Synthesis and Characteristics of 1,2,4,5-Tetrazines for Using as High Energy Density Materials (HEDMs)

Abstract

Nitrogen-rich heterocycles constitute a family of high energy density materials (HEDMs) that have been developing intensively in recent years. A representative of this class is 1,2,4,5-tetrazine, a six-membered aromatic compound containing four nitrogen atoms in the ring. Many energetic compounds with this scaffold exhibit thermal stability, high density, and insensitivity to various stimuli, including friction, impact, and electrostatic discharge. This review presents methods for constructing 1,2,4,5-tetrazine precursors from acyclic reagents and describes their chemical modifications, leading to new energetic compounds with potential applications in the industry as explosives, propellants, or pyrotechnics. Synthetic procedures and reaction conditions are discussed, along with the detonation parameters of new nitrogen-rich tetrazine-based products, which allow estimation of their application potential.

1. Introduction

Tetrazines are aromatic heterocyclic compounds consisting of a six-membered ring with four nitrogen atoms in their structure, accounting for approximately 68% of the mass in the unsubstituted moiety. These compounds exist as three isomers that differ in the positions of the nitrogen atoms (Figure 1): 1,2,3,4-tetrazine (v-tetrazine), 1,2,3,5-tetrazine (as-tetrazine), and 1,2,4,5-tetrazine (s-tetrazine) [1,2].

The first of the isomers presented in Figure 1, 1,2,3,4-tetrazine (A), is highly unstable and is usually not isolated on its own but rather as a structural scaffold in fused systems. Stable monocyclic derivatives of tetrazine A, in the form of the corresponding 1,3-dioxides, were obtained for the first time by Tyurin et al. in 2006 [3]. The literature reveals that cyclic 1,2,3,4-tetrazines exist in equilibrium with the corresponding diazonium salts, formed by the opening of the six-membered heterocyclic ring [4,5,6]. This equilibrium state between the respective forms depends strongly on the structure of the fused molecule and the nature of the substituents. Derivatives of 1,2,3,4-tetrazine are being studied, among other purposes, for their potential applications in medicine as platelet aggregation inhibitors (D, Figure 2), guanylate cyclase activators [7,8], or as high-energy density materials for industrial use (H, I, Figure 2) [9,10].

The second isomeric form, 1,2,3,5-tetrazine (B, Figure 1), and its derivatives are relatively poorly described in the literature. The first example of a monocyclic derivative, 2,6-diphenyl-1,2,3,5-tetrazine, with complete spectroscopic characterization and reactivity in Diels–Alder cycloaddition reactions, was reported in 2019 by Wu and Boger [11]. For this class of compounds, studies predominantly focus on fused polycyclic systems and their biological activity, particularly anticancer properties. Mitozolomide (E, Figure 2) and temozolomide (F, Figure 2) are examples of fused arrangements that have found practical applications in the treatment of malignant melanoma [12,13]. Due to the high nitrogen content in the 1,2,3,5-tetrazine ring, candidates for use in high-energy materials are also being investigated. Polycyclic compounds are designed in which the six-membered unit is fused with other heterocyclic compounds, such as 1,2,4-triazole or pyrazole, or converted into corresponding N-oxides (J, Figure 2) [14,15].

The last of the possible isomers of tetrazine is 1,2,4,5-tetrazine (C, Figure 1), also referred to as s-tetrazine. X-ray structural analysis reveals that this aromatic molecule has a planar structure, with carbon–nitrogen and nitrogen–nitrogen bond lengths of 1.334 Å and 1.321 Å, respectively [16]. Most 1,2,4,5-tetrazine compounds are characterized by intense colors, often in shades of violet and red. This phenomenon is a direct consequence of weak, forbidden n→π* electronic transitions, which are also associated with the fluorescent properties observed in some derivatives [17,18,19]. The 1,2,4,5-tetrazine derivatives are notable for their stability compared to all other possible isomers. Consequently, compounds of this type have attracted significant interest from scientists and are widely studied for their diverse applications. Over the last decade, approximately 300 articles have been published annually, covering various aspects of 1,2,4,5-tetrazine chemistry (Figure 3). 1,2,4,5-Tetrazine and its derivatives are compounds with applications in various fields, including high energy density materials (HEDMs), which are the subject of this publication, and bioorthogonal chemistry, where they serve as markers for monitoring or imaging cancer cells (M, N, O, Figure 2). Due to the presence of low-energy n→π* electronic transitions, they can be utilized in optoelectronics to fabricate organic light-emitting diodes (OLEDs) and organic field-effect transistors (OFETs) (K, L, Figure 2). Conversely, π→π* transitions are responsible for their excellent photoluminescent properties [17,20]. Furthermore, many of these compounds exhibit biological activities, including antifungal, antiviral, anti-inflammatory, analgesic, antibacterial, and antimalarial properties (G, Figure 2) [21,22].

In recent years, derivatives of 1,2,4,5-tetrazine, classified as nitrogen-rich high energy density materials, have attracted particular interest among scientists. This interest has been reflected in several review articles published between 1998 and 2023 [23,24,25,26,27]. High energy density materials (HEDMs) represent a specific group of chemical compounds characterized by a high ratio of potential energy to density. Key parameters used to assess the potential applications of such compounds include detonation velocity and pressure, heat of explosion, thermal stability, and sensitivities to impact, friction, and electrostatic discharge.

The aim of this study is to review methods for the construction of 1,2,4,5-tetrazines in transformations involving acyclic reagents and their subsequent chemical modification, leading to high energy density materials. The reaction conditions are presented, and the detonation performance of functionalized 1,2,4,5-tetrazines is discussed, including those substituted at positions 3 and 6 with explosion-enhancing groups, fused bicyclic and tricyclic tetrazines, and finally, N-oxides generated at both endo- and exocyclic nitrogen atoms.

2. General Methods for the Synthesis of 1,2,4,5-Tetrazines

The formation of arrangements containing the aromatic 1,2,4,5-tetrazine ring is typically performed in two steps. In the first step, acyclic reagents are converted into dihydro-1,2,4,5-tetrazines (1). In the second step, the dihydro-1,2,4,5-tetrazines are oxidized to the corresponding 1,2,4,5-tetrazines (2). The most important synthons used in the synthesis of 1,2,4,5-tetrazines include formamidinium acetate, imidoesters, carbonitriles, imidoyl chlorides, aldehydes, guanidine hydrochloride, thiocarbohydrazide, and ethyl diazoacetate. The versatile co-reagent that binds to the indicated synthons is hydrazine, which introduces nitrogen atoms into the cyclic structure. The initially formed dihydro-1,2,4,5-tetrazines are then subjected to oxidation, either after isolating the intermediate product (stepwise synthesis, Scheme 1) or through direct oxidation of the post-reaction mixture without isolating the intermediate product. The reagents and conditions for the procedure discussed are presented below.

2.1. Synthesis of 1,2,4,5-Tetrazines Using Formamidinium Acetate

The unsubstituted 1,2,4,5-tetrazine (6) was synthesized via a two-step methodology using formamidinium acetate (3) and hydrazine hydrate (4) under mild conditions (Scheme 2). The reaction mechanism has not been fully elucidated; however, it is known that the intermediate dihydro-1,2,4,5-tetrazine (5), existing in two tautomeric forms, is produced. The reaction was conducted in methylene chloride or methanol at 0 °C for 1 h. The next step involved oxidizing the separated intermediate 5 in glacial acetic acid using equimolar amounts of sodium nitrite at 0 °C for 3.5 h [28].

The reaction yielded 1,2,4,5-tetrazine (6) as dark red crystals that sublimed rapidly under atmospheric pressure, complicating and prolonging the isolation process. This method produced compound 6, with a yield not exceeding 26% [28,29,30].

2.2. Pinner Synthesis Using Iminoesters

Derivatives of 1,2,4,5-tetrazine (6) substituted at positions 3 and 6 are of greater importance. These compounds are prepared using a reaction developed in the late 19th century by Adolf Pinner (Scheme 3) [19,31]. In this transformation, the starting iminoester (7) reacts with hydrazine, yielding the corresponding amidrazone (8). The amidrazone then undergoes cyclization in the presence of excess hydrazine, resulting in the formation of dihydro-1,2,4,5-tetrazine derivatives (9). The final step involves oxidation to produce the corresponding 1,2,4,5-tetrazines (10) using an oxidizing agent [19]. It has been shown that performing this reaction with molecular oxygen is challenging due to high pressure requirements and its slow rate (Table 1).

Significantly improved results during the oxidation of dihydro-1,2,4,5-tetrazines to 1,2,4,5-tetrazines were obtained by using nitrogen oxides generated in situ from sodium nitrite dissolved in hydrochloric or acetic acid [32,33,34,35,36,37,38,39,40,41]. However, in some cases, side oxidation reactions affecting certain functional groups near the 1,2,4,5-tetrazine ring, particularly the amino group, have been observed [42]. Studies exploring the use of other inorganic compounds as oxidants include iron(III) chloride [43], hydrogen peroxide [44,45], molecular bromine [31], manganese(IV) oxide [21], and chromium(VI) oxide [46]. However, low reaction yields and safety concerns, especially the carcinogenicity of chromium compounds, have limited the utility of these methods.

Organic oxidants present an alternative to sodium nitrite for the oxidation of dihydro-1,2,4,5-tetrazines to 1,2,4,5-tetrazines. These include 2,3-dicyano-5,6-dichloro-1,4-benzoquinone (11, DDQ) [47], [bis(acetoxy)iodo]benzene (12, PIDA) [48], m-chloroperoxybenzoic acid (13, m-CPBA) [42], N-chloro-N-(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoroundecyl)-4-methylbenzenesulfonamide (14, F-CAT) [49], benzoyl peroxide (15) [42], isopentyl nitrite (16) [50], or 1,4-benzoquinone (17) [42] (Figure 4, Table 1).

• The search for an effective organic oxidizing agent led to an investigation of the oxidation of 3-(5-aminopyridin-2-yl)-6-(pyridin-2-yl)-1,4-dihydro-1,2,4,5-tetrazine (Scheme 4). The reaction of compound 18 with 2,3-dicyano-5,6-dichloro-1,4-benzoquinone (DDQ, 11) yielded product 19, with a yield of 81%. The authors reported challenges in isolating the target product due to the presence of the reduced form (DDQ-H2) [47]. A lower yield (38%) was obtained using [bis(acetoxy)iodo]benzene (12) in dichloromethane. However, this reaction was performed under milder conditions and required less time compared to the reaction with DDQ [51]. The best result (86% yield) was achieved when F-CAT (14) was used as the oxidizing agent, with the reaction conducted at 40 °C for 12 h [49].

Scheme 4. Oxidation of 3-(5-aminopyridin-2-yl)-6-(pyridin-2-yl)-1,4-dihydro-1,2,4,5-tetrazine (18) using (a) DDQ (11), (b) [bis(acetoxy)iodo]benzene (12), and (c) F-CAT (14) leading to 6-(6-(pyridin-2-yl)-1,2,4,5-tetrazin-3-yl)pyridin-3-amine (19).

Scheme 4. Oxidation of 3-(5-aminopyridin-2-yl)-6-(pyridin-2-yl)-1,4-dihydro-1,2,4,5-tetrazine (18) using (a) DDQ (11), (b) [bis(acetoxy)iodo]benzene (12), and (c) F-CAT (14) leading to 6-(6-(pyridin-2-yl)-1,2,4,5-tetrazin-3-yl)pyridin-3-amine (19).

• The oxidation of dihydro-1,2,4,5-tetrazines to 1,2,4,5-tetrazines using m-chloroperoxybenzoic acid (13, m-CPBA) resulted in the desired products with a 55% yield. Benzoyl peroxide (15) and benzoquinone (17) were also effective in producing final products with yields of 65% and 71%, respectively [42]. Oxidation of substituted dihydro-1,2,4,5-tetrazines was also performed enzymatically using horseradish peroxidase [52]. Table 1 summarizes the inorganic and organic oxidizing agents and the conditions applied in the oxidation of dihydro-1,2,4,5-tetrazines (1) to the corresponding 1,2,4,5-tetrazines (2).

Table 1. Oxidation of dihydro-1,2,4,5-tetrazines (1) to the corresponding 1,2,4,5-tetrazines (2)—reagents and conditions.

Entry	R1, R2	Oxidizing Agent	Conditions	Yield [%]	Ref.
INORGANIC OXIDANTS
1	R1 = R2, C6H5, p-ClC6H4CH2, p-CF3C6H4	NaNO2	AcOH, 0–20 °C	98–49	[40,53,54,55,56,57,58,59,60,61]
2	p-NH2C6H5	H2O2	AcOH, Δ	60	[44,45]
3	Br, p-CH3OC6H4, p-ClC6H4, C6H4	Br2	AcOH, 55 °C	27–37	[62]
4	C6H4C6H4CH2, BrC6H4CH2	O2	10% aq K2CO3, rt	61–91	[63]
5	SCH2C6H5	FeCl3	EtOH, 25 °C	72	[43]
6	2H-Tetrazol-5-yl	CrO3	H2SO4, −5 °C	72	[46]
7	3,5-Dimethyl-1H-pyrazol-1-yl	MnO2	DCM, rt	58	[21]
8	-NH2, R1 = R2	NaBO3	H2O, 25 °C, 2 h	60	[43]
ORGANIC OXIDANTS
9	Pyrid-2-yl, 5-Aminopyrid-2-yl	DDQ (11)	Toluene 12 h, reflux	81	[47]
10	SCH3, CH2OBn	PIDA (12)	rt, 30 min	70	[48]
11	Pyrid-2-yl, 5-Aminopyrid-2-yl	m-CPBA (13)	DCM, rt, 12 h	55	[42]
12	2-Pyridyl	F-CAT (14)	CH3CN, 40 °C, 12 h	86	[49]
13	Pyrid-2-yl, 5-Aminopyrid-2-yl	Benzoyl Peroxide (15)	DCM, rt, 12 h	65	[42]
14	Biphenyl-4-yl	Isopentyl nitrite (16)	EtOH, reflux, 4 h	83.5	[50]
15	Pyrid-2-yl, 5-Aminopyrid-2-yl	Benzoquinone (17)	DCM, rt, 12 h	71	[42]

Table 1. Oxidation of dihydro-1,2,4,5-tetrazines (1) to the corresponding 1,2,4,5-tetrazines (2)—reagents and conditions.

Entry	R1, R2	Oxidizing Agent	Conditions	Yield [%]	Ref.
INORGANIC OXIDANTS
1	R1 = R2, C6H5, p-ClC6H4CH2, p-CF3C6H4	NaNO2	AcOH, 0–20 °C	98–49	[40,53,54,55,56,57,58,59,60,61]
2	p-NH2C6H5	H2O2	AcOH, Δ	60	[44,45]
3	Br, p-CH3OC6H4, p-ClC6H4, C6H4	Br2	AcOH, 55 °C	27–37	[62]
4	C6H4C6H4CH2, BrC6H4CH2	O2	10% aq K2CO3, rt	61–91	[63]
5	SCH2C6H5	FeCl3	EtOH, 25 °C	72	[43]
6	2H-Tetrazol-5-yl	CrO3	H2SO4, −5 °C	72	[46]
7	3,5-Dimethyl-1H-pyrazol-1-yl	MnO2	DCM, rt	58	[21]
8	-NH2, R1 = R2	NaBO3	H2O, 25 °C, 2 h	60	[43]
ORGANIC OXIDANTS
9	Pyrid-2-yl, 5-Aminopyrid-2-yl	DDQ (11)	Toluene 12 h, reflux	81	[47]
10	SCH3, CH2OBn	PIDA (12)	rt, 30 min	70	[48]
11	Pyrid-2-yl, 5-Aminopyrid-2-yl	m-CPBA (13)	DCM, rt, 12 h	55	[42]
12	2-Pyridyl	F-CAT (14)	CH3CN, 40 °C, 12 h	86	[49]
13	Pyrid-2-yl, 5-Aminopyrid-2-yl	Benzoyl Peroxide (15)	DCM, rt, 12 h	65	[42]
14	Biphenyl-4-yl	Isopentyl nitrite (16)	EtOH, reflux, 4 h	83.5	[50]
15	Pyrid-2-yl, 5-Aminopyrid-2-yl	Benzoquinone (17)	DCM, rt, 12 h	71	[42]

2.3. Modified Pinner Synthesis Using Carbonitriles

The classical Pinner reaction, which originally employed iminoesters, has been modified to use carbonitriles and hydrazine in the presence of activating agents such as Lewis acids, elemental sulfur, or appropriate thiols and sulfides (Scheme 5). The reaction mechanism is not fully understood; however, it is postulated that elemental sulfur added to hydrazine enhances its nucleophilic properties and facilitates the attack of the lone electron pair located on the central nitrogen atom of the carbonitrile group. This sulfur-based method works well for aromatic carbonitriles; however, aliphatic carbonitriles are generally non-reactive, and the final products are obtained in low yields [19,64]. An alternative to elemental sulfur as the activating agent includes thiols, sulfides, or certain Lewis acids derived from zinc or nickel, such as Zn(OTf)₂ and Ni(OTf)₂ [35]. For thiols (e.g., N-acetylcysteine) as activating agents, a different mechanism has been proposed involving the formation of the appropriate amidrazone. The latter is transformed into the corresponding dihydro-1,2,4,5-tetrazine (1), with the activating sulfur compound being regenerated [36,65,66].

Table 2. Modified Pinner synthesis—reagents and conditions.

Entry	R1, R2	Reagents	Conditions	Product	Ref.
		Pinner
1	CH3	R1CN, N2H4 (excess)	N2H4, [Ox]	Symmetrical disubstituted 1,2,4,5-tetrazines	[31,67]
2	CH3, C6H5, C6H5, CH2C6H5	R1CN, R2CN	N2H4, [Ox]	Symmetrical and unsymmetrical disubstituted 1,2,4,5-tetrazines	[31,67]
		Devaraj
3	CH3, C6H4CH2OH, C6H4CH2NHBoc, C6H4OH, C6H4I, nC5H11	R1CN, R2CN	Zn(OTf)2 or Ni(OTf)2, N2H4, [Ox]	Unsymmetrical disubstituted 1,2,4,5-tetrazines	[35]
4	CH2C6H5, n-C5H11, C(CH3)3, NHBoc,	R1CN	Zn(OTf)2 or Ni(OTf)2, N2H4, [Ox]	Monosubstituted 1,2,4,5-tetrazines	[35]
		Wu
5	C6H5, (CH2)2OH, CH3, 4-Br-C6H4 (CH2)2NHBoc, 4-COOH-C6H4	R1CN, R2CN	3-Sulfanylpropanoic acid, N2H4∙H2O, EtOH, [Ox]	Unsymmetrical disubstituted 1,2,4,5-tetrazines	[36]
		Audebert
6	CH2COOH, COOH, CH2OH, CN, Br, CH3	R1CN, CH2Cl2	Sulfur, N2H4∙H2O, EtOH, MW, [Ox]	Monosubstituted 1,2,4,5-tetrazines	[37]

summarizes reagents and conditions applied in modified Pinner synthesis, leading to the corresponding 1,2,4,5-tetrazines (2).

2.4. Synthesis of s-Tetrazines Using Imidoyl Chlorides

Another method for synthesizing 1,2,4,5-tetrazine derivatives is the condensation of imidoyl chlorides with hydrazine (Scheme 6) [39,40]. The transformation is selective because specific structural elements are connected prior to cyclization. This eliminates the risk of forming a mixture of symmetrical and unsymmetrical 1,2,4,5-tetrazine derivatives and avoids difficulties in separating the reaction products. The method is particularly effective for synthesizing difficult-to-obtain unsymmetrical derivatives with alkyl substituents. The starting reagents, acid chlorides (or less frequently esters), react with hydrazine to form the corresponding hydrazides. These hydrazides are subsequently converted into unsymmetrical N,N′-diacylhydrazines by reacting with another molecule of a carboxylic acid derivative and treating the product with phosphorus pentachloride to produce imidoyl chlorides (20). Cyclization of the resulting acyclic intermediates is achieved by treatment with hydrazine. The yields of the final products, 3,6-disubstituted 1,2,4,5-tetrazines, are satisfactory, reaching 45% for alkyl substituents (R = t-butyl), and 49% (R = 3-NO₂-C₆H₄) and 61% (R = 3-F-C₆H₄) for aromatic substituents (Table 3).

2.5. Synthesis of 1,2,4,5-Tetrazines Using Aldehydes

1,2,4,5-Tetrazines can also be synthesized from aldehydes (Scheme 7). This method enables the preparation of derivatives with aliphatic substituents, which are challenging to isolate due to their high volatility and sublimation tendency. The cyclocondensation reaction between aldehyde (21) and hydrazine first forms the corresponding cyclic 1,2,3,4,5,6-hexahydro derivative, which is subsequently oxidized to dihydro-1,2,4,5-tetrazine in the presence of an activated carbon-supported palladium catalyst [19,68,69], platinum(IV) oxide, or Adam’s catalyst [70]. The final disubstituted 1,2,4,5-tetrazines are obtained from the intermediate dihydro-1,2,4,5-tetrazines by treatment with sodium nitrite in an acidic environment.

2.6. Synthesis of 1,2,4,5-Tetrazines Using Guanidine Derivatives

A highly significant method for synthesizing 1,2,4,5-tetrazines is the reaction between guanidine hydrochloride (22) and hydrazine. This multi-step procedure enables the preparation of valuable tetrazine precursors (e.g., hydrazines, chlorides) for further functionalization in nucleophilic substitution and coupling reactions. In the first step, the reaction between guanidine hydrochloride and hydrazine produces 1,2,3-triaminoguanidine hydrochloride with a high yield (Scheme 8). This compound reacts with penta-2,4-dione to form the dihydro-1,2,4,5-tetrazine symmetrically substituted with 3,5-dimethyl-1H-pyrazol-1-yl groups at positions 3 and 6. In the subsequent step, the corresponding substituted 1,2,4,5-tetrazine is obtained through oxidation using sodium nitrite in acetic acid [54,71,72,73].

• The oxidation product, 3,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazine (23), reacts with hydrazine in acetonitrile at room temperature to produce 3,6-dihydrazino-1,2,4,5-tetrazine (24, DHT)—the first reported member of the 1,2,4,5-tetrazine family classified as a high energy density material (HEDM) [54,71,74,75,76,77,78,79]. This compound can be further converted into another functional derivative, 3,6-dichloro-1,2,4,5-tetrazine (25), by treatment with trichloroisocyanuric acid in acetonitrile (Scheme 9) [71,77,78].

2.7. Synthesis of 1,2,4,5-Tetrazines Using Thiocarbohydrazide

A method to synthesize substituted 1,2,4,5-tetrazines without an oxidation step involves the reaction of hydrazinecarbothiohydrazide (26) with triethyl orthoesters (Scheme 10), yielding 3-(dodecylthio)-1,2,4,5-tetrazine derivatives (27) [80,81]. The key thiocarbohydrazide 26 is first converted into a salt by reaction with 1-iodododecane and subsequently reacted with triethyl orthoesters in the presence of triethylamine. Introducing a long-chain dodecyl substituent into the sulfur atom reduces the volatility of the resulting 1,2,4,5-tetrazine, facilitating the isolation process. This is particularly important for alkyl 1,2,4,5-tetrazines, which are highly volatile and difficult to purify. Alkyl derivatives of 3-(dodecylthio)-1,2,4,5-tetrazine (27) are valuable intermediates for synthesizing other reactive derivatives, such as 3-hydrazinyl-1,2,4,5-tetrazine and 3-bromo-1,2,4,5-tetrazine.

Another transformation described in the literature is the reaction of hydrazinecarbothiohydrazide (26) with methyl iodide, giving the condensation product methyl hydrazinecarbohydrazonothioate (Scheme 11). This intermediate, treated with trimethyl orthoacetate and subsequently oxidized with sodium nitrite in trifluoroacetic acid, was converted into 3-methyl-6-(methylthio)-1,2,4,5-tetrazine, with a yield of 23% [82].

The symmetrical 3,6-bis(methylthio)-1,2,4,5-tetrazine (28) was synthesized through a multi-step sequence of transformations involving hydrazinecarbothiohydrazide (26), bis(carboxymethyl) trithiocarbonate, and methyl iodide (Scheme 12). In the first step, thiocarbohydrazide reacted with bis(carboxymethyl) trithiocarbonate in the presence of sodium hydroxide, forming cyclic 1,2,4,5-tetrazine-3,6-dithione. This intermediate subsequently methylated with methyl iodide. The resulting 3,6-bis(methylthio)-1,4-dihydro-1,2,4,5-tetrazine then oxidized with iron(III) chloride in ethanol, yielding the final product 28, with a yield of 84% [83].

2.8. Synthesis of 1,2,4,5-Tetrazines Using Ethyl Diazoacetate

The six-membered 1,2,4,5-tetrazine ring can also be constructed via dimerization of ethyl diazoacetate (29) in the presence of sodium hydroxide (Scheme 13). The resulting disodium salt of 1,4-dihydro-1,2,4,5-tetrazine-3,6-dicarboxylic acid was neutralized, converted into acid chloride using thionyl chloride, esterified with methanol, and subsequently oxidized to form the 1,2,4,5-tetrazine ring [84,85]. The carboxyl groups at positions 3 and 6 of the 1,2,4,5-tetrazine core enable further structural modifications, allowing for the synthesis of a variety of derivatives [44,86]. The clear advantages of this method are its mild dimerization conditions and high yield (97%).

2.9. Synthesis of 1,2,4,5-Tetrazines Using Arylaldehyde-Derived Arylsulfonylhydrazones and N-Chlorosuccinimide

Symmetrically substituted 1,2,4,5-tetrazines were synthesized through reactions involving tosyl derivatives of hydrazones (31) (Scheme 14). The best result was obtained using N-chlorosuccinimide (NCS) in the presence of potassium hydroxide, with nitromethane as the solvent at 0 °C. Subsequent cleavage of the tosyl group from the intermediate product was performed in ethanol using tetra-n-butylammonium fluoride (TBAF), yielding the final product with a 92% yield [87]. Table 3 summarizes the acyclic precursors and reaction conditions for constructing the 1,2,4,5-tetrazine ring.

Table 3. Summary of other precursors and conditions for the construction of the 1,2,4,5-tetrazine ring.

Entry	Precursor (Method)	R1, R2	Conditions	Yield [%]	Ref.
1	Imidoyl chloride (20) (Method 2.4)	C(CH3)3, 3-NO2-C6H4, R = 3-F-C6H4, 3,5-bis(CF3)-C6H3, pyrid-2-yl, 4-CF3-C6H4, 2-NO2-C6H4	NH2NH2, EtOH, reflux, [Ox]	42–75	[39,40]
2	Aldehyde (21) (Method 2.5)	CH3, C2H5, C(CH3)3	NH2NH2, O2 (Pd/C), HNO3	5–30	[19,68,69]
3	Guanidine hydrochloride (22) (Method 2.6)	3,5-dimethylpyrazol-1-yl	2,4-pentadione, 70 °C, [Ox]	95	[71,77,78]
4	Thiocarbohydrazide (26) (Method 2.7)	H, CH3, C6H5	RC(OC2H5)3, NEt3, EtOH,	16–24	[80,81]
5	Ethyl diazoacetate (29) (Method 2.8)	COOCH3	NaOH, HCl, SOCl2, MeOH, −30 °C, [Ox]	100	[84,85]
6	Arylsulfonylhydrazones (31) (Method 2.9)	p-NO2C6H4	1. NCS, KOH, CH3NO2, 0 °C 2. TBAF, EtOH, reflux	88 92	[87]

Table 3. Summary of other precursors and conditions for the construction of the 1,2,4,5-tetrazine ring.

Entry	Precursor (Method)	R1, R2	Conditions	Yield [%]	Ref.
1	Imidoyl chloride (20) (Method 2.4)	C(CH3)3, 3-NO2-C6H4, R = 3-F-C6H4, 3,5-bis(CF3)-C6H3, pyrid-2-yl, 4-CF3-C6H4, 2-NO2-C6H4	NH2NH2, EtOH, reflux, [Ox]	42–75	[39,40]
2	Aldehyde (21) (Method 2.5)	CH3, C2H5, C(CH3)3	NH2NH2, O2 (Pd/C), HNO3	5–30	[19,68,69]
3	Guanidine hydrochloride (22) (Method 2.6)	3,5-dimethylpyrazol-1-yl	2,4-pentadione, 70 °C, [Ox]	95	[71,77,78]
4	Thiocarbohydrazide (26) (Method 2.7)	H, CH3, C6H5	RC(OC2H5)3, NEt3, EtOH,	16–24	[80,81]
5	Ethyl diazoacetate (29) (Method 2.8)	COOCH3	NaOH, HCl, SOCl2, MeOH, −30 °C, [Ox]	100	[84,85]
6	Arylsulfonylhydrazones (31) (Method 2.9)	p-NO2C6H4	1. NCS, KOH, CH3NO2, 0 °C 2. TBAF, EtOH, reflux	88 92	[87]

3. High Energy Density Materials (HEDMs)

High energy density materials (HEDMs) are a class of compounds characterized by a high ratio of potential energy to density. They are used in various fields, including quarries, pyrotechnics, artillery weapons, and even rocket fuels [88]. The first high-energy material to be developed was nitroglycerin (32, Figure 5), which was discovered by Ascanio Sobrero in the late 19th century. Glycerol trinitrate (32, TNG) is notable for its high nitrogen (18.5%) and oxygen (63.4%) content, making it both an oxidant and a reductant.

Recent efforts have focused on designing new HEDM compounds with the highest possible density, as density influences potential energy (E) and other parameters such as detonation pressure (P) and detonation velocity (D). The detonation velocity and detonation pressure are correlated with density (ρ) through the Kamlet–Jacobs equations (Formulas (1) and (2)).

$$D=1.01{\phi }^{0.5}\left(1+1.30\rho \right)$$

(1)

Formula (1). Kamlet–Jacobs equation for detonation velocity (D, km/s).

$$P=15.58\phi {\rho }^2$$

(2)

Formula (2). Kamlet–Jacobs equation for detonation velocity (P, kbar).

• Detonation parameters depend not only on density but also on the detonation parameter (φ), as described in Formula (3):

$$\phi =N{M}_{ave}^{0.5}{Q}^{0.5}$$

(3)

Formula (3). Equation for the detonation parameter (φ).

• The parameter φ is influenced by the number of moles of gaseous detonation products per gram of explosive (N), the average molar mass of gaseous products (M_ave, g/mol), and the total heat released during detonation (Q), expressed in calories per gram of explosive (Q) [89].
  Generally, for substances composed of carbon and hydrogen atoms, a critical density value of approximately 2.00 g/cm³ poses a challenge for achieving higher density while maintaining stability under normal conditions [90]. Table 4 presents the detonation parameters of the selected high energy density materials. Incorporating nitrogen atoms into the molecular structure enhances explosive properties and allows for the introduction of additional oxygen atoms, for example, in the form of nitro groups (NO₂), which improve the oxygen balance (Ω). For a substance represented by the formula C_aH_bO_cN_d, the oxygen balance is calculated using Formula (4):

$$\mathsf{\Omega }={\displaystyle \frac{\left(c-2a-\frac{b}{2}\right)\times 16}{M}}\times 100\%$$

(4)

Formula (4). Oxygen balance of a high-energy compound, where M is its molar mass, and a, b, and c are the number of carbon, hydrogen, and oxygen atoms.

• The factor “16” in the numerator corresponds to the molar mass of oxygen. The oxygen balance (Ω) reflects the ability of a high-energy material to form energetically favorable compounds with oxygen.

Table 4. Characteristics of some representatives of the HEDM family [91].

Entry	Compound	Oxygen Balance Ω [%]	Density ρ [g/cm3]	Detonation Velocity D [km/s]	Impact Sensitivity IS [J]
1	TNG (32)	+3.5	1.59	7.6	0.2
2	TNT (33)	−73.9	1.65	6.9	15
3	RDX (34)	−21.6	1.82	8.8	7.5
4	Lead azide (35)	−5.5	3.60	4.5	2.5–4.0
5	PA (36)	−45.4	1.78	7.4	7.4
6	Tetryl (37)	−47.4	1.73	7.6	3

Table 4. Characteristics of some representatives of the HEDM family [91].

Entry	Compound	Oxygen Balance Ω [%]	Density ρ [g/cm3]	Detonation Velocity D [km/s]	Impact Sensitivity IS [J]
1	TNG (32)	+3.5	1.59	7.6	0.2
2	TNT (33)	−73.9	1.65	6.9	15
3	RDX (34)	−21.6	1.82	8.8	7.5
4	Lead azide (35)	−5.5	3.60	4.5	2.5–4.0
5	PA (36)	−45.4	1.78	7.4	7.4
6	Tetryl (37)	−47.4	1.73	7.6	3

A positive oxygen balance indicates sufficient oxygen atoms for complete oxidation, resulting in greater energy release during decomposition. Nitrogen atoms in the molecule also influence decomposition products; the released nitrogen molecule (N₂) is both environmentally safe and associated with significant energy release (941 kJ/mol). Current research aims to synthesize HEDMs with maximum density, good oxygen balance, high detonation pressure, and velocity, while ensuring material stability. The desired properties of nitrogen-rich, highly energetic compounds are summarized in

Table 5. Desired properties of new nitrogen-rich, highly energetic compounds [88].

Performance	Detonation velocity Detonation pressure Heat explosion	D > 8500 m/s P > 340 kbar (34 GPa) Q > 6000 kJ/kg
Stability	Thermal stability Impact sensitivity Friction sensitivity Electrostatic sensitivity	Tdec ≥ 180 °C IS > 7 J FS > 120 N ESD > 0.2 J
Chemical properties	Hydrolytically stable Compatible with binder and plasticizer Low water solubility Non-toxic Smoke-free combustion

.

1,2,4,5-Tetrazine Derivatives as HEDMs

The high nitrogen content, positive enthalpy of formation, and thermal stability of 1,2,4,5-tetrazine make its derivatives excellent candidates for HEDM materials. Introducing explosion-enhancing groups (-NO₂, -N=N-, -N₃) into the 1,2,4,5-tetrazine core is challenging due to the formation of unstable compounds. For instance, 3,6-dinitroamino-1,2,4,5-tetrazine (DNAT) readily hydrolyzes in the presence of trace amounts of water to form 3,6-diamino-1,2,4,5-tetrazine. The first synthesized derivative of the HEDM family was 3,6-dihydrazino-1,2,4,5-tetrazine (24, DHT). This compound is produced with 100% yield via the substitution reaction of 3,6-bis-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (23) with hydrazine in acetonitrile (Scheme 9). DHT is thermally stable, decomposing above 160 °C, and exhibits an enthalpy of formation of 124.3 kcal/mol, an enthalpy of combustion of −517.3 kcal/mol, and a density of 1.73 g/cm³ [92]. 3,6-Dihydrazino-1,2,4,5-tetrazine can react with organic anions to form more energetic salts (38) (Scheme 15). These salts are more stable, exhibit superior energetic properties, and have an improved oxygen balance compared to DHT [74].

• Another compound exhibiting high thermal stability (252 °C), a high density of 1.84 g/cm³, and an enthalpy of formation of 862 kJ/mol is 3,3′-azobis(6-amino-1,2,4,5-tetrazine) (39, DAAT). Kerth and Löbbecke synthesized this compound using a multi-step methodology, starting with 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (23) as the substrate (Scheme 16). The reaction sequence involved substituting the pyrazole ring in the substrate with hydrazine, followed by oxidation of the hydrazine fragment with NBS and final substitution with ammonia [93].

Scheme 16. Synthesis of 3,3′-azobis(6-amino-1,2,4,5-tetrazine) (DAAT) from 3,6-bis-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine.

Scheme 16. Synthesis of 3,3′-azobis(6-amino-1,2,4,5-tetrazine) (DAAT) from 3,6-bis-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine.

• In 2004, Huynh et al. synthesized 3,6-diazido-1,2,4,5-tetrazine (40, DIAT), a compound sensitive to sparks, friction, and impact, with a decomposition temperature lower than that of the previously discussed compounds (130 °C). The synthesis of DIAT involved diazotizing 3,6-dihydrazino-1,2,4,5-tetrazine (24) using sodium nitrite and hydrochloric acid at 0 °C (Scheme 17) [79].

Scheme 17. Transformation of 3,6-dihydrazino-1,2,4,5-tetrazine (24) into DIAT (40).

Scheme 17. Transformation of 3,6-dihydrazino-1,2,4,5-tetrazine (24) into DIAT (40).

• The previously mentioned 3,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazine (23) was also used as a substrate in the synthesis of two other high-energy derivatives reported by Saikia and co-workers: 3,6-bis(1H-1,2,3,4-tetrazol-5-ylamino)-1,2,4,5-tetrazine (41, BTATz) and 3-(1H-1,2,3,4-tetrazol-5-ylamino)-6-(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (42, TADPTz, Scheme 18). BTATz is a solid with low sensitivity to impact. After heat initiation, it decomposes rapidly and flamelessly, generating a large amount of nitrogen gas (0.7 dm³/g _BTATz). This property makes BTATz useful for applications such as fire extinguishing systems and airbags. The compound decomposes at 270 °C, has a heat of formation of 883 kJ/mol, and a density of 1.78 g/cm³ at room temperature. Anhydrous 5-amino-1H-1,2,3,4-tetrazole was used in the reaction at an approximately two-and-a-half-fold molar excess compared to the tetrazine substrate (23) with sulfolane as the solvent. The mixture was heated at 135 °C for 16 h. BTATz was purified by dissolving it in DMSO and precipitating it with methanol, yielding the product in 70%. The second derivative, 3-(1H-1,2,3,4-tetrazol-5-ylamino)-6-(3,5-dimethyl-pyrazol-1-yl)- 1,2,4,5-tetrazine (42, TADPTz), was synthesized by heating 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine with a two-fold molar excess of 5-amino-1H-1,2,3,4-tetrazole in N,N-dimethylformamide (DMF). The TADPTz was obtained as a red solid with a decomposition temperature of 250 °C and a 65% yield [94].

Scheme 18. Synthesis of two high-energy 1,2,4,5-tetrazine derivatives: BTATz (41) and TADPTz (42).

Scheme 18. Synthesis of two high-energy 1,2,4,5-tetrazine derivatives: BTATz (41) and TADPTz (42).

• Chavez et al. synthesized two other high-energy 3,6-disubstituted polynitroalkoxy-1,2,4,5-tetrazines via nucleophilic substitution involving 3,6-dichloro-1,2,4,5-tetrazine (25) (Scheme 19). The transformations were conducted using two molar equivalents of polynitro alcohols (2,2,2-trinitroethanol or 2-fluoro-2,2-dinitroethanol) in dry dichloromethane, with 2,4,6-collidine as a base, at room temperature for 48 h. The products obtained were 3,6-bis(2,2,2-trinitroethoxy)-1,2,4,5-tetrazine (43) in 54% yield and 3,6-bis(2-fluoro-2,2-dinitroethoxy)-1,2,4,5-tetrazine (44) in 60% yield. These compounds exhibit good detonation parameters, with detonation velocities (D) of 8.1–8.7 km/s and detonation pressures (P) of 33–35 GPa. According to the authors, these derivatives can be utilized as melt-castable explosives [95].

Scheme 19. Synthesis of 3,6-disubstituted polynitroalkoxy-1,2,4,5-tetrazines from 3,6-dichloro-1,2,4,5-tetrazine (25).

Scheme 19. Synthesis of 3,6-disubstituted polynitroalkoxy-1,2,4,5-tetrazines from 3,6-dichloro-1,2,4,5-tetrazine (25).

• Polynitroalcohols can also react with 3,6-diamino-1,2,4,5-tetrazine (45) to produce N³,N⁶-bis(2,2,2-trinitroethyl)-1,2,4,5-tetrazine-3,6-diamine (46, BTAT, Scheme 20). The reaction was performed with the addition of hydrochloric acid in water at 70 °C, yielding the product in 63%. This compound exhibits a favorable oxygen balance (Ω = −10.9%), a high enthalpy of formation (Δ_fH = +336 kJ/mol), and a lower decomposition temperature (T_dec = 184 °C) compared to 1,3,5-trinitro-1,3,5-triazinane (RDX) (Ω = −21.6%; Δ_fH = +85 kJ/mol; T_dec = 202 °C). Additionally, BTAT demonstrates excellent detonation parameters (D = 9261 m/s; P = 389 kbar) and a density of 1.886 g/cm³ [96,97].

Scheme 20. Synthesis of N³,N⁶-bis(2,2,2-trinitroethyl)-1,2,4,5-tetrazine-3,6-diamine (46, BTAT) from 3,6-diamino-1,2,4,5-tetrazine (45).

Scheme 20. Synthesis of N³,N⁶-bis(2,2,2-trinitroethyl)-1,2,4,5-tetrazine-3,6-diamine (46, BTAT) from 3,6-diamino-1,2,4,5-tetrazine (45).

• Korepin and co-workers nitrated the resulting BTAT (46), introducing nitro groups onto the exocyclic nitrogen atoms (Scheme 21). The reaction was conducted stepwise: in the first step, nitration was carried out using fuming nitric acid, followed by the addition of trifluoroacetic acid anhydride in the second step. The product NBTAT (47) was obtained with a 32% yield and an enthalpy of formation Δ_fH = +546 kJ/mol, which is higher than that of its precursor, 46. The introduction of two nitro groups also enhanced the compound’s oxidizing properties [97].

Scheme 21. Nitration of BTAT (46) leading to NBTAT (47).

Scheme 21. Nitration of BTAT (46) leading to NBTAT (47).

• 3,6-Diamino-1,2,4,5-tetrazine (45) can also be directly nitrated to produce N,N′-dinitro-1,2,4,5-tetrazine-3,6-diamine (48, DNAT, Scheme 22). This compound was synthesized by reacting 3,6-diamino-1,2,4,5-tetrazine (45) with fuming nitric acid at 0 °C for 1 h with a yield of 65%. The resulting yellow DNAT precipitate has a density of 1.915 g/cm³ and a detonation temperature of 106.4 °C. DNAT was further converted into the corresponding salts (49) in satisfactory yields (67–75%) using bases such as LiOH, KOH, NaOH, Rb₂CO₃, and Cs₂CO₃ under mild reaction conditions (30 min., rt).

Scheme 22. Synthesis of DNAT (48) and its salts (49).

Scheme 22. Synthesis of DNAT (48) and its salts (49).

• The resulting salts exhibit significantly higher detonation temperatures (241–260 °C) compared to the starting dinitroamine 48 and have a favorable oxygen balance. They are also characterized by low impact sensitivity, comparable to primary explosives (IS ≤ 4 J), but much higher friction sensitivity (FS = 108–360 N), in contrast to DNAT (12 N) [98,99].
• Tetrazine derivatives connected with guanidine fragments have also garnered considerable scientific interest. 3,6-Diguanidino-1,2,4,5-tetrazine (50) was synthesized from 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (23) and two molar equivalents of guanidine in methanol as the solvent (Scheme 23). The main reaction product was the disubstituted derivative 50, although a monoguanidine derivative, 6-methoxy-1,2,4,5-tetrazine (51), was also formed as a side product. Both compounds were subsequently converted into corresponding high-energy salts bearing inorganic and organic anions (Figure 6). These salts are characterized by high densities and excellent detonation parameters [100,101,102,103].

Scheme 23. Reaction of 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (23) with guanidine, leading to substitution products 50 and 51.

Scheme 23. Reaction of 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (23) with guanidine, leading to substitution products 50 and 51.

Figure 6. 3,6-Diguanidino-1,2,4,5-tetrazine salts derived from compound 50 as HEDMs.

Figure 6. 3,6-Diguanidino-1,2,4,5-tetrazine salts derived from compound 50 as HEDMs.

• Similar to the guanidine derivatives of 1,2,4,5-tetrazine described above, substitution with a 2-nitroguanidine moiety was also performed (Scheme 24). The synthesis of the sodium salt of bis(nitroguanidyl)tetrazine (52) was carried out using sodium methoxide in methanol at 45–50 °C, achieving a yield of 90%. Chavez et al. also investigated the reaction of 1 equivalent of nitroguanidine with sodium hydride in N,N-dimethylformamide to synthesize a monosubstituted nitroguanidyl-1,2,4,5-tetrazine [104].

Scheme 24. Synthesis of 3,6-bis(nitroguaindyl)-1,2,4,5-tetrazine (52) from 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (23).

Scheme 24. Synthesis of 3,6-bis(nitroguaindyl)-1,2,4,5-tetrazine (52) from 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (23).

• 3,6-Bis(nitroguanidyl)-1,2,4,5-tetrazine (52) was converted into high-energy salts using alkaline earth metal nitrates (Mg, Ca, Sr, Ba), achieving high yields (86–93%) [73]. The resulting tetrazine–alkali metal salts (53, Scheme 25) are characterized by high densities (ρ = 1.75–2.30 g/cm³) and high sensitivity to impact (IS > 40 J). The barium salt derived from 52 was identified as the most energetic compound, with a density of 2.30 g/cm³ and high thermal stability (T_d = 195 °C). Organic salts of 3,6-bis(nitroguanidyl)-1,2,4,5-tetrazine (54) were also synthesized using organic cations derived from the corresponding chlorides (RCl). According to the authors, these compounds are insensitive to impact below 24 J due to the existence of hydrogen and ionic bonds [105].

Scheme 25. Transformation of 3,6-bis(nitroguanidyl)-1,2,4,5-tetrazine (52) into high-energy salts.

Scheme 25. Transformation of 3,6-bis(nitroguanidyl)-1,2,4,5-tetrazine (52) into high-energy salts.

• Zhao-yang Yin and his team reported notable results by synthesizing a derivative of 1,2,4,5-tetrazine (56, BHDT, Scheme 26) with remarkable energetic properties (IS = 30 J, FS = 300 N, T_d = 240 °C). The compound was synthesized by heating a suspension of 1,1-diamino-2-nitro-2-(1H-triazol-5-yl)ethene (55, tri-FOX) with 85% hydrazine hydrate at 100 °C for 5 h. The red solid product 56 was isolated in a 79% yield [106].

Scheme 26. Synthesis of 1,4-dihydro-1,2,4,5-tetrazine derivative (56) from 1,1-diamino-2-nitro-2-(1H-triazol-5-yl)ethene (55).

Scheme 26. Synthesis of 1,4-dihydro-1,2,4,5-tetrazine derivative (56) from 1,1-diamino-2-nitro-2-(1H-triazol-5-yl)ethene (55).

• An equally intriguing group of high-energy 1,2,4,5-tetrazines includes oxadiazole and triazole derivatives, where the tetrazine core serves as a linker between two azole rings (Scheme 27). The substrate for these reactions was 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (23), which reacted with a 1,2,5-oxadiazole-3-amine derivative in the presence of a base (NaH, K₂CO₃, Cs₂CO₃). The transformations proceeded via different pathways, yielding monosubstitution, disubstitution, and tetrazine-to-oxadiazole system disubstitution products. Monosubstitution (57) was performed with 1.1 molar equivalents of the 1,2,5-oxadiazole-3-amine derivative in refluxing acetonitrile for 0.8–4 h, yielding the desired products at 73–92%. When twice the molar amount of tetrazine relative to 1,2,5-oxadiazole was used, disubstitution products 58, consisting of two 1,2,4,5-tetrazine units bonded via amino groups to 1,2,5-oxadiazole, were obtained in yields ranging from 42% to 97% [107,108]. Using a four-fold excess of 3,4-diamino-1,2,5-oxadiazole relative to the tetrazine reagent enabled the preparation of 3,6-bis(3-amino-1,2,5-oxadiazol-4-ylamino)-1,2,4,5-tetrazine (59). In this case, sodium hydride in N,N-dimethylformamide was employed as the base, and the reaction mixture was stirred at room temperature for 1 h. After workup, the product was obtained as a red solid with a satisfactory yield of 91%.

Scheme 27. Reactions of 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine with 1,2,5-oxadiazole-3-amine derivatives.

Scheme 27. Reactions of 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine with 1,2,5-oxadiazole-3-amine derivatives.

• Yu and co-workers investigated the reaction of 3,6-bis(3-amino-1,2,5-oxadiazol-4-ylamino)-1,2,4,5-tetrazine (59, BOAT) with 2,2,2-trinitroethanol in the presence of hydrochloric acid at 70 °C (Scheme 28). The symmetrical product of the disubstitution at both terminal amino groups (60) was obtained with a yield of 89%. This compound exhibits a high decomposition temperature (T_d = 204 °C) and density (ρ = 1.86 g/cm³), resulting in excellent detonation properties (D = 9.04 km/s; P = 37 GPa). Derivative 60 was then nitrated with 100% nitric acid at −5 °C, and after 4 h of agitation, the mixture was poured into water, yielding product 61 as an orange solid (yield = 88%). This compound features a positive oxygen balance (Ω = 11.5%) and high density (ρ = 1.92 g/cm³), and the following detonation parameters: D = 9.6 km/s and P = 42 GPa. Another efficient route to high-energy salts is the direct nitration of 3,6-bis(3-amino-1,2,5-oxadiazol-4-ylamino)-1,2,4,5-tetrazine (59, BOAT) with fuming nitric acid at −10 °C. The resulting dinitration product 62 has a high heat of formation (Δ_fH = 3.00 kJ/g), high density (ρ = 1.85 g/cm³) and detonation parameters: D = 9.1 km/s, P = 36 GPa. This compound was further converted into a series of high-energy salts 63 using appropriate bases in acetonitrile as the solvent. The red-brown solid products were obtained with yields of 89–91% and exhibited notable energetic properties (T_d = 211–225 °C; ρ = 1.76–1.87 g/cm³; D = 8.8–9.4 km/s; P = 31–39 GPa; Δ_fH = 2.45–4.37 kJ/g; IS = 28–40 J; FS > 360 N) [109].

Scheme 28. Transformations of 3,6-bis(3-amino-1,2,5-oxadiazol-4-ylamino)-1,2,4,5-tetrazine (59, BOAT) to other high-energy products.

Scheme 28. Transformations of 3,6-bis(3-amino-1,2,5-oxadiazol-4-ylamino)-1,2,4,5-tetrazine (59, BOAT) to other high-energy products.

• In 2017, Zhang et al. synthesized high-energy 1,2,4,5-tetrazine-1,2,4-triazole hybrids by reacting dimethyl 1,4-dihydro-1,2,4,5-tetrazine-3,6-dicarboxylate (30) with aminoguanidine sulfate (VI) in the presence of sodium methoxide at 0 °C (Scheme 29). The product 5,5′-(1,4-dihydro-1,2,4,5-tetrazine-3,6-diyl)bis(1H-1,2,4-triazol-3-amine) (64) was obtained with a 66% yield and subjected to nitration using a nitrating mixture consisting of concentrated nitric and sulfuric acids at −10 °C. The transformation led to the corresponding dinitro derivative 65 with a 69% yield. Isolated as a red solid, this compound is characterized by high density (ρ = 1.88 g/cm³), high detonation velocity and pressure (D = 9.1 km/s; P = 31.7 GPa), and other notable properties, including impact sensitivity IS = 20 J, friction sensitivity FS = 270 N, decomposition temperature T_d = 162 °C, and enthalpy of formation Δ_fH = 1336 kJ/mol [110].

Scheme 29. Synthesis of N,N′-((1,2,4,5-tetrazine-3,6-diyl)bis(4H-1,2,4-triazole-5,3-diyl))dinitramide (65) and its salts.

Scheme 29. Synthesis of N,N′-((1,2,4,5-tetrazine-3,6-diyl)bis(4H-1,2,4-triazole-5,3-diyl))dinitramide (65) and its salts.

• The dinitro compound 65 was transformed into a series of salts (66) (Scheme 29, Figure 7) exhibiting interesting properties as high-energy materials, including high impact and friction sensitivities (IS > 40 J; FS > 360 N). These salts were synthesized by reacting compound 65 with appropriate bases in methanol for 2 h at room temperature [110].

Figure 7. Characteristic of N,N′-((1,2,4,5-tetrazine-3,6-diyl)bis(4H-1,2,4-triazole-5,3-diyl))dinitramide salts.

Figure 7. Characteristic of N,N′-((1,2,4,5-tetrazine-3,6-diyl)bis(4H-1,2,4-triazole-5,3-diyl))dinitramide salts.

• Schlomovich et al. synthesized three distinct triazole hybrids in which 1,2,4,5-tetrazine served as a bridge (Scheme 30). The derivative 67 was formed in a substitution reaction between 3,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazine (23, BPT) and 1H-1,2,4-triazole-3,5-diamine. This reaction involved the nitrogen atom at position 1 of the triazole ring and the nitrogen of the amino group at position 6. The transformation was conducted in sulfolane at 140 °C for 24 h. The product was precipitated with DMSO, washed with methanol, and dried. This compound (67), obtained in 82% yield, exhibited a high decomposition temperature (T_d = 313 °C), density (ρ = 1.87 g/cm³), and the following detonation properties: D = 8.6 km/s; P = 269 kbar. Another symmetrical substitution product of BPT with 1H-1,2,4-triazole-3,5-diamine was obtained by performing the reaction in a similar manner at a temperature of 210 °C. This compound (68) had the highest decomposition temperature (T_d = 357 °C) among the three derivatives, high impact sensitivity (IS > 98 J), typical density, and strong detonation properties (ρ = 1.81 g/cm³; D = 8.2 km/s; P = 239 kbar). Finally, the reaction of 1H-1,2,4-triazole-3,5-diamine with 3,6-dichloro-1,2,4,5-tetrazine (25) in a mixture of acetonitrile and N,N-dimethylformamide at room temperature resulted in substitution involving the nitrogen atom from the triazole ring. The resulting red-brown solid product (69) was obtained with an 85% yield and exhibited notable detonation properties (T_d = 370 °C; ρ = 1.75 g/cm³; D = 7.7 km/s; P = 227 kbar; IS > 40 J; FS > 360 N) [111].

Scheme 30. Reactions of 1H-1,2,4-triazole-3,5-diamine with BPT (23) and with 3,6-dichloro-1,2,4,5-tetrazine (25).

Scheme 30. Reactions of 1H-1,2,4-triazole-3,5-diamine with BPT (23) and with 3,6-dichloro-1,2,4,5-tetrazine (25).

• The presence of amino groups attached to the triazole ring in the resulting products (70–75) enabled the synthesis of other potential high-energy materials, specifically the corresponding azides and nitro derivatives. The typical synthetic procedures involved dissolving the appropriate triazole-1,2,4,5-tetrazine derivative (67–69) in sulfuric acid at 0 °C, introducing an aqueous solution of sodium nitrite, and then adding sodium azide solution at 0 °C (for azides 70–72) or sodium nitrite solution at 40 °C (for nitro compounds 73–75). The detonation properties of the obtained compounds are presented in Figure 8 [111].

Figure 8. Characteristics of azides and nitro derivatives obtained from triazole-1,2,4,5-tetrazine hybrids 67, 68, 69.

Figure 8. Characteristics of azides and nitro derivatives obtained from triazole-1,2,4,5-tetrazine hybrids 67, 68, 69.

• In 2017, Rudakov and co-workers converted 3-(3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazine (76) into novel high-energy derivatives using aminotetrazines (Scheme 31). The reaction of the pyrazole-1,2,4,5-tetrazine moiety (76) with 3,6-diamino-1,2,4,5-tetrazine was conducted in a 2:1 molar ratio in acetonitrile with the addition of potassium carbonate. After workup, the corresponding high-energy N,N′-di(1,2,4,5-tetrazin-3-yl)-1,2,4,5-tetrazine-3,6-diamine (77) was obtained with a high yield as a red solid (T_d = 279 °C; ρ = 1.69 g/cm³; D = 8.1 km/s; P = 22.9 GPa; Q_exp = 3782 kJ/kg). When 1,2,4,5-tetrazin-3-amine was used in a similar reaction with compound 76, the adequate N-(1,2,4,5-tetrazin-3-yl)-1,2,4,5-teterazin-3-amine (78) was obtained as a dark-pink solid with a 55% yield. This compound exhibited slightly lower energetic parameters (T_d = 210 °C; ρ = 1.63 g/cm³; D = 7.9 km/s; P = 21.0 GPa; Q_exp = 3778 kJ/kg) compared to the precursor 76. However, compound 78 was further transformed in a reaction with 3-chloro-1,2,4,5-tetrazine to produce a more energetic derivative, N,N-di(1,2,4,5-tetrazin-3-yl)-1,2,4,5-tetrazin-3-amine (79) (T_d = 231°C; ρ = 1.88 g/cm³; D = 9.1 km/s; P = 30.5 GPa; Q_exp = 4067 kJ/kg). This transformation was carried out using sodium hydride in THF under reflux for 2 h, yielding a brown product with a 58% yield [112].

Scheme 31. Substitution of 3-(3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazine (76) with amino and chloro derivatives of 1,2,4,5-tetrazine.

Scheme 31. Substitution of 3-(3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazine (76) with amino and chloro derivatives of 1,2,4,5-tetrazine.

One of the subgroups of tetrazine derivatives that has recently gained attention is fused systems. Chen et al. synthesized 6-(3,5-dimethyl-1H-pyrazol-1-yl)-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine (81) by reacting 3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-hydrazinyl-1,2,4,5-tetrazine (80) with triethyl orthoformate. The intermediate 81 was then treated with potassium hydroxide followed by hydrochloric acid, resulting in the transformation into [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazin-6-ol (82, Scheme 32). The solid product 82, obtained with a 93% yield, exhibits good detonation parameters (ρ = 1.84 g/cm³; T_d = 232 °C; D = 8.5 km/s; P = 28.6 GPa; IS = 30 J) [113].

Scheme 32. A two-step synthesis of [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazin-6-ol (82).

Scheme 32. A two-step synthesis of [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazin-6-ol (82).

• Compound 80 was also reacted with cyanogen bromide to synthesize 6-(3,5-dimethyl-1H-pyrazol-1-yl)-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazin-3-amine (83). Subsequent treatment of the resulting product 83 with potassium hydroxide, followed by the work-up with hydrochloric acid, gave the corresponding 3-amino-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazin-6-ol (84, Scheme 33) with a high yield (ρ = 1.86 g/cm³; T_d = 227 °C; D = 8.6 km/s; P = 28.0 GPa; IS = 34 J) [113].

Scheme 33. A two-step synthesis of 3-amino-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazin-6-ol (84).

Scheme 33. A two-step synthesis of 3-amino-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazin-6-ol (84).

• The solid fused tetrazine products 82 and 84 were further converted into their corresponding salts by reacting with various bases under mild conditions in methanol (Scheme 34).

Scheme 34. Transformations of (a) [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazin-6-ol (82) and (b) 3-amino-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazin-6-ol (84) into the corresponding salts.

Scheme 34. Transformations of (a) [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazin-6-ol (82) and (b) 3-amino-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazin-6-ol (84) into the corresponding salts.

• Another compound used to prepare fused 1,2,4,5-tetrazine derivative is 6-hydrazinyl-N-(1H-tetrazol-5-yl)-1,2,4,5-tetrazin-3-amine (85, HTATz). In 2022, Chen et al. heated this compound with cyanogen bromide in 1M hydrochloric acid for 4 h to obtain the corresponding 3-amino-6-(1H-tetrazol-5-yl)-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine (86, Scheme 35). The product was isolated as a brown solid with a 60% yield (ρ = 1.76 g/cm³; T_d = 189 °C; D = 8.5 km/s; P = 26.1 GPa; IS = 36 J) [114].

Scheme 35. Synthesis of 3-amino-6-(1H-tetrazol-5-yl)-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine (86).

Scheme 35. Synthesis of 3-amino-6-(1H-tetrazol-5-yl)-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine (86).

• Compound 86 was later utilized in nitration and oxidation reactions to synthesize other valuable energetic derivatives (Scheme 36). Nitration was performed using fuming nitric acid at −15 °C for 30 min., followed by an additional 6 h at room temperature. After dissolving the reaction mixture and washing the product, 3-nitroamino-(1H-tetrazol-5-yl)-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine (87) was obtained as a yellow solid with a high yield. This compound 87 exhibited the following detonation parameters: ρ = 1.80 g/cm³; T_d = 167 °C; D = 8.6 km/s; P = 29.0 GPa; IS = 6 J. Another interesting reaction involving compound 86 was the synthesis of 3,3′-(diazene-1,2-diyl)bis(N-1H-tetrazol-5-yl)-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazin-6-amine (88, Scheme 36). The transformation was carried out in concentrated hydrochloric acid by dropwise addition of an aqueous solution of potassium permanganate at −5 °C, followed by heating at 45 °C for 4 h. After workup, a yellow solid product 88 was obtained with a yield of 92% (ρ = 1.79 g/cm³; T_d = 240 °C; D = 8.5 km/s; P = 26.9 GPa; IS = 10 J). The resulting compound 88 has the highest enthalpy of formation among all derivatives synthesized by Chen and co-authors (Δ_fH = 2175.3 kJ/mol) [114].

Scheme 36. Nitration and oxidation of 3-amino-6-(1H-tetrazol-5-yl)-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine (86).

Scheme 36. Nitration and oxidation of 3-amino-6-(1H-tetrazol-5-yl)-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine (86).

• Liu and co-workers used 3-hydrazinyl-1,2,4,5-tetrazine (89) to synthesize other fused 1,2,4,5-tetrazine derivatives. Cyanogen bromide and hydrochloric acid served as co-reagents, and the mixture was stirred for 24 h to produce [1,2,4]triazolo[4,3-b][1,2,4,5]teterazin-3-amine (90) as a purple solid with a 71% yield (Scheme 37). This compound was treated with potassium permanganate, resulting in 1,2-bis([1,2,4]triazolo[4,3-b][1,2,4,5]tetrazin-3-yl)diazene (91) with an 82% yield. The symmetrical product exhibited a high detonation temperature T_d = 305 °C and density (ρ = 1.91 g/cm³), which influences its detonation properties (D = 9.2 km/s; P = 34.8 GPa). It also has a high enthalpy of formation Δ_fH = 1525.2 kJ/mol and friction sensitivity FS > 360 N. The authors highlighted compound 91 as a potential heat-resistant explosive. The intermediate product 90 was also nitrated using fuming nitric acid at 0 °C. After several hours of agitation, trifluoroacetic acid was added, leading to the precipitation of N-([1,2,4]triazolo[4,3-b][1,2,4,5]tetrazin-3-yl)nitramide (92) as an orange solid with a 74% yield (ρ = 1.81 g/cm³; T_d = 132 °C; D = 8.8 km/s; P = 33.2 GPa; IS = 31 J). The intermediate 92 was further utilized to synthesize a series of high-energy salts through reactions with bases. Among them, the salt 93, formed in the reaction with ammonia, demonstrated the best properties (ρ = 1.83 g/cm³; D = 9.4 km/s; P = 37.8 GPa; IS = 43 J) [115].

Scheme 37. Synthesis of [1,2,4]triazolo[4,3-b][1,2,4,5]teterazin-3-amine (90) and the derived high-energy products (91–93).

Scheme 37. Synthesis of [1,2,4]triazolo[4,3-b][1,2,4,5]teterazin-3-amine (90) and the derived high-energy products (91–93).

• In their synthesis of high-energy compounds, Liu and co-workers used the fused tetrazine 83 (Scheme 38). This compound was converted to 6-hydrazinyl-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazin-3-amine (94) by reacting it with hydrazine hydrate in acetonitrile, followed by treatment with nitrous acid generated in situ from hydrochloric acid and sodium nitrite. A colored product 95, substituted at position 6 with an azide group, was obtained with a 68% yield (ρ = 1.74 g/cm³; D = 8.6 km/s; P = 28.5 GPa; IS = 30 J). The next transformations focused on modifying the amino group attached to the triazole ring. A nitration reaction using concentrated nitric acid produced N-(6-azido-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazin-3-yl)nitramide (96), which was precipitated using trifluoroacetic acid. The orange product was obtained with a 67% yield and exhibited the following detonation parameters: ρ = 1.85 g/cm³; D = 9.2 km/s; P = 36.3 GPa; IS = 1 J. Compound 96 was further transformed into a series of salts. Among these, the hydroxylammonium salt 97 displayed the best parameters (Yield = 72%; ρ = 1.79 g/cm³; D = 9.3 km/s; P = 36.8 GPa; IS = 2 J). The authors concluded that the salt 97 could serve as a primary explosive due to its low impact sensitivity (IS) [115].

Scheme 38. Synthesis of 6-hydrazinyl-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazin-3-amine (94) and its subsequent reactions to high-energy derivatives.

Scheme 38. Synthesis of 6-hydrazinyl-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazin-3-amine (94) and its subsequent reactions to high-energy derivatives.

• In 2022, Qiong Yu et al. synthesized a fused derivative of 1,2,4,5-tetrazine and triazole (98) consisting of three rings (Scheme 39). The transformation, carried out in ethanol, used 3,6-dihydrazinyl-1,2,4,5-tetrazine and cyanogen bromide as starting reagents. The product 98 was obtained as a yellow solid with a 75% yield and was characterized by a high enthalpy of formation Δ_fH = 4.27 kJ/g and favorable detonation parameters (ρ = 1.76 g/cm³; D = 8.5 km/s; P = 27.3 GPa; IS > 40 J). Compound 98 was then nitrated with fuming nitric acid, yielding the corresponding nitro derivative 99 as a brown solid (yield = 57%; ρ = 1.88 g/cm³; D = 9.1 km/s; P = 34.0 GPa; IS > 40 J). The latter was subsequently reacted with bases to produce its corresponding salts with excellent yields, between 93% and 95% (M = K⁺, NH₃OH⁺, NH₄⁺, N₂H₅⁺). Among the obtained products, the hydrazinium salt 99·N₂H₄ was identified as the most energetic 1,2,4,5-tetrazine derivative (ρ = 1.84 g/cm³; D = 9.1 km/s; P = 32.3; GPa; IS > 40 J; Δ_fH = 2.72 kJ/g) [116].

Scheme 39. Synthesis of fused tricyclic 1,2,4,5-tetrazine-1,2,4-triazole hybrids (98, 99) and their salts.

Scheme 39. Synthesis of fused tricyclic 1,2,4,5-tetrazine-1,2,4-triazole hybrids (98, 99) and their salts.

• Sinditskii and his team also undertook the synthesis of a fused tricyclic 1,2,4,5-tetrazine-1,2,4-triazole hybrid (100) and its derivatives [117]. Heating N³,N⁶-di(1H-tetrazol-5-yl)-1,2,4,5-tetrazine-3,6-diamine (41, BTATz) in polyphosphoric acid (PPA) for 3–4 h at 180 °C resulted in the formation of bis([1,2,4]triazolo)[1,5-b:5′,1′-f][1,2,4,5]tetrazine-2,7-diamine (100, Scheme 40). The product was obtained as a light red solid with a yield of 40% and exhibited the following detonation parameters: ρ = 1.71 g/cm³; D = 8.3 km/s; P = 29.2 GPa; IS > 45 J. Compound 100 was subsequently subjected to oxidation reactions, yielding other high-energy derivatives depicted in Scheme 41.

Scheme 40. Synthesis of bis([1,2,4]triazolo)[1,5-b:5′,1′-f][1,2,4,5]tetrazine-2,7-diamine precursor (100) for the subsequent oxidation.

Scheme 40. Synthesis of bis([1,2,4]triazolo)[1,5-b:5′,1′-f][1,2,4,5]tetrazine-2,7-diamine precursor (100) for the subsequent oxidation.

Scheme 41. High-energy derivatives obtained from bis([1,2,4]triazolo)[1,5-b:5′,1′-f][1,2,4,5]tetrazine-2,7-diamine (100).

Scheme 41. High-energy derivatives obtained from bis([1,2,4]triazolo)[1,5-b:5′,1′-f][1,2,4,5]tetrazine-2,7-diamine (100).

• In 2020, Sinditskii et al. also synthesized bicyclic fused 1,2,4,5-tetrazines connected to the 1,2,5-oxadiazole ring via an amino group [118]. The N-heteroarylation of aminofurazans was performed by refluxing 6-(3,5-dimethyl-1H-pyrazol-1-yl)-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine (81, Scheme 42) in a mixture of acetonitrile and cesium carbonate as the base for 0.3–2 h. This reaction yielded three yellow products (101–103), all of which were characterized by favorable detonation parameters.

Scheme 42. Synthesis of fused 1,2,4,5-tetrazine-1,2,4-triazole hybrids 101, 102, and 103 bearing 1,2,5-oxadiazole cores.

Scheme 42. Synthesis of fused 1,2,4,5-tetrazine-1,2,4-triazole hybrids 101, 102, and 103 bearing 1,2,5-oxadiazole cores.

• In 2016, Myers et al. heated 6-(3,5-dimethyl-1H-pyrazol-1-yl)-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine (81, Scheme 43) with 2-amino-2-(hydroxymethyl)propane-1,3-diol in a mixture of acetonitrile and N,N-dimethylformamide to produce the corresponding substitution product. The resulting intermediate was then nitrated with nitronium acetate, generated in situ from glacial acetic acid, acetic anhydride, and nitric acid at 5 °C, to produce a yellow trinitro derivative 104 with a 76% yield (ρ = 1.79 g/cm³; D = 8.3 km/s; P = 29.4 GPa; IS > 3.9 J) [119].

Scheme 43. The transformation of 6-(3,5-dimethyl-1H-pyrazol-1-yl)-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine (81) into nitrogen-rich derivative 104.

Scheme 43. The transformation of 6-(3,5-dimethyl-1H-pyrazol-1-yl)-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine (81) into nitrogen-rich derivative 104.

• Fu-Xue Chen and his co-workers utilized the primary amine group-containing compound 83, specifically 6-(3,5-dimethyl-1H-pyrazol-1-yl)-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazin-3-amine, in a diazotization reaction with sodium nitrite_, followed by displacement with 65% nitric acid, to synthesize the nitro derivative: 3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-nitro-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine 105 (Scheme 44) [120]. This compound was then treated with an aqueous ammonia solution under reduced pressure, resulting in the substitution of the 3,5-dimethylpyrazole group with an amine group to yield a yellow compound 106 (TTNA) with a 72% yield.

Scheme 44. Synthesis of 6-nitro-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazin-3-amine (106).

Scheme 44. Synthesis of 6-nitro-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazin-3-amine (106).

• Lu Hu et al. synthesized a series of high-energy fused 1,2,4,5-tetrazine derivatives using the symmetrical reagent, the adequate 1,2-bis(6-(3,5-dimethyl-1H-pyrazol-1-yl)-[1,2,4]triazolo[4,3-b][1,2,4,5]tetrazin-3-yl)diazene (107, Scheme 45) [121]. When compound 107 reacted with ammonia in acetonitrile, it produced product 108, in which the 3,5-dimethylpyrazole rings were replaced by ammonia. Nitration of this compound yielded the corresponding symmetrical N-nitro derivative 109 with a yield of 72%, and notable detonation parameters (ρ = 1.85 g/cm³; D = 9.5 km/s; P = 39.8 GPa; IS = 14 J). The yellow solid product 109 was then transformed into a silver salt, which served as a precursor for the synthesis of other high-energy salts (NH₄⁺, NH₃OH⁺). These salts exhibited excellent detonation parameters (for NH₄⁺ salt: Yield = 82%; ρ = 1.84 g/cm³; D = 9.6 km/s; P = 38.8 GPa; IS = 10 J, and for NH₃OH⁺ salt: Yield = 82%; ρ = 1.99 g/cm³; D = 10.2 km/s; P = 48.6 GPa; IS = 14 J, respectively).

Scheme 45. The synthesis of N′,N-(6,6′-(diazene-1,2-diyl)bis([1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine-6,3-diyl))dinitramide (109) and its salts.

Scheme 45. The synthesis of N′,N-(6,6′-(diazene-1,2-diyl)bis([1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine-6,3-diyl))dinitramide (109) and its salts.

• The same authors also utilized [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine-3,6-diamine (110) to synthesize a series of high-energy salts [121]. In the first step, both amino groups in compound 110 were nitrated using 100% nitric acid, yielding an orange product: 3,6-dinitramino-1,2,4-triazolo[4,3-b][1,2,4,5]tetrazine (111, Scheme 46) with a yield of 70%. The resulting compound, which exhibited excellent detonation parameters (ρ = 1.91 g/cm³; D = 9.3 km/s; P = 38.3 GPa; IS = 3 J), was then transformed into a silver salt. This salt served as the precursor for the synthesis of a series of other high-energy salts, as shown in Scheme 46. Among these derivatives, the hydroxyammonium salt derived from 111 demonstrated the best detonation properties (ρ = 1.92 g/cm³; D = 9.7 km/s; P = 42.9 GPa; IS = 25 J).

Scheme 46. Transformation of [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine-3,6-diamine (110) into other high-energy derivatives.

Scheme 46. Transformation of [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazine-3,6-diamine (110) into other high-energy derivatives.

Corresponding N-oxides derived from 1,2,4,5-tetrazines also constitute an intriguing class of high-energy materials due to their potential applications in material science and industry. Generally, introducing an oxygen atom into the structure of a high-energy material enhances the oxygen balance, increases density, and consequently improves the detonation parameters of such compounds. Wei and co-workers investigated the synthesis of N-oxides using selected 1,2,4,5-tetrazines and popular oxidizing agents, including hypofluorous acid HOF, peroxysulfuric acid, also known as Caro’s acid (H₂SO₅), peroxytrifluoroacetic acid (PTFA), or oxone (KHSO₅·KHSO₄·K₂SO₄) [122]. Each of these agents presents distinct advantages and disadvantages: while hypofluoric acid HOF is effective, its synthesis requires fluorine, which is harmful to the environment. Conversely, oxone is relatively less effective, whereas Caro’s acid (H₂SO₅) is overly strong as an oxidizing agent. The literature indicates that peroxytrifluoroacetic acid is the most commonly employed oxidant for converting 1,2,4,5-tetrazines into their corresponding N-oxides (Figure 9). The typical procedure involves generating PTFA in situ from trifluoroacetic anhydride and 50% hydrogen peroxide, then reacting it with the tetrazine precursor in methylene chloride at 0 °C to produce the desired N-oxides with moderate yields.

4. Conclusions

Nitrogen-rich heterocyclic compounds have attracted significant interest from research groups due to their potential applications as high-energy density materials (HEDMs). Among the representatives of this class is aromatic 1,2,4,5-tetrazine, which is characterized by the highest nitrogen content possible in a six-membered ring system while maintaining stability. Thermal decomposition of tetrazine derivatives leads to ring opening, resulting in the release of nitrogen gas and the formation of nitriles. The exothermic nature of this reaction, involving the evolution of gaseous decomposition products, forms the basis for the use of tetrazine derivatives as high-energy materials. Tetrazine precursors used in the synthesis of energetic materials are typically derived from acyclic reagents, including formamidinium acetate, imidoesters, carbonitriles, imidoyl chlorides, aldehydes, guanidine hydrochloride, thiocarbohydrazide, and ethyl diazoacetate. The versatile co-reagent used in the construction of the title heterocycle is hydrazine, which introduces nitrogen atoms into the cyclic skeleton. Structural modifications of 1,2,4,5-tetrazine derivatives to produce high-energy compounds include, among other approaches, substitution reactions at positions 3 and 6 of the heterocyclic ring using explosion-enhancing groups such as nitro, azo, azido, hydrazinyl, guanidyl, or cyclic pyrazolyl, triazolyl, tetrazolyl, and oxadiazolyl groups. Other valuable compounds are fused bicyclic or tricyclic tetrazines and N-oxides generated at both ring nitrogen atoms and nitrogen atoms in exocyclic groups. A significant advantage of such tetrazine derivatives is their high heat of formation and excellent thermal stability. The planar structure of the aromatic heterocyclic ring facilitates crystal packing, leading to beneficial detonation parameters and high density. As a result, high-energy derivatives of 1,2,4,5-tetrazine find applications as safe explosives, solid rocket fuels, propellants, fire suppressant gases, and components in car airbags.