was sealed in a glass tube and heated to 75 °C for 14 days. After filtration, the solvent and remaining BuN₃ were removed in vacuo at 45 °C. The residue was treated with ethanol. After separation of the insoluble starting material, the solvent was evaporated to give 610 mg (1.26 mmol, 57%) of pure 54 as yellow crystals, mp 60–61 °C (from EtOH) (Found: C, 82.12; H, 6.21. Calc. for C₃₃H₂₉N₃O: C, 81.96; H, 6.04%); ν_max (CCl₄)/cm⁻¹ 1708 (CO); δ_H(300 MHz; CDCl₃) 0.86 (3 H, t, 4′-Me), 1.35 (2 H, sext., 3′-H), 1.81 (2 H, quint., 2′-H), 3.43 (1 H, m, 1′-H), 3.69 (1 H, m, 1′-H), 6.8–7.6 (20 H, m, arom. H); δ_C(75 MHz, CDCl₃) 13.7 (C-4′), 20.1 (C-3′), 31.1 (C-2′), 47.1 (C-1′), 77.3 (C-5), 98.7 (C-4), 127.1, 127.5, 127.7, 127.9, 128.4, 129.5, 129.6, 130.6, 131.1, 133.0, 133.1, 135.8 (arom. C), 141.5 (C-7), 167.9 (C-8), 199.5 (C-6).

Compound 61 (with a structure assumed to be analogous to that of allyl azide dimer¹⁶): A solution of methallyl azide¹⁷ (5.0 g, 51.5 mmol) in toluene (50 ml) was heated under reflux for 3 days. The solvent was removed in vacuo to yield the crude product (2.1 g, 42%) which furnished a colorless solid (0.64 g, 13%), mp 220 °C (from CH₂Cl₂–Et₂O); δ_H(300 MHz, CDCl₃) 1.40 (3 H, s, Me), 3.37 (1 H, d, J 14.4, 6-H), 3.75 (1 H, d, J 14.4, 6-H), 3.68 (1 H, d, J 16.3, 4-H), 4.40 (1 H, d, J 16.3, 4-H); δ_C(75 MHz, CDCl₃) 19.6 (Me), 47.0 (C-6), 58.9 (C-5), 74.9 (C-4).

Compounds 9a, 19a, 27a, 29a, 44a, 50a and 55a, ¹⁵N labelled in positions 1 and 3 (compare Fig. 1), were synthesized from the corresponding ¹⁵N labelled azides. These were obtained by nucleophilic substitution reactions from sodium azide having both terminal positions enriched with ¹⁵N (49%). ¹⁵N labelled neopentyl azide was synthesized in 97% yield from 1-iodo-2,2-dimethylpropane and molten (n-C₁₆H₃₃)Bu₃P⁺¹⁵N=N=¹⁵N⁻, which was prepared from ¹⁵N labelled sodium azide according to the modified method reported in ref. 18. The heterocycles 51a/52a and 51c/52c were obtained from appropriately labelled sodium azide according to the procedure described in ref. 19. Compounds 9b and 44b, ¹⁵N enriched at positions 2 and 3, were obtained by a 1,3 dipolar cycloaddition reaction from p-nitrophenyl azide, which was prepared by coupling of p-nitrobenzenediazonium chloride with sodium azide, having both terminal positions labelled with ¹⁵N (49%). The resulting p-nitrophenyl azide was labelled weakly in the β and strongly in the γ position. The ¹³C labelled compounds 51d/52d, 53d were prepared according to ref. 19 and 54d as described above for 54, respectively, using 2,3,4,5-tetraphenylcyclopentadienone labelled with 10% ¹³C in the positions 2 and 5. This starting material was prepared as described²⁰ from 1,2-diphenylethanedione and 1,3-¹³C-1,3-diphenylpropan-2-one. The latter was obtained from 2-¹³C-2-phenylacetic acid (10% ¹³C by mixing of ¹³C labelled and unlabelled material in a 1 ∶ 9 ratio).²¹ The positions of ¹³C labelling of all substances were checked by ¹³C NMR spectroscopy.

NMR spectra were recorded from 0.5 to 1.5 molar solutions in CDCl₃ (unless stated otherwise) at a temperature of 309 K (unless stated otherwise) using standard pulse programs. ¹⁵N NMR spectra were recorded without proton decoupling on BRUKER WH-400 and AMX-400 spectrometers operating at 40.53 MHz and on a VARIAN Gemini 2000 spectrometer operating at 30.40 MHz. Nitromethane was employed as external reference (δ = 0 ppm) without susceptibility correction using an inner capillary tube of the standard. ¹⁴N NMR spectra were recorded on a BRUKER WH-400 spectrometer operating at 28.89 MHz. ¹H NMR spectra were recorded on BRUKER WH-400 and AMX-400 spectrometers operating at 400 MHz and on a VARIAN Gemini 2000 spectrometer operating at 300 MHz and referenced with TMS or solvent signals, which were standardized to TMS. ¹³C NMR spectra were recorded on BRUKER WH-400 and AMX-400 spectrometers operating at 100.58 MHz and on a VARIAN Gemini 2000 spectrometer operating at 75.43 MHz. Referencing was performed as described for ¹H NMR spectra.

Results and discussion

¹⁵N NMR chemical shifts and assignments of signals

The ¹⁵N NMR chemical shifts of all dihydrotriazoles studied (1–62, Schemes 1–5) are summarized in Table 3. Although the ¹⁵N NMR spectra were measured without proton decoupling, no long-range J_NH couplings could be resolved. The numbering scheme of the molecules does not follow in all cases the nomenclature rules for the sake of the comparability of chemical shifts, i.e. N-1 is always the highly substituted, amine-like (saturated) nitrogen atom of the dihydrotriazole ring bonded to N-2 and C-5, see for example 18–21. The sulfur heterocycle 25 [1,2,3,4-thiatriazol-5(4H)-one] could be regarded as a formal derivative of a 4,5-dihydro-1H-1,2,3-triazole. There were no differences in ¹⁵N chemical shifts observed for the ¹⁵N labelled (Fig. 1) and the unlabelled compounds.

Scheme 1

Scheme 2

Scheme 3

Scheme 4

Scheme 5

For the assignment of the ¹⁵N NMR signals of the 4,5-dihydro-1H-1,2,3-triazoles to N-1, N-2 and N-3, the electronic difference between pseudo-sp³ and sp² hybridized nitrogen atoms was used to assign the signal at highest field to N-1. For the unequivocal distinction of N-2 and N-3 (both sp² hybridized nitrogen atoms), 29a was investigated, which is labelled at the N-1 and N-3 positions.

The amine-like nitrogen N-1 shows in all cases the signal at the highest field in the range δ = −201 to −138 ppm. The resonance of nitrogen N-2 is observed usually at lowest field, i.e. in the range δ = 12 to 62 ppm. The chemical shift of nitrogen N-3 is found in the range −54 to 6 ppm, except in the case of compounds with a ring carbonyl group (18–21) which causes strong downfield shifts to δ values of ca. 30 ppm.

Generally, the ¹⁵N NMR data of 4,5-dihydro-1H-1,2,3-triazoles are clearly distinguished from those of cyclic azimines (4,5-dihydro-1H-1,2,3-triazol-2-ium-1-ides) as structurally isomeric compounds⁵⁴ and those of open chain triazenes⁵⁵ as well.

The four ¹⁵N NMR resonances of 9 could be assigned by means of labelling N-1 and N-3 (9a) and N-2 and N-3 (9b), respectively (Fig. 1). Thus, the ¹⁵N NMR signals of N-3 (−17.6 ppm) and NO₂ (−12.7 ppm) became assignable. For the compounds 44 (labelled 44a and 44b) and 55 (labelled 55a), a similar assignment was done.

For the ¹⁵N chemical shift assignment of dihydrotriazolone 19, especially to N-2 and N-3, the corresponding N-1 and N-3 ¹⁵N labelled isotopomer 19a was prepared. The signal at δ = 32.8 ppm stems from N-3 without doubt; nitrogen N-2 gives rise to the remaining ¹⁵N resonance at δ = 44.0 ppm.

The assignments of the ¹⁵N NMR signals of the thiatriazolone 25⁸ are easily performed by comparison with the data of 18–21.

The four nitrogen NMR signals of compound 50, especially the differentiation of N-1 and the imide-N, could be achieved by ¹⁵N labelling of N-1 and N-3 (compound 50a, Fig. 1).

Tautomeric and diastereomeric compounds

Several years ago, two of us employed ¹⁵N NMR spectroscopy for the elucidation of the prevailing tautomer of 5,5-diphenyldihydro-1,2,3-triazol-4(4H)-one, which exhibits the structure 20.⁷

The bicyclic [3 + 2] cycloadduct obtained from tetraphenylcyclopentadienone and sodium azide under acidic conditions has been reported to have a single tautomeric structure, namely 51, without experimental evidence.¹⁹ However, our ¹⁵N spectrum of this substance in DMSO-d₆ shows two signal sets with different intensity (ratio ca. 4 ∶ 1) in accord with the possible tautomers 51 and 52 (Fig. 1, Scheme 4, Table 3). The ¹³C NMR and ¹H NMR spectra also indicate the presence of both tautomeric forms. To assign the tautomers, the ¹³C enriched compounds 51d/52d were investigated. ¹³C NMR spectroscopy proved that 51 is the major and 52 the minor tautomeric structure. By ¹³C labelling (53d), it could be evidenced that the methylation product of 51/52, proposed to be 53,¹⁹ really possesses this structure, which is homologous to that of 51. The other conceivable methylation product with a structure similar to that of 52 was not observed. The ¹³C chemical shifts of the bridgehead carbons (C-4, C-5) and the carbonyl groups of 51–53 and of the related compound 54 are summarized in Table 4.

Table 4 Selected ¹³C NMR chemical shifts of 51–54 (ppm, in CDCl₃)

Carbon	51	52	53	54
In the case of the labelled compounds, signal enhancements were observed for C-4 of 52d and for C-5 of 51d, 53d and 54d.
C=O	200.8	198.8	199.0	199.5
C-4	97.7	97.2	99.0	98.7
C-5	75.1	77.2	76.6	77.3

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The intramolecular 1,3 dipolar cycloaddition reaction of 5-azidohex-1-ene did not afford a single diastereomer as reported in ref. 53; instead, a 4 ∶ 1 mixture of the exo (58) and the endo diastereomer (59) was formed (Scheme 5). The structure assignment was performed both by lanthanide induced shift experiments (Fig. 2) and by 2D NOESY NMR spectroscopy.

Fig. 2 Effects of Yb(thd)₃ shift reagent on ¹H chemical shifts in Δδ (in ppm, downfield) at 1 ∶ 1 molar ratio (calculated by linear regression with a correlation coefficient better than 0.97) of selected protons of 58–60 (concentrations during LIS measurement: 58/59ca. 45 mmol l⁻¹, 60ca. 3 mmol l⁻¹).

As proved by ¹⁵N NMR LIS experiments (see below) and by strong downfield shifts of the adjacent protons 4-H, the complexing site of 4,5-dihydro-1H-1,2,3-triazoles is N-3. Thus, the lanthanide induced shift of the signal of the methyl group is less effective in the case of 58 since the exo-methyl group is more distant from N-3 as compared to the case of 59. Additionally, the endo-proton geminal to the exo-methyl group of 58 (8-H) shows nearly the same LIS as the bridgehead proton (5-H). So a second piece of evidence for the exo position of the methyl group of the major isomer 58 is given. By adding the shift reagent to 60, the same influence on proton chemical shifts was observed although the effect was not as strong as for 58 and 59 (compare Fig. 2), probably caused by a smaller concentration of 60 during the measurement. The 2D NOESY spectrum shows cross signals between the methyl group and 5-H for 58 which indicates also the exo position of the methyl group. If the methyl group were in the endo position, a NOE should be observed between 5-H and 8-H which was not detected, however. The ¹H and ¹³C NMR data of the 1,2,3-triazabicyclo[3.3.0]oct-2-enes 58–60 are summarized in Table 5.

Table 5 ¹H and ¹³C NMR data (δ in ppm, J in Hz, solvent CDCl₃) of 58–60 (obtained by ¹³C APT, ¹H–¹H COSY, ¹³C–¹H COSY and simulation of 4-H_a, 4-H_b and 5-H couplings)

	^1H		^13C
a Signals of 59 partially covered by those of 58.
58	6-H (m)	1.17	Me	21.7
	Me (d, J 6.9)	1.33	C-6	30.0
	7-H (m)	1.41	C-7	31.7
	6-H (m)	1.81	C-5	56.8
	7-H (m)	1.84	C-8	57.5
	5-H (m)	3.66	C-4	71.8
	4-Ha (dd, J 16.5, 9.6)	4.07
	4-Hb (dd, J 16.5, 2.6)	4.29
	8-H (m)	4.34
59 ^a	Me (d, J 6.7)	1.66	Me	16.8
	5-H (m)	3.60	C-6/C-7	30.3
	4-Ha (dd, J 16.5, 9.7)	4.13		31.8
			C-5/C-8	57.0
				59.9
			C-4	73.7
60	exo-Me (s)	1.28	exo-Me	25.9
	6-H (m)	1.30	endo-Me	25.6
	7-H (m)	1.55	C-6	30.0
	endo-Me (s)	1.65	C-7	37.4
	6-H (m)	1.86	C-5	56.2
	7-H (m)	1.86	C-8	64.9
	5-H (m)	3.76	C-4	73.0
	4-Ha (dd, J 16.5, 9.9)	4.10
	4-Hb (dd, J 16.5, 2.7)	4.32

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Influence of concentration, solvents and shift reagents

The effect Δδ on the ¹⁵N chemical shifts caused by different concentrations of 4,5-dihydro-1H-triazoles was less than 2 ppm. For example, on comparison of a 0.64 molar and a 1.1 molar solution of 15 in CDCl₃, the absolute Δδ values were as follows: 0.05 ppm for N-1, 0.39 ppm for N-2 and 1.64 ppm for N-3. The use of solvents other than CDCl₃ (see Table 6) affects the signals of N-1 and N-2 (Δδ < 2 ppm) less than that of N-3 whose shift values vary up to 15 ppm (for 1 in CD₃OD vs. cyclohexane-d₁₂).

Table 6 Solvent influence on ¹⁵N chemical shifts

Compound	Solvent	^15N Chemical shifts
		N-1	N-2	N-3
1	CDCl3	−195.5	54.6	−31.4
	Cyclohexane-d12	−195.9	56.4	−24.4
	CD3OD	−195.1	54.6	−39.1
28	CDCl3	−184.0	48.0	−25.4
	Acetone-d6	−184.1	48.0	−21.2
	Benzene-d6	−184.8	47.7	−20.9
	DMSO-d6	−183.7	48.0	−22.4
50	CDCl3	−193.7	46.2	−53.6
	DMSO-d6	−193.1	47.1	−48.7

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The application of lanthanide induced shift reagents to 4,5-dihydro-1H-triazoles can cause strong changes of ¹⁵N shifts (Δδ > 150 ppm). Interaction of Yb(thd)₃ [tris(2,2,6,6-tetramethylheptane-3,5-dionato)ytterbium(III)] and 38 leads to the strongest downfield shift for N-3 while the effect on N-1 was the smallest. This behavior was found with all investigated compounds. Its accordance with the calculated preference for protonation⁵⁶ at N-3 allows the conclusion that this is the nitrogen which interacts with the shift reagent. The results are summarized in Fig. 3.

Fig. 3 Effects of Yb(thd)₃ shift reagent on ¹⁵N chemical shifts (Δδ in ppm, downfield) at 1 ∶ 1 molar ratio calculated by linear regression with a correlation coefficient better than 0.989.

For 50a, not so strong downfield shifts were observed. This is probably caused by the additional two complexing sites (C=O groups) in the molecule.

¹⁴N NMR measurements

Despite considerable line broadening, the ¹⁴N NMR spectrum of 1 (Fig. 4) consists of singlets which are sharp enough for the measurement of accurate chemical shifts. But this example is, unfortunately, not representative. In most other cases, no ¹⁴N NMR chemical shifts could be measured because of excessive broad lines.

Fig. 4 ¹⁵N and ¹⁴N NMR spectra of compound 1.

The effect of substituents on the ¹⁵N chemical shifts

Effects of substituents at N-1. If the number of β carbons of the N-1 substituent increases, a substantial downfield shifting of the N-1 resonance is found, compare 19 (CH₂tBu) vs.18 (tBu) and 24 (Me) vs.23 (CH₂tBu, Scheme 2, Table 3) as well as 33 (Bu) vs.30 (1-adamantyl, Scheme 3). This β effect resembles that observed with aliphatic amines.⁵⁷

Formal change of the N-1 substituent from aliphatic to aromatic causes strong and variable downfield shifts of the N-1 and N-3 signals, respectively, and a strong upfield shift of the N-2 resonance, see compounds 1 (Bu) and 2 (CH₂Ph) vs.3 (Ph, Scheme 1) and 33 (Bu) and 29 (CH₂Ph) vs.38 (Ph, Scheme 3) as well as 50 (Bu) vs.49 (Ph, Scheme 4). The effect on the N-1 shielding is similar in the case of amines, compare, for example, butylamine (δ = −359.4 ppm) with aniline (δ = −320.3 ppm).⁵⁸ Furthermore, electronic (resonance) effects cause changes of the N-2 and N-3 chemical shifts.

If the N-1 substituent is changed from a phenyl to a carbonyl group, strong or even very strong downfield shifts of N-1 and N-3 signals are observed, compare 26 (Ph) vs.27 (CO₂Et, Scheme 2) and 38 (Ph) vs.32 (CO₂Et, Scheme 3) as well as 46 (Ph) vs.47 (COPh, Scheme 4).

A change from alkyl to silyl substituent at N-1 causes downfield shifts both of N-1 and N-3 signals, see 33 (Bu) vs.28 (SiMe₃, Scheme 3). The fact that this shift is towards lower field is remarkable because in the case of amines the same structural change results in a shift into the opposite direction, see, for example, Bu–NMe₂ (δ = −352.8 ppm)⁵⁷ and Me₃Si–NMe₂ (δ = −378.5 ppm).⁵⁸

As may be anticipated on consideration of the substituent effects discussed above, the downfield shifts of the signals of N-1 and N-3, and the opposite shifts of N-2, which originate from increasingly electron-withdrawing substituents at the para position of the phenyl rings of 35–44, result in satisfactory linear relationships with Hammett's σ_p constants⁵⁹ (Fig. 5). While the signs of the slopes are as expected, their absolute values surprise, however. The signal of N-3 rather than that of N-1, to which the p-substituted phenyl ring is actually attached, is affected most strongly by variation of the p-substituent. On the other hand, the signal of N-2 is almost invariant toward these changes.

Fig. 5 Correlation of Hammett σ_p constants vs.¹⁵N chemical shifts of compounds 35–44.

Since ¹⁹F chemical shifts of p-substituted fluorobenzenes⁶⁰ are linearly correlated with the σ_p constants of the substituents, it comes as no surprise that the ¹⁵N shifts of the 1-aryldihydrotriazoles 35–44 yield linear relationships with those ¹⁹F shifts as well (Fig. 6). Their slopes, viz. 0.302 for N-1, −0.078 for N-2 and 0.877 for N-3, show that the electronic effects of p-substituents on the ¹⁵N nuclei of 35–44 indeed closely resemble those on the ¹⁹F nuclei in the corresponding fluorobenzenes.

Fig. 6 Correlation of ¹⁹F chemical shifts of p-substituted fluorobenzenes vs.¹⁵N chemical shifts of compounds 35–44.

Effects of substituents at C-4. If electron acceptors, like –COR, –SO₂NR₂, or –CN are bound to C-4, the N-3 signal is strongly shifted upfield, compare 1 (H) vs.7 (CN) and 3 (H) vs.4 (CO₂Me) and 10 (SO₂NEt₂) as well as 5 (H) vs.12 (CO₂Me) and 13 (CO₂Et, Scheme 1). The explanation of this effect may, perhaps, be based on the polarization of the π bond between the nitrogens N-2 and N-3 affording an increased electron density at N-3. Surprisingly, however, no significant effects on the shifts of N-2 and N-1 are found.

Effects of substituents at C-5. A formal exchange of hydrogen at C-5 for phenyl [compare 3vs.5 (Scheme 1)] shifts the N-1 signal downfield and the N-3 signal upfield because of the β effect of the phenyl group on N-1 and the γ effect on N-3, respectively.

The butyl group at C-5 of 8 has a γ effect on N-1 while the C-5 isopropenyl group of 6 causes two γ effects on the same nitrogen. Thus, a small overall upfield shift is observed in the latter case.

Upfield shifts of the N-1 and N-2 resonances and very strong upfield shifts for the N-3 resonance are observed when the oxo group in position 5 is formally exchanged for an N-methylimino or a methylene group [compare 19vs.23vs.22 (Scheme 2)]. These upfield shifts are readily interpreted in terms of the electronegativity of the elements that are doubly bonded at C-5. However, the differences between the oxo compound (19) and the imino compound (23) are surprisingly greater than that between the latter (23) and the methylene compound (22).

Conclusions

¹⁵N NMR spectroscopy is still not widely used, and the presented chemical shift data of 4,5-dihydro-1H-triazoles and their dependence on the nature of substituents detailed here may be useful for further structure determinations of such heterocycles by this method or for the assignment of ¹⁵N signals of similar heterocyclic compounds.

Acknowledgements

This work is dedicated to Professor Siegfried Hünig on the occasion of his 80th birthday. We thank Professor Dr H. Günther and his coworkers, especially Dr D. Moskau, for stimulating and helpful discussions while a great part of the measurements were performed at the University of Siegen. This research was supported by the Deutsche Forschungsgemeinschaft and the Fonds der Chemischen Industrie. K. B. and J. L. wish to thank Dynamit Nobel GmbH, Leverkusen, for providing chemicals.

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