Synthesis and Characterization of a Series of 1-Aryl-4-[Aryldiazenyl]-piperazines. Part II1. 1-Aryl-4-(2-Aryl-1-Diazenyl)-piperazines with Fluoro-, chloro-, Methyl-, Cyano- and Acetyl Substituents in The 1-Aryl Group



Karen O’Malleya, *, Keith Vaughanb, *
a ALS Environmental, Calgary, AB Canada
b Department of Chemistry, Saint Mary’s University Halifax, Nova Scotia B3H 3C3, Canada


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© O’Malley and Vaughan; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

* Address correspondence to these authors at the Department of Chemistry, Saint Mary’s University Halifax, Nova Scotia B3H 3C3; Phone: (902)-420-5650; Fax: (902)-496-8104; E-mail: keith.vaughan@smu.ca, karen.omalley@alsglobal.com
1 For part I in this series please see the Open Org Chem J, 2015, 9, 35-42.


Abstract

This paper reports the synthesis and characterization of eight series of 1-aryl-4-(2-aryl-1-diazenyl)-piperazines (12 to 19). Several series of these triazenes have been synthesized by the diazotization of a primary arylamine followed by diazonium coupling with a secondary arylpiperazine . The arylpiperazines used in this study are: 1-phenylpiperazine, 1-(4-fluorophenyl-)piperazine, 1-(4-chlorophenyl-)piperazine, 1-(3,4-dichlorophenyl-)piperazine, 1-(2-methylphenyl-)-piperazine, 1-(4-acetophenyl-)-piperazine, 1-(2-pyridyl-)piperazine and 2-cyanophenylpiperazine. These new triazenes (series 12-19) have been identified with a cocktail of contemporary spectroscopic techniques, notably infra-red and nuclear magnetic spectroscopy, supported by high resolution electron ionization mass spectrometry.

Keywords: 1-Arylpiperazine, Aryldiazenylpiperazines, Diazonium Coupling, IR spectroscopy, Mass Spectrometry, NMR, Triazene.



INTRODUCTION

The chemistry of triazenes has been explored since the latter part of the eighteenth century. Most of the work centered on the chemistry of the 1-aryl-3,3-dialkyltriazenes (1) and to a lesser extent on the chemistry of the monoalkyltriazenes (2). The field of investigation of anti-tumour triazenes was established in the 1950s with the discovery of the biological activity of DTIC, also known as Dacarbazine, 5-(3,3-dimethyltriazen-1-yl)imidazole-4-carboxamide (3) [1] and in the 1980s with the discovery of temozolomide, also known as Temodal, (3,4-dihydro-3-methyl-4-oxoimidazo 5,1-d -as-tetrazine-8-carboxamide) (4) [2]. The mechanism of action of these drugs is only partially understood, but researchers do agree that the effectiveness of triazene-based antitumour agents may be due to their ability to alkylate DNA. These drugs are still considered very effective therapies, especially Dacarbazine in the treatment of malignant melanomas [3] and Temodal for brain cancers [4].

From an alternative perspective, the medicinal chemistry of piperazine derivatives has attracted considerable interest. Research on arylpiperazines (5) is quite extensive due to their biological applications. They are especially known for their high affinity toward serotonin receptors, chiefly 5-HT1A receptors. Many common anxiolytics (antianxiety agents) and antidepressants incorporate arylpiperazines [5]. It is believed that arylpiperazine derivatives act as 5-HT1A receptor antagonists [6]. The possibility of combining the structural unit of a triazene with that of a piperazine raises interesting questions regarding the biological activity that might be generated from such a combination.

Vaughan et al. recently explored and expanded the range of triazene derivatives of piperazines in a series of papers. The structures investigated use (1, x)-diazocycloalkanes (6) where m = 1 or 2 and n = 2, 3, 4, or 5, as the general structure. The specific structures varied the R moiety, the homology of the piperazine ring, or a combination of the two. In a previous report [7], the 1-(2-aryl-1-diazenyl-) 4-methylpiperazines (7a) were prepared by reaction of 1-methylpiperazine with the appropriate diazonium salt; this work also reported the analogous synthesis of the N-ethoxycarbonylpiperazines (7b). A subsequent study [8] of the diazonium coupling reaction with piperazine itself in 2 : 1 proportions resulted in the isolation and identification of the bis-triazene series (8). Some of the compounds in this series had been previously synthesized, but characterization had not been in depth [9].

A further paper in Vaughan’s series [10] studied the effects of different piperazine ring homology, specifically diazepanes (9 and 10). One possible direction for further study arising from these papers would involve the synthesis of a series of compounds maintaining the (1, x)-diazocycloalkane base structure (6) with the piperazine ring, while further adding to different functional groups on the R group. The R group has included alkylated and esterified substituents, as well as the aryldiazenyl group in bis-triazenes (8 - 10). A logical next step would be to synthesize a series with the R group as an aryl moiety (11). This extension will further add to the information on similar series, and provide a synthetic method for future studies. Additional interest in these new compounds is derived from the potential medicinal applications of compounds of type 11.

In this paper, several novel compounds of a new series of triazenes (12-17) have been synthesized and characterized.

The series has also been extended to the triazene series (18 and 19).

All compounds have been purified and characterized by IR and NMR spectroscopy and high resolution mass spectrometry (EI).

EXPERIMENTAL

For details of the experimental methods such as IR, NMR, mass spectrometry, melting point measurement, etc., see any of the prior references of this author [7, 8, 10].

1-Aryl-4-(2-aryl-1-Diazenyl)-Piperazines (Series 12 to 19 Inclusive)

General Procedure

An aromatic primary amine (0.010 mol) was dissolved in 3M HCl (12.0 mL), and placed in an ice bath to cool to 0ºC. Sodium nitrite (0.011 mol), dissolved in water (3.0 mL) was added to the solution, and stirred for 0.5 hours. Concurrently, the appropriate aryl-piperazine (0.011 mol) was dissolved in water (1.0 mL), and cooled to 0ºC. If necessary to dissolve the alkylpiperazine, a small amount of 3M HCl (1.0 to 3.0 mL) was added. The piperazine solution was added slowly to the diazonium salt solution, and the resulting mixture was stirred for 0.5 hours. The solution was then neutralized with saturated sodium bicarbonate and left stirring in the cold for two hours. The product was collected using vacuum filtration if it was a solid and by extraction procedures if it was an oil. The solids were purified by recrystallization using an appropriate solvent. Oily products were isolated by extraction of the aqueous reaction mixture with dichloromethane, drying the organic layer over anhydrous magnesium sulphate, followed by evaporation of the solvent under vacuum.

RESULTS AND DISCUSSION

1-Aryl-4-(2-aryl-1-diazenyl)-piperazines: Synthesis

1-Aryl-4-(2-aryl-1-diazenyl)-piperazines (Series 12-17) were produced in good to excellent yields (20 - 99%) by reaction of a diazonium salt with a specific N-arylpiperazine. Physical data and IR spectroscopic data of these compounds are listed in Tables 1-6. The integrity of all compounds was verified by high-resolution mass spectrometry (EI) (see Tables 7-12). { See structures in the Introduction section above.}

Table 1.

Summary of physical and IR spectroscopic data of the 1-phenyl-4-(2-aryl-1-diazenyl)-piperazine series (12).


Series # X %
Yield
M.P. (C) Recr. Solv. Crystal
Appearance
IR (cm-1)
12c p-CH3 39 164 - 166 Ethanol Tiny pale
Yellow needles
OOP 819
12d p-Br 55 157 - 159 Ethanol Tiny
Orange needles
OOP 830
12e p-OCH3 20 182 - 184 Ethanol lustrous metallic
Plates
OOP
C-O
834
1157, 1245
12f p-COCH3 51 165 - 167 Ethanol Small
Orange plates
OOP
C=O
843
1681
12g p-Cl 38 161 - 162 Ethanol Lustrous gold
Plates
OOP 834
12i o-Br 95 Oil Oil - OOP 760
Table 2.

Summary of physical and IR spectroscopic data of the 1-(4-fluorophenyl)-4-(2-aryl-1-diazenyl)-piperazine series (13).


Series # X %
Yield
M.P. (°C) Recr. Solv. Crystal
appearance
IR (cm-1)
13a p-CO2CH3 99 151.8 - 152.4 Ethanol Orange
Fibrous
Needles
OOP
C=O
C-O
865
1710
1277
13b p-Br 99 185.9 - 186.5 Ethanol Tiny pale
Yellow needles
OOP 837
13c p-CH3 72 171.9 - 172.8 Ethanol Pale flesh-colored
plates
OOP 814
Table 3.

Summary of physical and IR spectroscopic data of the 1-(4-chlorophenyl)-4-(2-aryl-1-diazenyl)-piperazine series (14).


Series # X % Yield M.P. (°C) Recr. Solv. Crystal
Appearance
IR (cm-1)
14a p-CO2CH3 36 211.0 - 211.8 Ethanol Orange-Yellow
Needles
OOP
C=O
C-O
865
1704
1272
14b p-CN 49 185.3 - 186.0 Ethanol Gold needles OOP
C≡N
850
2218
14c p-Br 93 226.8 - 227.8 Ethanol Creamy yellow
Needles
OOP 837
14d p-CH3 52 195.2 - 196.3 Ethanol Pale pink
Needles
OOP 816
14e p-OCH3 30 192.9 - 194.0 Ethanol Pale pink
Plates
OOP
C-O
836
1028, 1240
14f p-NO2 89 218.5 - 221.4 Ethyl acetate Lustrous
Blood-red
needles
OOP
NO2
863
1327, 1506
Table 4.

Summary of physical and IR spectroscopic data of the 1-(3, 4-dichlorophenyl)-4-(2-aryl-1-diazenyl)-piperazine series (15).


Series # X % Crude M.P. (°C) Recr. Solv. Crystal
Appearance
IR(cm-1)
15a p-CN 98 162 - 163 Ethanol Fibrous
Off-white
Prisms
OOP
C≡N
842
2223
15b p-CHOCH3 98 155 - 156 Ethanol Lustrous reddish
gold plates
OOP
C=O
846
1675
15c p-Br 55 146 - 147 Ethanol Light brown needles OOP 836
15d p-OCH3 34 131 - 133 Ethanol Pale pink needles OOP
C-O
837
1034, 1245
15e p-NO2 53 150 - 151 Ethanol Small lustrous red
Needles
OOP
NO2
851
1339, 1595
15f p-CH3 36 130.3 - 130.9 Ethanol Small pale pink
Needles
OOP 823
15g 3-py 104 Oil Oil - OOP 838
15h m-CF3 48 Oil Oil - OOP 803
Table 5.

Summary of physical and IR spectroscopic data of the 1-(ortho-tolyl)-4-(2-aryl-1-diazenyl)-piperazine series (16).


Series # X % Yield M.P. (°C) Recr. Solv. Crystal
Appearance
IR (cm-1)
16a p-NO2 46 143.0 - 144.1 Cyclohexane Blood-red
Needles
OOP
NO2
855
1321, 1507
16b p-Cl 60 104.9 - 105.5 Ethanol Creamy yellow
needles
OOP 846
16c p-CO2C2H5 62 105.5 - 106.1 Ethanol Large orange
needles
OOP
C=O
C-O
859
1711
1269
16d p-COCH3 53 115.1 - 115.9 Ethanol Red-gold
lustrous needles
OOP
C=O
845
1675
16e p-CONH2 11 222.2 - 223.4 Ethanol Orange prisms OOP
C=O
N-H
857
1658
3289, 3328
16f p-OCH3 53 131.6 - 133.2 Cyclohexane Dark red prisms OOP
C-O
833
1010, 1242
16g H 61 Oil Oil - OOP 813
Table 6.

Summary of physical and IR spectroscopic data of the 1-(4-acetophenyl)-4-(2-aryl-1-diazenyl)-piperazine series (17).


Series # X % Yield M.P. (°C) Recr. Solv. Crystal
Appearance
IR (cm-1)
17a p-CO2CH3 98 235.3 - 236.1 Ethanol Yellow prisms OOP
C=O ester
C=O ketone
C-O ester
861
1706
1664
1280
17b p-Br 93 231.6 - 232.4 Ethanol Pale yellow
prisms
OOP
C=O ketone
837
1659
17c p-CH3 65 193.7 - 194.6 Ethanol Lustrous pink
plates
OOP
C=O ketone
847
1674
17d p-NO2 90 217-218 Ethanol Fine rusty-
red needles
C═O ketone
Nitro group
OOP
1665
1513 &
1337
861
17e p-CN 90 150-165 - Amorphous
brown clumps
C≡N
C═O ketone
OOP
2222
1658
843
17f p-CO2Et 93 177-178 Ethanol Fine Lemon-
yellow prisms
C═O ester
C═O ketone
C―O
OOP
1705
1664
1282
859
17g H 94 179-180 Ethanol Fine pale
yellow plates
C═O ketone
OOP para
OOP mono
1673
817
771
Table 7.

Summary of mass spectroscopic data of the 1-phenyl-4-(2-aryl-1-diazenyl)-piperazine series (12).


Series # X Formula Calc. Mass (amu) Found Mass (amu)
12c p-CH3 C17H20N4 280.1688 280.1697
12d p-Br C16H17N4Br 344.0636 344.0632
12e p-OCH3 C17H20N4O 296.1637 296.1622
12f p-COCH3 C18H20N4O 308.1637 308.1636
12g p-Cl C16H17N4Cl 300.1142 300.1143
12i o-Br C16H17N4Br 344.0636 344.0653
Table 8.

Summary of mass spectroscopic data of the 1-(4-fluorophenyl)-4-(2-aryl-1-diazenyl)-piperazine series (13).


Series # X Formula Calc. Mass (amu) Found Mass (amu)
13a p-CO2CH3 C18H19N4O2F 342.1492 342.1487
13b p-Br C16H16N4FBr 362.0542 362.0525
13c p-CH3 C17H19N4F 298.1594 298.1603
Table 9.

Summary of mass spectroscopic data of the 1-(4-chlorophenyl)-4-(2-aryl-1-diazenyl)-piperazin series (14).


Series # X Formula Calc. Mass (amu) Found Mass (amu)
14a p-CO2CH3 C18H19N4O2Cl 358.1196 358.1195
14b p-CN C17H16N5Cl 325.1094 325.1101
14c p-Br C16H16N4ClBr 378.0247 378.0248
14d p-CH3 C17H19N4Cl 314.1298 314.1295
14e p-OCH3 C17H19N4OCl 330.1247 330.1239
14f p-NO2 C16H16N5O2Cl 345.0992 345.1000
Table 10.

Summary of mass spectroscopic data of the 1-(3, 4-dichlorophenyl)-4-(2-aryl-1-diazenyl)-piperazine series (15).


Series # X Formula Calc. Mass (amu) Found Mass (amu)
15a p-CN C17H15N5C12 359.0704 359.0700
15b p-COCH3 C18H18N4OC12 376.0857 376.0846
15c p-Br C16H15N4C12Br 411.9857 411.9848
15d p-OCH3 C17H18N4OC12 364.0857 364.0821
15e p-NO2 C16H15N5O2C12 379.0602 379.0613
15f p-CH3 C17H18N4C12 348.0908 348.0917
15g 3-py C15H15N5C12 335.0704 335.0700
15h m-CF3 C17H15N4F3C12 402.0626 402.0611
Table 11.

Summary of mass spectroscopic data of the 1-(ortho-tolyl)-4-(2-aryl-1-diazenyl)-piperazine series (16).


Series # X Formula Calc. Mass (amu) Found Mass (amu)
16a p-NO2 C17H19N5O2 325.1538 325.1548
16b p-Cl C17H19N4Cl 314.1298 314.1298
16c p-CO2C2H5 C20H24N4O2 352.1899 352.1881
16d p-COCH3 C19H22N4O 322.1793 322.1801
16e p-CONH2 C18H21N5O 323.1746 323.1751
16f p-OCH3 C18H22N4O 310.1793 310.1797
16g H C17H20N4 280.1688 280.1689

The 1-(2-pyridyl)-4-(2-aryl-1-diazenyl-)piperazines (series 18) were prepared by diazotization of the arylamine and coupling with 1-(2-pyridyl-)piperazine. The 1-(2-cyanophenyl)-4-(2-aryl-1-diazenyl-)piperazines (series 19) were prepared by diazotization of the aryl amine and coupling with 1-(2-cyanophenyl-)piperazine. Physical data and infrared frequencies of the compounds of 18 and 19 are provided in Tables 13 and 15. Mass spectrometric data on these compounds are given in Tables 14 and 16.

Table 12.

Summary of mass spectroscopic data of the 1-(4-acetophenyl)-4-(2-aryl-1-diazenyl)-piperazine series (17).


Series # X Formula Calc. Mass (amu) Found Mass (amu)
17a p-CO2CH3 C20H22N4O3 366.1692 366.1682
17b p-Br C18H19N4OBr 386.0742 386.0726
17c p-CH3 C19H22N4O 322.1793 322.1801
17e p-CN C19H19N5ONa 356.1482 356.1483
17f p-CO2Et C21H24N4O3Na 403.1741 403.1726
Table 13.

Summary of physical and IR spectroscopic data of the 1-(2-pyridyl)-4-(2-aryl-1-diazenyl)-piperazine series (18).


Series # X % Yield M.P. (°C) Recr. Solv. Crystal Appearance IR (cm-1)
18a p-NO2 71 197.5 - 198.2 Ethanol Tiny orange-red
prisms
OOP
NO2
855
1333, 1504
18b p-CN 69 150.2 - 151.1 Ethanol Lustrous creamy-
orange plates
OOP
C≡N
835
2217
18c 3-py 79 Oil Oil Lustrous metallic
needles
OOP 810
18d p-CO2CH3 59 146.3 - 147.0 Ethanol Yellow prisms OOP
C=O
C-O
855
1710
1282
18e p-COCH3 61 166.4 - 166.8 Ethanol Buff prisms OOP
C=O
850
1672
18f p-CH3 55 111.7 - 112.3 Ethanol Off-white
needles
OOP 844
18g o-Br 74 Oil Oil - OOP 756
18h H 51 99.4 - 100.4 Ethanol Large lustrous
pale brown
plates
OOP 758
Table 14.

Summary of mass spectroscopic data of the 1-(2-pyridyl)-4-(2-aryl-1-diazenyl)-piperazine series (18).


Series # X Formula Calc. Mass (amu) Found Mass (amu)
18a p-NO2 C17H19N5O2 312.1334 312.1339
18b p-CN C16H16N6 292.1436 292.1431
18c 3-py C14H16N6 268.1436 268.1438
18d p-CO2CH3 C17H19N5O2 325.1538 325.1538
18e p-COCH3 C17H19N5O 309.1589 309.1600
18f p-CH3 C16H19N5 281.1640 281.1629
18g o-Br C15H16N5Br 345.0589 345.0588
18h H C15H17N5 267.1484 267.1495
Table 15.

Physical and IR Spectroscopic data of the 1-(2-cyanophenyl-)4-(2-aryl-1-diazenyl-)piperazine series (19).


Series
#
KS# X %
yield
m.p.
°C
Recr. Solv. Crystal
appearance
IR
cm.-1
19a KS72 p-CO2CH3 87 130 - 131 Ethanol Lustrous
yellow
needles
755
1714
2228
OOP
C=O
C≡N
19b KS75 p-CH2 91 107- 108 Cyclohexane Chunky pink
needles
769
822
2224
OOP
OOP
C≡N
19c KS74 p-Br 96 104.9- 105.3 Ethanol Off-white
plates
755
2221
OOP
C≡N
19d KS76 p-OCH3 36 130- 131 Ethanol Metallic buff
needles
765
828
1247
2218.5
OOP
OOP
C–O
C≡N
Table 16.

Mass spectroscopic data of the 1-(2-cyanophenyl)-4-(2-aryl-1-diazenyl)-piperazine series (19).


Cpd KS Formula Calc. mass
(amu)
Found mass
(amu)
19a KS72 C19H19N5O2 349.1538 349.1534
19b KS75 C18H19N5 305.1640 305.1640
19c KS74 C17H16N5Br 369.0589 369.0585
19d KS76 C18H19N5O 321.1589 321.1580

Infrared Spectral Analysis

All compounds in series 12 - 19 were characterized by IR spectroscopy in order to confirm the presence of the appropriate aryl substituents and to confirm the expected substitution pattern of the aryl rings with reference to the OOP bending vibrations of aromatic-Hgroups C. All of the compounds in series 12 show out-of-plane (OOP) bending vibrations of the substituted benzene ring. The compounds of other series display analogous IR bands. Aliphatic and aromatic carbon-hydrogen stretches are not reported because the nujol peaks overwhelm the peaks of interest. In the case of the oil (12i), for which the IR spectrum was collected as a neat liquid, aliphatic carbon-hydrogen peaks were found at 2820 and 2976 cm-1, and an aromatic carbon-hydrogen peak was found at 3064 cm-1.

Significantly, it should be noted here that the analysis of the compounds of series 12 with the strongly electron-withdrawing substituent, p-nitro-, p-cyano- and p-methoxycarbonyl-, namely compounds 12h, 12a and 12b, is not included in this paper. The reason for this omission is that the products of these reactions are not pure and we believe that the formation of these triazenes is accompanied by the formation of isomeric azo-compounds. The formation of azo-compounds is only observed in the case of these three compounds. All other compounds of series 12 behave “normally” and afford single compounds characterized as the triazenes shown. Furthermore, the compounds of series 13 - 19 behave “normally“ and do not give rise to isomeric azo compounds. The evidence that corroborates the azo compound hypothesis is somewhat involved, requiring the synthesis and characterization of model azo compounds. These results will be described in full detail in a follow-up paper to this one.

1H NMR Spectral Analysis of Series 12 to 19

The proton nuclear magnetic resonance data of the members of series 12 to 19 is listed in Tables 17-24. These results provided unequivocal structural information for the new triazenes of series 12 to 19. Fig. (1) shows the labeling of the piperazine-ring protons described in the analysis information found in the Tables 17-24. The aromatic resonance signals of the para-disubstituted compounds (12c–g) displayed the expected multiplicity of an AA‘BB’ system.

Table 17.

Summary of 1H NMR spectroscopic data of the 1-phenyl-4-(2-aryl-1-diazenyl)-piperazine series (12).


Series # X Aromatic (9H) Ha (4H) Hb (4H) Jab (Hz) X
Phenyl Ring Aryl Ring
12c p-CH3 6.92 (1H, t, J=6.2), 7.00 (2H, d, J=7.6) 7.30 (2H, t, J=7.9) 7.16 (2H, d, J=8.1), 7.37 (2H, d, J=8.2) 3.36 (t) 3.92
(t)
5.2 2.35
(3H, s)
12d p-Br 6.92 (1H, t, J=7.3), 6.98(2H, d, J=7.9), 7.31 (2H, t, J=8.0) 7.34 (2H, d, J=8.8), 7.46 (2H, d, J=8.8) 3.36
(t)
3.95
(t)
5.3 ---
12e p-OCH3 6.89 - 6.93 (1H, m), 6.99 (2H, d, J=8.1), 7.30 (2H, t, J=7.9) 6.90 (2H, d, J=8.9), 7.44 (2H, d, J=8.9) 3.60
(t)
3.89
(t)
5.2 3.82
(3H, s)
12f p-COCH3 6.84 (1H, t, J=7.3), 7.01 (2H, d, J=7.9), 7.26 (2H, t, J=7.9) 7.48 (2H, d, J=8.7), 7.97 (2H, d, J=8.7) 3.39
(br)
3.98
(t)
5.4 2.56
(3H, s)
12g p-Cl 6.92 (1H, t, J=7.3), 6.98 (2H, d, J=7.8) 7.31 (2H, t, J=8.3) 7.28 - 7.32 (2H, m), 7.40 (2H, d, J=8.7) 3.36
(t)
3.95
(t)
5.3 ---
12i o-Br 6.93 (1H, t, J=7.1), 6.99 - 7.05 (2H, m), 7.26 - 7.32 (2H, m) 6.99 - 7.05 (1H, m), 7.26 - 7.32 (1H, m),
7.44 (1H, d, J=8.1), 7.60 (1H, d, J=7.5)
3.38
(t)
4.04
(t)
5.1 ---
Table 18.

Summary of 1H NMR spectroscopic data of the 1-(4-fluorophenyl)-4-(2-aryl-1-diazenyl)-piperazine series (13).


Series # X Aromatic (8H) Ha (4H) Hb (4H) Jab (Hz) X
4-F-Ph Ring Aryl Ring
13a p-CO2CH3 6.96 - 7.04 (4H, m) 7.51 (2H, d,
J=8.7), 8.05
(2H, d, J=8.7)
3.29 (t) 4.04 (t) 5.2 3.92 (3H, s)
13b p-Br 7.01 - 7.04 (4H, m) 7.36 (2H, d,
J=8.7), 7.48
(2H, d, J=8.8)
3.29 (t) 3.99 (br) 5.2 ---
13c p-CH3 6.99 - 7.07 (4H, m) 7.29 (2H, d,
J=7.8), 7.41
(2H, d, J=8.4)
3.30 (t) 3.96 (t) 5.2 2.39 (3H, s)

Fig. (1).

Structure and substituents of 1-aryl-4-(2-aryl-1-diazenyl)-piperazines (12, 13,14, and 17)) with piperazine ring protons labeled.


The piperazine resonance signals (12c - g and 12i) displayed the expected multiplicity of an A2B2 system. The 4-fluorophenyl ring resonance signals (13a - c) displayed a complicated splitting pattern. The signals were consistent within the series, and were found as a multiplet in the range δ6.96 - 7.04. This complicated pattern is due to the NMR activity of fluorine. The protons of the tolyl methyl substituent (13c) had δ2 a.39 singlet. The signal full NMR at information for series (13) can be found in Table 18.

Table 19.

Summary of 1H NMR spectroscopic data of the 1-(4-chlorophenyl)-4-(2-aryl-1-diazenyl)-piperazine series (14).


Series # X Aromatic (9H) Ha (4H) Hb (4H) Jab (Hz) X
4-Cl-Ph Ring Aryl Ring
14a p-CO2CH3 6.94 (2H, d, J=8.9),
7.27 (2H, d, J=8.8)
7.51 (2H, d, J=8.4),
8.04 (2H, d, J=8.5)
3.36 (t) 4.05 (t) 5.3 3.93 (3H, s)
14b p-CN 6.92 (2H, d, J=8.8),
7.27 (2H, d, J=9.0)
7.53 (2H, d, J=8.5),
7.64 (2H, d, J=8.7)
3.36 (br t) 4.05 (t) 5.1 ---
14c p-Br 6.96 (2H, d, J=8.9),
7.29 (2H, d, J=8.6)
7.37 (2H, d, J=8.7),
7.51 (2H, d, J=8.7)
3.37 (t) 4.00 (t) 5.3 ---
14d p-CH3 6.91 (2H, d, J=9.0),
7.25 (2H, d, J=9.0)
7.18 (2H, d, J=8.1),
7.38 (2H, d, J=8.3)
3.33 (t) 3.92 (t) 5.4 2.37 (3H, s)
14e p-OCH3 6.89 - 6.92 (2H, m),
7.25 (2H, d, J=8.9)
6.89 - 6.92 (2H, m),
7.45 (2H, d, J=9.0)
3.33 (t) 3.89 (t) 5.3 3.83 (3H, s)
14f p-NO2 6.94 (2H, d, J=8.9),
7.28 (2H, d, J=8.9)
7.55 (2H, d, J=9.0),
8.23 (2H, d, J=9.2)
3.38 (br) 4.10 (t) 5.4 ---

The 1H NMR analysis information of the 1-(4-chlorophenyl)-4-(2-aryl-1-diazenyl)-piperazines (14) is shown in Table 19. 1H NMR spectral analysis of the 1-(3,4-dichlorophenyl)-4-(2-aryl-1-diazenyl)-piperazines (series 15) provided unequivocal structural information for these triazenes. The NMR analysis information can be found in Table 20, and the proton labeling is shown in Fig. (2).

Table 20.

Summary of 1H NMR spectroscopic data of the 1-(3, 4-diclorophenyl)-4-(2-aryl-1-diazenyl)-piperazine series (15).


Series # X Aromatic (7H) Ha (4H) Hb (4H) Jab (Hz) X
Aryl Ring (4H) 3,4-diCl-Ph Ring
He (1H) Hd (1H) Hc (1H)
15a p-CN 7.51 (2H, d, J=8.5),
7.62 (2H, d, J=8.6)
7.32 (d, J=8.8) 6.81 (dd, J=2.8, 8.9) 7.03 (d, J=2.7) 3.37 (t) 4.03 (t) 5.2 ---
15b p-COCH3 7.52 (2H, d, J=5.1),
7.97 (2H, d, J=4.9)
7.32 (d, J=9.0) 6.80 (dd, J=2.9, 8.8) 7.02 (d, J=2.9) 3.37 (t) 4.02 (t) 5.4 2.60 (3H, s)
15c p-Br 7.34 (2H, d, J=8.7),
7.47 (2H, d, J=8.7)
7.30 (d, J=8.8) 6.79 (dd, J=2.9, 8.8) 7.01 (d, J=2.9) 3.35 (t) 3.93 (t) 5.3 ---
15d p-OCH3 6.90 (2H, d, J=6.8),
7.44 (2H, d, J=8.9)
7.30(d, J=8.8) 6.78 (dd, J=2.9, 8.8) 6.78 (dd, J=2.9, 8.8) 3.33 (t) 3.87 (t) 5.4 3.82 (3H, s)
15e p-NO2 7.55 (2H, d, J=9.0),
8.23 (2H, d, J=9.0)
7.33 (d, J=8.9) 6.80 (dd, J=2.8, 8.9) 7.02 (d, J=2.9) 3.39 (br) 4.07 (t) 5.4 ---
15f p-CH3 7.19 (2H, d, J=5.3),
7.38 (2H, d, J=8.4)
7.32 (d, J=8.9) 6.80 (dd, J=2.9, 8.8) 7.02 (d, J=2.9) 3.35 (t) 3.91 (t) 5.3 2.39 (3H, s)
15g 3-py 7.27 - 7.30 (1H, m),
7.76 (1H, dd, J=0.5, 8.2),
8.44 (1H, dd, J=0.5, 4.7),
8.72 (1H, d, J=2.3)
7.33 (d, J=8.9) 6.81 (dd, J=3.0, 8.9) 7.02 (d, J=2.9) 3.37 (t) 4.00 (t) 5.3 ---
15h m-CF3 7.44 - 7.49 (2H, m),
7.64 (1H, d, J=7.2),
7.74 (1H, s)
7.33 (d, J=8.8) 6.81 (dd, J=2.9, 8.9) 7.03 (d, J=2.8) 3.37 (t) 4.00 (t) 5.3 ---

The 3, 4-dichlorophenyl ring resonance signals (15a – h) displayed the general splitting pattern of a 1,3,4-trisubstituted aryl ring. Three hydrogen atoms, Hc, Hd, and He, were all identifiable (refer to Fig. 2). Proton assignments were based on multiplicity and coupling constants. Hc was assigned its position because of its doublet and small coupling constant due to W-coupling with Hd. Its doublet signals resonate in the range δ7.30 – 7.33. Hd was assigned its position because of its doublet of doublets and two coupling constants. The small coupling constant matches Hc’s, and its large coupling constant corresponds to vicinal coupling with He. Its doublet of doublet signals resonates in the range δ 6.78 – 6.81. He was assigned its position because of its doublet and large coupling constant which matches Hd. Its doublet signals resonate between δ 7.01 – 7.03.

The piperazine resonance signals (15a – h) also displayed the expected multiplicity of an A2B2 system. The triplet signals were found between δ 3.33 – 4.07. The O-methyl group of the alkoxy substituent (15d) appears as a singlet atδ 3.82. The methyl protons that were part of the acetyl group (15b) appear as a singlet at δ 2.60. The tolyl methyl substituent (15f) had a singlet signal at δ 2.39.

Table 21.

Summary of 1H NMR spectroscopic data of the 1-(ortho-tolyl)-4-(2-aryl-1-diazenyl)-piperazine series (16).


Series # X Aromatic (8H) CH3 (3H) Ha (4H) Hb (4H) Jab (Hz) X
2-CH3 Ring Aryl Ring
16a p-NO2 7.08 (2H, t, J=6.8),
7.21 (1H, d, J=7.6),
7.25 (1H, d, J=7.5)
7.56 (2H, d, J=9.2),
8.24 (2H, d, J=9.1)
2.41 (s) 3.14 (br) 4.11 (br) --- ---
16b p-Cl 7.05 - 7.08(2H, m),
7.19-7.24(2H, m)
7.33 (2H, d, J=8.7),
7.42 (2H, d, J=8.7)
2.39 (s) 3.10 (t) 3.98 (t) 4.7 ---
16c p-CO2C2H5 7.10 (2H, t, J=8.0),
7.21 (1H, d, J=7.6),
7.25 (1H, d, J=7.4)
7.52 (2H, d, J=8.7),
8.06 (2H, d, J=8.7)
2.43 (s) 3.16 (br) 4.11 (br) --- 1.41 (3H, t, J=7.1),
4.39 (2H, q, J=7.1)
16d p-COCH3 7.08 (2H, d, J=8.6),
7.21(1H, d, J=7.3),
7.25 (1H, d, J=7.3)
7.54 (2H, d, J=8.5),
7.98 (2H, d, J=8.4)
2.41 (s) 3.13 (br) 4.08 (br) --- 2.61 (3H, s)
16e p-CONH2 7.08 (2H, d, J=8.9),
7.21(1H, d, J=7.2),
7.24 (1H, d, J=7.5)
7.54 (2H, d, J=8.4),
7.83 (2H, d, J=8.4)
2.41 (s) 3.13 (br) 4.06 (br) --- 5.69 (1H, br),
6.03 (1H, br)
16f p-OCH3 6.91 (2H, d, 8.9),
7.20 (1H, d, J=7.3),
7.23 (1H, d, J=8.3)
7.04 - 7.06 (2H, m),
7.45 (2H, d, J=8.8)
2.37 (s) 3.08 (t) 3.90 (t) 5.1 3.84 (3H, s)
16g H 6.90 (2H, d, J=7.9),
7.03 (1H, d, J=8.2),
7.10 (1H, d, J=7.2)
6.96 (1H, t, J=7.4),
7.23 (1H, t, J=7.6),
7.26 - 7.30 (3H, m)
2.40 (s) 3.18 (t) 4.46 (t) 5.2 ---

Table 21 shows the details of the 1H NMR analysis of the 1-(ortho-tolyl)-4-(2-aryl-1-diazenyl)-piperazines 16a-f. The piperazine resonance signals (16a - g) displayed the multiplicity of an A2B2 system. The triplet signals were found between δ3.08 – 4.46. 1H NMR spectral analysis of the 1-(4-Acetophenyl)-4-(2-aryl-1-diazenyl)-piperazines (17 a-c) (Fig. 1) gave very similar results which are detailed in Table 22.

Fig. (2).

Structure and substituents of the 1-(3, 4-dichlorophenyl)-4-(2-aryl-1-diazenyl)-piperazines (15).


Table 22.

Summary of 1H NMR spectroscopic data of the 1-(4-acetophenyl)-4-(2-aryl-1-diazenyl)-piperazine series (17).


Series # X Aromatic (8H) Ha (4H) Hb (4H) Jab (Hz) Hc (3H) X
4-COCH3
Ph
Aryl Ring
17a p-CO2CH3 6.89 (2H, d, J=9.0),
7.89 (2H, d, J=9.0)
7.47 (2H, d, J=8.7),
8.01 (2H, d, J=8.7)
3.57 (t) 4.01 (t) 5.4 2.51 (s) 3.89 (3H, s)
17b p-Br 6.92 (2H, d, J=9.0),
7.92 (2H, d, J=9.0)
7.35 (2H, d, J=8.8),
7.48 (2H, d, J=8.7)
3.58 (t) 3.98 (t) 5.4 2.55 (s) ---
17c p-CH3 6.93 (2H, d, J=9.0),
7.92 (2H, d, J=9.0)
7.18 (2H, d, J=8.1),
7.38 (2H, d, J=8.2)
3.57 (t) 3.94 (t) 5.5 2.54 (s) 2.36 (3H, s)
17d p-NO2 6.96(2H, d, J=9Hz)
7.96(2H, d, J=9Hz)
7.59(2H, d, J=7Hz)
8.26(2H,d ,J=7.1HZ
4.14 (t) 3.66 br (t) 5.5 2.59 (s) -
17e p-CN 6.90(2H,d J=9Hz)
7.91(2H,d, J=9Hz
7.50(2H,d, J=8.7Hz
7.62(2H,d, J=8.6Hz)
4.05 (t) 3.59 (t) 5.3 2.53 (s) -
17f p-CO2Et 6.92(2H,d, J=9Hz)
7.91(2H,d, J=9.1Hz)
7.48(2H,d, J=8.8Hz)
8.04(2H,d, J=8.8 Hz
4.04 (t) 3.59 (t) 5.5 2.53 (s) 1.39(3H,t, J=7.2Hz
4.36(2H,q, J=7.5Hz
17g H 6.91(2H,d, J=8.9Hz)
7.91(2H, d J=9.0Hz
7.20(1H,t J=7.3Hz)
7.36(2H,t, J=7.8Hz)
7.46(2H,dd J=5.8Hz)
3.96 (t) 3.57 (t) 5.4 2.53 (s) -

1H NMR analysis of the 1-(2-pyridyl)-4-(2-aryl-1-diazenyl)-piperazines (18 a to h) provided unequivocal structural information for these triazenes. The NMR analysis information can be found in Table 23. 1H NMR analysis of the 1-(2-cyanophenyl)-4-(2-aryl-1-diazenyl)-piperazines (19 a to d) provided unequivocal structural information for these triazenes. The NMR analysis information can be found in Table 24.

Table 23.

Summary of 1H NMR spectroscopic data of the 1-(2-pyridyl)-4-(2-aryl-1-diazenyl)-piperazine series (18).


Series # X Aromatic (8H) Ha (4H) Hb (4H) Jab (Hz) X
2-Py Ring Aryl Ring
18a p-NO2 6.70 - 6.73 (2H, m),
7.53 - 7.57 (1H, m),
8.21 - 8.24 (1H, m)
7.54 (2H, d, J=9.0),
8.23 (2H, d, J=9.0)
3.83 (br t) 4.07 (t) 5.2 ---
18b p-CN 6.70 - 6.73 (2H, m),
7.53 (1H, d, J=8.6),
8.24 (1H, dd, J=1.1, 4.9)
7.52 (2H, d, J=8.6),
7.63 (2H, d, J=8.7)
3.82 (br t) 4.03 (t) 5.4 ---
18c 3-py 6.68 - 6.69 (1H, m),
6.72 (1H, d, J=8.7),
7.52 - 7.55 (1H, m),
8.23 (1H, dd, J=1.2, 4.9)
7.27 - 7.29 (1H, m),
7.77 (1H, d, J=8.3),
8.42 (1H, dd, J=1.6, 4.8),
8.72 (1H, d, J=2.3)
3.80 (t) 3.99 (t) 5.4 ---
18d p-CO2CH3 6.69 - 6.70 (1H, m),
6.72 (1H, d, J=8.9),
7.53 - 7.56 (1H, m),
8.24 (1H, dd, J=1.1, 4.9)
7.51 (2H, dd, J=1.8, 8.7),
8.04 (2H, dd, J=1.8, 8.7)
3.81 (br t) 4.01 (t) 5.4 3.92 (3H, s)
18e p-COCH3 6.69 - 6.70 (1H, m),
6.72 (1H, d, J=8.6),
7.54 - 7.56 (1H, m),
8.24 (1H, dd, J=1.2, 4.9)
7.52 (2H, d, J=8.5),
7.97 (2H, d, J=8.7)
3.81 (br t) 4.02 (t) 5.3 2.60 (3H, s)
18f p-CH3 6.67 - 6.70 (1H, m),
6.72 (1H, d, J=8.6),
7.52 - 7.55 (1H, m),
8.24 (1H, dd, J=1.1, 5.0)
7.17 (2H, d, J=8.1),
7.39 (2H, d, J=8.4)
3.78 (br t) 3.91 (t) 5.4 2.36 (3H, s)
18g o-Br 6.68 - 6.70 (1H, m),
6.72 (1H, d, J=8.6),
7.52 - 7.56 (1H, m),
8.24 (1H, dd, J=1.2, 4.9)
7.03 - 7.06 (1H, m),
7.26 - 7.29 (1H, m),
7.46 (1H, d, J=8.0),
7.61 (1H, d, J=7.9)
3.81 (br t) 4.02 (t) 5.4 ---
18h H 6.68 - 6.70 (1H, m),
6.72 (1H, d, J=8.5),
7.54 (1H, m),
8.24 (1H, dd, J=1.1, 4.7)
7.21 (1H, t, J=7.3),
7.37 (2H, t, J=7.9),
7.48 (2H, d, J=8.4)
3.79 (t) 3.95 (t) 5.4 ---
Table 24.

1H NMR spectroscopic data of the 1-(2-cyanophenyl)-4-(2-aryl-1-diazenyl)-piperazine series (19).


Series # KS # X Piperazine
Ha and Hb
Aryl-p
Hc & Hd
Aryl-o
He-Hh
X
19a KS72 p-CO2CH3 3.55 4H, t
4.08 4H, t
J=5.2Hz
8.02 2H, d
7.49 2H, d
AA’BB’
7.05 2H, m
7.50 1H, m
7.60 1H, dd
3.90 3H, s
19b KS75 p-CH3 3.35 4H t
3.98 4H t
J=5.15Hz
7.37 2H d
7.16 2H d
AA’BB’
7.05 2H ddd
7.51 1H dt
7.60 1H dd
2.35 3H s
19c KS74 p-Br 3.34 4H t
4.01 4H t
J=5.2Hz
7.45 2H d
7.34 2H d
AA’BB’
7.10 2H m
7.51 1H dt
7.61 1H dd
-
19d KS76 p-OCH3 3.35 4H t
3.95 4H t
J=5.15Hz
6.89 2H d
7.43 2H d
AA’BB’
7.05 2H m
7.51 1H dt
7.60 1H dd
3.82 3H s

CONCLUSION

Eight series of 1-aryl-4-(2-aryl-1-diazenyl)-piperazines were successfully synthesized: 1-phenyl-4-(2-aryl-1-diazenyl)-piperazines, 1-(4-fluorophenyl)-4-(2-aryl-1-diazenyl)-piperazines, 1-(4-chlorophenyl)-4-(2-aryl-1-diazenyl)-piperazines, 1-(3,4-dichlorophenyl)-4-(2-aryl-1-diazenyl)-piperazines, 1-(ortho-tolyl)-4-(2-aryl-1-diazenyl)-piperazines, 1-(4-acetophenyl)-4-(2-aryl-1-diazenyl)-piperazines, 1-(2-pyridyl)-4-(2-aryl-1-diazenyl)-piperazines and 1-(2-cyano phenyl)-4-(2-aryl-1-diazenyl)-piperazines. These compounds were identified by IR and 1H NMR, and confirmed by high-resolution mass spectroscopy (EI).

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

The authors are grateful to the Natural Sciences and Engineering Research Council of Canada (NSERC) for a Discovery Grant to the principal author (KV) and an Undergraduate Summer Research Award to Karen O’Malley (née Schurman). We are also grateful to the Faculty of Graduate Studies and Research at Saint Mary’s University for on-going support. We are also grateful to the Atlantic Region Magnetic Resonance Centre at Dalhousie University for providing NMR spectra, and to Dalhousie University for providing mass spectral data. In particular, we would like to thank Dr. Mike Lumsden for assistance with the NMR spectral data, and Mr. Xiao Feng for assistance with mass spectra.

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