Figure 1
The benzene (1) and nitrobenzene (2) were drawn in the Spartan 14 program11 Spartan, 14; Wavefunction inc., Irvine, USA, 2014. and the equilibrium geometry was calculated with Hartree-Fock 3-21G. The electrostatic potential map, lowest unoccupied molecular orbital (LUMO) and potential surfaces was determined. Comparative area, volume, cLogP, polarizability, dipole moment, number of hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) was calculated to each fragment, as well as their E-LUMO. From left to right is shown the LUMO surface, electrostatic potential map, potential surface, and physicochemical properties. (a) Benzene; (b) nitrobenzene.
Figure 2
The fragments 3-7 were drawn in the Spartan 14 program11 Spartan, 14; Wavefunction inc., Irvine, USA, 2014. and the equilibrium geometry was calculated with Hartree-Fock 3-21G. The electrostatic potential map, lowest unoccupied molecular orbital (LUMO) and potential surfaces was determined. Comparative area, volume, cLogP, polarizability, dipole moment, number of hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) was calculated to each fragment, as well as their E-LUMO. From left to right is shown the LUMO surface, electrostatic potential map, potential surface, and physicochemical properties. (a) Furan (3); (b) nitrofuran (4); (c) imidazole (5); (d) 2-nitroimidazole (6); (e) 5-nitroimidazole (7).
Figure 3
Timeline showing the nitroaromatic drugs approved until 2023.
Figure 4
Nitroaromatic drugs approved by FDA in the past 30 years. (a) Nitroheterocycle drugs; (b) nitroarene drugs.
Scheme 1
Synthesis of nifurtimox.2727 Herlinger, H.; Mayer, K. H.; US pat. 3,541,090 1970.
Scheme 2
Synthesis of benznidazole.3131 Watson, L.; WO pat. 2017205622 2017.
Scheme 3
Synthesis of fexinidazole.
3434 McInturff, E. L.; France, S. P.; Leverett, C. A.; Flick, A. C.; Lindsey, E. A.; Berritt, S.; Carney, D. W.; DeForest, J. C.; Ding, H. X.; Fink, S. J.; Gibson, T. S.; Gray, K.; Hubbell, A. K.; Johnson, A. M.; Liu, Y. ; Mahapatra, S.; McAlpine, I. J.; Watson, R. B.; O’Donnell, C. J.; J. Med. Chem. 2023, 66, 10150. [Crossref]
Crossref...
Scheme 4
Synthesis of tinidazole.3838 Wang, H.; Li, X.; Yang, M.; Xu, C.; Song, X.; Yu, S.; Ding, N.; CN pat. 111689902A 2020.
Scheme 5
Synthesis of secnidazole.4242 Jeanmart, C.; Messer, M. N.; GB pat. 1278758A 1970.
Scheme 6
Synthesis of nitazoxanide.4747 Xu, Y.; Wang, L.; CN pat. 115504941A 2022.
Scheme 7
Synthesis of pretomanid.4949 Baker, W. R.; Shaopei, C.; Keeler E. L.; WO pat. 1997001562A1 1997.
Scheme 8
Synthesis of delamanid.5454 Yamamoto, A.; Shinhama, K.; Fujita, N.; Aki, S.; Ogasawara, S.; Utsumi N.; WO pat 2011093529A1 2011.
Scheme 9
Synthesis of nisoldipine.5757 Pullagurla, M. R.; Rangisetty, J. B.; IN pat. 41013460 2018.
Scheme 10
Synthesis of nilutamide.5959 Bonne, C.; Perronnet, J.; Girault, P.; FR pat. 33084 1975.
Scheme 11
Synthesis of tolcapone.6262 Bernauer, K.; Borgulya, J.; Bruderer, H.; Da Prada, M.; Zurcher, G.; CH pat. 980 1986.
Scheme 12
Synthesis of entacapone.6565 Fu, Y.; Zhong, H.; Lin, F.; Xiao, H.; Zheng, Y.; Lin, X.; Tang, X.; CN pat.11624351 2020.
Scheme 13
Synthesis of nitisinone.6969 Pullagurla, M. R.; Pitta, B. R.; Rangisetty, J. B.; IN pat. 41016377 2018.
Scheme 14
Synthesis of opicapone.7474 Liao, R.; CN pat. 10797629 2018.
Scheme 15
Synthesis of venetoclax.
7979 Ku, Y. Y.; Chan, V. S.; Christesen, A.; Grieme, T.; Mulhern, M.; Pu, Y. M.; Wendt, M. D.; J. Org. Chem. 2019, 84, 4814. [Crossref]
Crossref...
Figure 5
Bioreduction of the nitro group by nitroreductases (NTR) or others flavoenzymes and/or their physiological redox partners (i.e., metalloproteins) and their involvement with antimicrobial activity and toxicity. (a) Two-electron nitroreduction; (b) one-electron nitroreduction.
Figure 6
Gut bacterial nitroreduction of chloramphenicol, clonazepam and nitrazepam.
Figure 7
Proposed mechanism of bioactivation of the prodrugs nifurtimox (a) and benznidazole (b).
Figure 8
Reactive electrophiles in the nitration of aromatic compounds with nitric acids with different concentrations and with H
2SO
4/HNO
3.
109109 Bruckner, R.; Advanced Organic Chemistry: Reaction Mechanisms, vol. 1, 1st ed.; Elsevier: London, UK, 2002. [Link] accessed in April 2024
Link...
Scheme 16
Nitration reaction of benzene with NO
2 over HPW/MCM-41.
118118 You, K.; Deng, R.; Jian, J.; Liu, P.; Ai, Q.; Luo, H.; RSC Adv. 2015, 5, 73083. [Crossref]
Crossref...
Scheme 17
Copper-mediated mononitration (a) and dinitration (b) of carboxylic acid derivatives.
119119 Liu, J.; Zhuang, S.; Gui, Q.; Chen, X.; Yang, Z.; Tan, Z.; Adv. Synth. Catal. 2015, 357, 732. [Crossref]
Crossref...
Scheme 18
ipso-Nitration of arylboronic acids.
120120 Prakash, G. K. S.; Panja, C.; Mathew, T.; Surampudi, V.; Petasis, N. A.; Olah, G. A.; Org. Lett. 2004, 6, 2205. [Crossref]
Crossref...
DCM: dichloromethane; TMSCl: trimethylsilyl chloride; r.t.: room temperature.
Scheme 19
ipso-Nitration of arylboronic acids.
121121 Chatterjee, N.; Bhatt, D.; Goswami, A.; Org. Biomol. Chem. 2015, 13, 4828. [Crossref]
Crossref...
NBS:
N-bromosuccinimide; PIFA: PhI(OCOCF
3)
2; r.t.: room temperature.
Scheme 20
Preparation of nitro compounds via an ipso-nitration reaction using MIL-101(Cr)-N(PC)-PdCl
2/NaNO
2.
123123 Sepehrmansourie, H.; Zarei, M.; Zolfigol, M. A.; Kalhor, S.; Shi, H.; Mol. Catal. 2022, 531, 112634. [Crossref]
Crossref...
Scheme 21
ipso-Nitration of arylboronic acids.
124124 Wu, X.-F.; Schranck, J.; Neumann, H.; Beller, M.; Chem. Commun. 2011, 47, 12462. [Crossref]
Crossref...
Scheme 22
Mono-nitration of indolines under mild condition. (a) C-5 nitration with 100% selectivity; (b) in C-7 with 100% selectivity and (c) mixture of C-5 and C-7 nitrations.
125125 Sau, S.; Bose, A.; Mal, P.; Asian J. Org. Chem. 2019, 8, 1854. [Crossref]
Crossref...
Scheme 23
Nitration of haloarenes catalyzed by Cu-bronze.
126126 Saito, S.; Koizumi, Y.; Tetrahedron Lett. 2005, 46, 4715. [Crossref]
Crossref...
Scheme 24
Nitration of quinoxalinones (a) and 5-aryl pyrazin-2-ones (b).
127127 Moon, J.; Ji, H. K.; Ko, N.; Oh, H.; Park, M. S.; Kim, S.; Ghosh, P.; Mishra, N. K.; Kim, I. S.; Arch. Pharm. Res. 2021, 44, 1012. [Crossref]
Crossref...
Scheme 25
Conversion of aryl chlorides (a), aryl triflates and nonaflates (b) to nitroaromatics.
128128 Fors, B. P.; Buchwald, S. L.; J. Am. Chem. Soc. 2009, 131, 12898. [Crossref]
Crossref...
Scheme 26
Nitration of aromatic compounds (phenols) using Zn(NO
3)
2 in PEG-400.
129129 Rajanna, K. C.; Chary, V. S.; Kumar, M. S.; Krishnaiah, G.; Srinivas, P.; Venkanna, P.; Venkateswarlu, M.; Ramesh, K.; Reddy, K. R.; Suresh, B.; Green Chem. Lett. Rev. 2015, 8, 50. [Crossref]
Crossref...
Scheme 27
Nitration of aromatic compounds (phenols) using FeTSPP/H
2O
2/NO
2– system in phosphate sodium buffer (PBS) (pH = 7).
130130 Sun, W.; Liu, Y. ; Zhang, H.; Xian, M.; Liu, H.; Catal. Lett. 2015, 145, 1991. [Crossref]
Crossref...
Scheme 28
Regioselective synthesis of dinitronaphthalene from 1-nitronaphthalene with nitrogen dioxide as nitrating reagent.
131131 You, K.; Zhou, Z.; Jian, J.; Deng, R.; Liu, P.; Ai, Q.; Luo, H.; Res. Chem. Intermed. 2015, 41, 8307. [Crossref]
Crossref...
Scheme 29
Nitration of the norcorrole ring with isoamyl nitrite.
132132 Deng, Z.; Li, X.; Stępień, M.; Chmielewski, P. J.; Chem. - Eur. J. 2016, 22, 4231. [Crossref]
Crossref...
Scheme 30
(a) Nitration of
o-silylaryl triflates by sodium nitrite; (b) multicomponent reaction (MCR): preparation of carabinol
o-nitroderivatives from aldehydes and o-silylaryl triflates.
133133 Dhokale, R. A.; Mhaske, S. B.; Org. Lett. 2016, 18, 3010. [Crossref]
Crossref...
Scheme 31
Nitration of oxazoles (a) and imidazoles (b and c).
134134 Katritzky, A. R.; Ramsden, C. A.; Joule, J. A.; Zhdankin, V. V. In Handbook of Heterocyclic Chemistry, vol. 1, 3rd ed.; Elsevier: London, UK, 2010, p. 473-604. [Crossref]
Crossref...
,
135135 Duddu, R.; Zhang, M.-X.; Damavarapu, R.; Gelber, N.; Synthesis 2011, 2011, 2859. [Crossref]
Crossref...
Scheme 32
Synthesis of 1-methyl-4-nitro-1
H-imidazole.
136136 Shahid, H. A.; Jahangir, S.; Yousuf, S.; Hanif, M.; Sherwani, S. K.; Arabian J. Chem. 2016, 9, 668. [Crossref]
Crossref...
Scheme 33
Products of solid-phase nitration. Anisoles (a) and phenols (b).
137137 Matsumoto, T.; Yamauchi, A.; Ishikawa, J.; Jin, G.-H.; Matsumoto, J.; Fueda, Y. ; Yasuda, M.; Int. J. Org. Chem. 2017, 7, 1. [Crossref]
Crossref...
Scheme 34
Benzene nitration with 15% FeCl
3-SiO
2.
138138 Zhou, S.; You, K.; Gao, H.; Deng, R.; Zhao, F.; Liu, P.; Ai, Q.; Luo, H.; Mol. Catal. 2017, 433, 91. [Crossref]
Crossref...
Scheme 35
Nitration of 2,4-ditertiarybutylphenol from the Co-nitrite complex [(Cl
4TPP)Co(NO
2)].
139139 Saha, S.; Gogoi, K.; Mondal, B.; Ghosh, S.; Deka, H.; Mondal, B.; Inorg. Chem. 2017, 56, 7781. [Crossref]
Crossref...
Scheme 36
Nitration of toluene with NO
2 and HNO
3 over sulfated SO
42-/WO
3 catalyst.
140140 Jiao, Y.; Zhu, M.; Deng, R.; Jian, J.; Yin, Y. ; You, K.; Res. Chem. Intermed. 2017, 43, 3961. [Crossref]
Crossref...
thus demonstrating that this type of process can be more environmentally acceptable. For the reaction with SO
42–/WO
3 and HNO
3, the yield was 56.8% for
o-NT, 4.3 for
m-NT and 38.9% for
p-NT, however, the conversion drops from 100%, in the second cycle to 63% and in the fifth to 22%, showing the advantage of the process with NO
2.
Scheme 37
Catalytic nitration of 1-nitronaphthalene (1-NN) with NO
2(g) over SZr catalyst promoted by O
2(g) and acetic anhydride.
141141 Yan, J.; Ni, W.; You, K.; Duan, T.; Deng, R.; Chen, Y.; Zhao, F.; Liu, P., Luo, H.; Res. Chem. Intermed. 2021, 47, 3569. [Crossref]
Crossref...
Scheme 38
Silver-catalyzed regioselective
ortho-nitration of anilides.
155155 Kianmehr, E.; Nasab, S. B.; Eur. J. Org. Chem. 2018, 2018, 6447. [Crossref]
Crossref...
Scheme 39
Catalytic nitration of toluene over immobilized AlCl
3-SiO
2.
160160 Deng, R.; You, K.; Yi, L.; Zhao, F.; Jian, J.; Chen, Z.; Liu, P.; Ai, Q.; Luo, H.; Ind. Eng. Chem. Res. 2018, 57, 12993. [Crossref]
Crossref...
Scheme 40
Catalytic nitration of naphthyridine (a) and naphthyridinone (b).
161161 Lowe, P. A. In Comprehensive Heterocyclic Chemistry, vol. 2; Elsevier: Oxford, UK, 1984, p. 581-627. [Crossref]
Crossref...
Scheme 41
Catalytic nitration of 2-phenyl-1
H-indole in the presence of HNO
3/AcOH and KNO
3/H
2SO
4.
162162 Hurst, D. T.; Adv. Heterocycl. Chem. 1993, 58, 215. [Crossref]
Crossref...
Scheme 42
Electrophilic nitration of arenes and five- and six-membered heteroarenes using
N-nitrosaccharin.
163163 Calvo, R.; Zhang, K.; Passera, A.; Katayev, D.; Nat. Commun. 2019, 10, 3410. [Crossref]
Crossref...
Scheme 43
Oxidation of aromatic amines with potassium peroxymonosulfate - oxone (O
3) in aqueous acetone.
164164 Webb, K. S.; Seneviratne, V. ; Tetrahedron Lett. 1995, 36, 2377. [Crossref]
Crossref...
Scheme 44
Oxidation of amines with Ti superoxide as catalyst.
165165 Dewkar, G. K.; Nikalje, M. D.; Ali, I. S.; Paraskar, A. S.; Jagtap, H. S.; Sudalai, A.; Angew. Chem., Int. Ed. 2001, 40, 405. [Crossref]
Crossref...
Scheme 45
Selective oxidation of various aromatic and diamines with peroxoic acid.
166166 Patil, V. V. ; Shankarling, G. S.; J. Org. Chem. 2015, 80, 7876. [Crossref]
Crossref...
Scheme 46
Selective oxidation of aromatic amines with HCOOH/H
2O
2.
167167 Ravi, K.; Bankar; B. D., Jindani, S.; Biradar, A. V.; ACS Omega 2019, 4, 9453. [Crossref]
Crossref...
Scheme 47
Oxidation of anilines in the presence of H
3PW
12O
40·
nH
2O/ NaBO
3·4H
2O.
168168 Firouzabadi, H.; Amani, N. I. K.; Green Chem. 2001, 3, 131. [Crossref]
Crossref...
Scheme 48
Oxidation of anilines in the presence of
m-CPBA.
169169 Liu, J.; Li, J.; Ren, J.; Zeng, B.-B.; Tetrahedron Lett. 2014, 55, 1581. [Crossref]
Crossref...
Scheme 49
Oxidation of heterocyclic amines to nitro compounds using N
2O
5.
174174 Churakov, A. M.; Semenov; S. E.; Loffe, S. L.; Strelenko, Y. A.; Tartakovskii, V. A.; Mendeleev Commun. 1995, 5, 102. [Crossref]
Crossref...
Scheme 50
Synthesis of 5-amino-3-nitro-1,2,4-triazole (ANTA) (a) and 1-methyl-3,4,5-trinitropyrazole (MTNP) (b) on a multigram scale.
175175 Wu, B.; Jiang, X.; Yang, Y.; Du, H.; Shi, X.; Li, Z.; Pei, C.; Org. Process Res. Dev. 2022, 26, 2823. [Crossref]
Crossref...
Scheme 51
Synthesis of bis(nitrofurazano)furazan (BNFF) using a mixture of 50% H
2O
2 and concentrated H
2SO
4.
176176 Tang, J.; Yang, H.-w.; Cheng, G.-b.; Energ. Mater. Front. 2023, 4, 110. [Crossref]
Crossref...
,
177177 Feng, Z.-C.; Du, M.-Y.; Zhai, L.-J.; Xu, K.-Z.; Song, J.-R.; Zhao, F.-Q.; J. Therm. Anal. Calorimetry 2018, 133, 1379. [Crossref]
Crossref...
,
178178 Zhang, Y.; Zhou, C.; Wang, B.; Zhou, Y. ; Xu, K.; Jia, S.; Zhao, F.; Propellants, Explos., Pyrotech. 2014, 39, 809. [Crossref]
Crossref...