Synthetic Strategies for Nitramines: From Energetic Materials to Atmospheric Byproducts

Abstract

Nitramines are nitrogen-containing organic compounds with the formula R¹R²N–NO₂. They are well-known as explosives and have been produced industrially for more than a century. A few nitramine-containing natural products have also been identified in recent years. Nitramines have also found their way into specific synthetic procedures, usually as intermediates, and for the last decades, the implementation of amine-based carbon capture and storage (CCS) technologies to mitigate CO₂ emissions from fossil fuel combustion is of particular concern since small amounts are produced. Both environmental and health implications are of particular interest, and little is known today. The need for efficient and safe synthetic procedures is, therefore, vital for further research in the field. The present review gives a detailed summary of published methods and research post-millennium. Many new as well as well-established methods are presented. Representative examples with basic conditions and yields are given. Finally, indications for future research are discussed.

1. Introduction

Nitramines are nitrogen-containing organic compounds with the formula R¹R²N–NO₂, as shown in Figure 1. Historically, nitramines are best known as explosives. Some well-known compounds with the nitramine moiety can be seen in Figure 2.

Figure 1. Generic structure of a nitramine.

Figure 2. Well-known explosive nitramines.

Nitramines such as hexahydro-1,3,5-trinitro-1,3,5-triazine (1, RDX) and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (2, HMX) continue to be important explosives, renowned for their exceptional energy density, thermal resilience, and controlled detonation properties [1].

In recent years, the environmental significance of nitramines has gained prominence, particularly in relation to their formation during the atmospheric degradation of amines employed in industrial processes [2,3]. The implementation of amine-based carbon capture and storage (CCS) technologies to mitigate CO₂ emissions from fossil fuel combustion is of particular concern [4,5,6]. Given the scale of post-combustion CCS facilities, it is likely that there will be small but significant discharges of amines to the atmosphere during operation. Once in the atmosphere, amines will undergo photo-oxidation, leading to nitrogenous products including nitramines [6,7,8]. Experimental data suggest that some nitramines are persistent, mobile, and potentially carcinogenic. However, detailed toxicological profiles are lacking for most compounds in this class [9], in addition to their possible harm to the environment [2,10,11].

The Norwegian Institute for Public Health recommends that the total amount of nitrosamines and nitramines in the atmosphere should be below 0.3 ng m⁻³ in air and below 4 ng dm⁻³ in drinking water for a risk level of 10–5. Such low detection levels are virtually impossible to monitor with today’s technology, and it is therefore imperative to acquire quantitative information on the degradation pathways for the relevant amines under atmospheric conditions. Consequently, there is a need for pure nitramine reference samples for both toxicology, environmental, and laboratory photo-oxidation studies in the years to come [12].

The nitramine functionality has also been found in a few natural products [13,14].

1.1. Overview of Nitramine Synthesis

Nitramine synthesis has a history going back to the late 1800s. Most of the methods used today have roots in the early reported procedures and strategies. Nonetheless, several researchers have attempted to improve nitramine synthesis, regarding the scope, safety, atom economy, environmental concerns, and economic aspects, to meet modern expectations. This has led to a wide range of approaches, with different strengths and weaknesses.

In this review paper, we cover some historic papers but focus on the more recent applications (last 25 years) when available. For readers that are interested in more historic papers, we recommend an earlier review by Agrawal [15].

This review is organized around four principal synthetic strategies:

-

Direct nitration;

-

Oxidation;

-

Reduction;

-

Hydrolysis/nitrolysis or rearrangements.

Unless otherwise specified, references to nitric acid in this review denote fuming nitric acid (≈100% HNO₃).

The approaches that are discussed in this review paper are summarized in Table 1 and compared in the following section.

Table 1. Summary of the nitration methods discussed in this review.

Method	Representative Conditions	Applicable Substrates	Key Advantages	Limitations/Safety Issues	Typical Yield
Direct Nitration	Fuming HNO3; HNO3/H2SO4	Aromatic and weakly basic amines	Simple	Highly corrosive; poor selectivity	Low–High
Acetyl Nitrate Route	HNO3 + Ac2O (in situ AcONO2)	Secondary, hindered primary amines	Cleaner than mixed acid; avoids salts	Moisture-sensitive; strong oxidant	Moderate–Good
Chloramine-Catalyzed Nitration	HNO3/Ac2O + HCl or ZnCl2	Secondary, tertiary amines	Expands scope of nitric acid nitration	Toxic intermediates; handling risk	Moderate–Good
Protected Amine Approach	Carbamates, amides; nitration + hydrolysis	Primary or unstable amines	Access to unstable nitramines; safer	Multi-step; lower atom economy	Moderate–Good
Nitrolysis	HNO3-TFAA; N2O5, AcONO2, HNO3-NH4NO3	Amides, hexamine derivatives	Key for RDX/HMX synthesis; scalable	Strong oxidants; scale-up hazard	Moderate–High
Nitronium Salts	NO2BF4, NO2OTf (anhydrous)	Secondary amines, heterocycles	Highly selective; acid-free	Expensive; moisture-sensitive	Good–Excellent
Dinitrogen Pentoxide (N2O5)	Generated in situ; aprotic solvents	Secondary amines, azetidines	Neutral, mild, clean nitrations	Destroys primary nitramines	High
Base-Promoted Nitration	BuLi, NaH + Alkyl nitrate	Aromatic or aliphatic amines	Acid-free, selective	Poor yield; cryogenic; hazardous	Low–Moderate
Nitro-Transfer Reagents	CF3-propyl nitrate, pyridazinone nitrates	Secondary amines	Neutral, selective, mild	Specialized reagents	Good–Excellent
Oxidation of Nitrosamines	H2O2, peroxy acids, electrochemical	Dialkyl nitrosamines	High yield, clean	Requires toxic intermediates	Good–Excellent
Reduction of Nitroimines	NaBH4, LiAlH(OtBu)3	Nitroimines	Access to unique derivatives	Over-reduction risk	Variable

1.2. Comparative Perspective on Strategy Selection

While the methods discussed above share the common goal of forming the N–NO₂ bond, their practical utility differs markedly depending on substrate stability, basicity, and functional group tolerance.

Strongly acidic direct nitration and nitrolysis remain the most robust and scalable strategies, particularly suited for simple, highly substituted, or industrial targets such as RDX (1), HMX (2), and CL-20 (6), where substrate frameworks tolerate harsh oxidative conditions and established protocols outweigh selectivity concerns.

In contrast, neutral and anhydrous nitration systems, such as dinitrogen pentoxide and nitronium salts, are better suited for sensitive or strained substrates, including small heterocycles and acid-labile amines, where controlled reactivity and avoidance of protonation are critical. These methods typically offer higher selectivity and cleaner product profiles but at the expense of cost, operational complexity, and limited scalability.

Base-promoted nitration and organic nitro-transfer reagents occupy a complementary niche, enabling access to acid-sensitive and primary amines that are otherwise incompatible with classical nitric acid chemistry. Although generally less general and often giving moderate yields, these approaches provide unique entry points to nitramines that cannot be obtained by acidic routes.

Finally, oxidation of nitrosamines and reduction of nitroimines occupy more specialized niches. These strategies are especially useful when nitrosamines or nitroimine precursors arise naturally or are easily prepared, enabling efficient access to certain nitramines, but their broader applicability has so far been constrained by precursor availability and safety considerations. Moreover, this type of strategy can have special relevance for preparation of reference compounds for atmospheric and environmental studies, where such intermediates are readily accessible and closely related to real degradation pathways.

Taken together, method choice is governed less by mechanistic preference than by a balance between substrate sensitivity, desired selectivity, safety constraints, and scale, underscoring the need for a diversified synthetic toolbox rather than a single universal approach.

Independent of nitration method, one should always still be careful: because nitration often produces compact, high-density structures associated with high energetic performance, the detonation characteristics and safety implications of the resulting compounds should be considered already at the stage of synthesis.

2. N-Nitration Reactions

The classical and still-dominant methods rely on nitric acid or mixed acids, where the nitronium ion (NO₂⁺) serves as the active electrophile. Variants such as acetyl nitrate or chloride-catalyzed systems reflect refinements of this core chemistry, maintaining high reactivity while improving selectivity and safety.

In contrast, base-promoted and neutral routes achieve N-nitration through nitro-transfer from alkyl nitrates or other electrophilic nitro donors. These reactions, though less general, enable access to substrates that decompose or are deactivated under strongly acidic conditions.

Between these extremes are nitronium salts, dinitrogen pentoxide, and specialized organic donors that provide controlled, anhydrous conditions and extend nitration to new substrate classes.

Collectively, these strategies encompass the principal mechanistic pathways to the N–NO₂ bond: acidic, basic, and neutral. Understanding their relationships and trade-offs is essential for selecting efficient, safe, and scalable routes to nitramines.

2.1. Nitration Using Acidic Conditions

From the earliest preparation of organic nitramines to modern industrial routes, nitric acid methods continue to dominate in published literature. Their appeal lies in their simplicity, robustness, low cost, and established infrastructure—few alternative nitrating agents offer comparable accessibility or proven scalability. These reactions proceed via in situ generation of the nitronium ion (NO₂⁺) from nitric acid, which acts as a strong electrophile and attacks the amine nitrogen to form the N–NO₂ bond. The so-called mixed acid, nitric acid mixed with sulfuric acid, acts the same way, with sulfuric acid protonating nitric acid and acting as a dehydration agent, to enhance the generation of the nitronium ion.

Variants such as acetyl nitrate, mixed acid, with catalysts (e.g., ZnCl₂ or HCl), and protected-amine nitration all stem from attempts to tame the same powerful but hazardous chemistry. Thus, rather than being replaced, classical nitric acid nitration has evolved into a flexible framework that accommodates diverse substrate classes—from simple aliphatic amines to complex heterocycles—while maintaining its position as the most practical and experimentally accessible route to nitramines.

While this approach is simple in principle, it poses significant safety concerns due to the highly corrosive, oxidizing, and potentially explosive nature of fuming nitric acid. Moreover, this method has low selectivity, and there are concerns about over-nitration. Scaling up a batch can lead to uncontrolled reactions and detonation, severely limiting their applicability in practical settings [16].

The pure nitric acid approach has challenges when it comes to scope.

• It does not work well with primary amines, as they often are not stable under the strong acidic conditions [17].
• With the strong acid, the acid–base reaction occurs faster than the nitration reaction and leads to the ammonium nitrate salt, rather than the nitramine [18]. These salts can be transformed into nitramines with dehydrating agents (e.g., H₂SO₄, Ac₂O, etc.).

However, with less basic amines, the fuming nitric acid approach is more successful [19]. Most anilines are accessible for direct nitration [20,21,22,23,24,25,26,27,28,29], e.g., as seen in the work of Atkins on polynitro anilines, see synthesis of compound 8 in Scheme 1 [28,30]. Nonetheless, one should be careful with acidic conditions when aromatic nitramines are obtained, as the nitro group easily migrates to the aromatic ring system when possible [31,32,33].

Scheme 1. One example of nitration of anilines by Atkins (8 is unstable and yield is not given) [28,30].

The route is also applicable to secondary amines with reduced basicity due to electron-withdrawing groups in proximity [34,35,36,37,38,39,40,41,42], e.g., see the synthesis of nitramine 10 depicted in Scheme 2.

Scheme 2. The synthesis of 1,3,3,5,7,7-hexanitro-1,5-diazocane (11) via nitramine 10 by Cichra et al. [41].

2.1.1. Acetyl Nitrate

Acetyl nitrate represents a milder, more selective variant of classical nitric acid nitration. It will also minimize salt formation and over-oxidation [43]. The reagent is generated in situ from acetic anhydride and a nitrate source, e.g., nitric acid [44,45,46,47] or dinitrogen pentoxide [43]. An illustrative example is nitration of compound 12 to yield nitramine 13, shown in Scheme 3.

Scheme 3. An example of the use of acetyl nitrate to prepare a nitramine (specific yield not given) [46].

Recent examples of this type of protocol are found in the synthesis of several FOX-7 derived nitramines 16–19 via a rearrangement of triazine 14 [48,49], see Scheme 4.

Scheme 4. The synthesis of several FOX-7 derived nitramines [48].

Despite its milder reactivity compared to pure nitric acid, acetyl nitrate is highly moisture- and temperature-sensitive, decomposing readily to nitric and acetic acids that can lead to salt formation or uncontrolled oxidation. Its limited stability and tendency to acetylate or over-nitrate substrates restrict its practicality and scalability, especially for primary or acid-sensitive amines. Bottaro et al. showed that a isocyanate can be treated with acetyl nitrate in methanol to give primary nitramine [50].

2.1.2. Chloramines

Chloride-catalyzed nitration employs transient or preformed chloramines to lower amine basicity and extend nitric acid nitration to substrates otherwise too reactive or unstable under standard conditions [51,52,53], see example in Scheme 5.

Nitric acid/acetic anhydride with either chloride ion catalyst or chloramine has been used in various syntheses of explosives, such as N-nitrodiethanolamine dinitrate (DINA) [51,54,55]—including a continuous-flow synthesis of DINA [56], n-Butyl nitroxyethylnitramine (BuNENA) [57], and triethylenetetranitramine (TETN) [58].

Scheme 5. Chloride-catalyzed nitration employing preformed chloramines [58].

Scheme 5. Chloride-catalyzed nitration employing preformed chloramines [58].

Archibald et al. synthesized N-nitroazetidines 23a–c from azetidine hydrochlorides 22a–c, as depicted in Scheme 6 [59]. This synthesis was of interest to investigate the effect of ring strain in nitramine synthesis. The nitration was successful, with a yield of 87%. Rykaczewski et al. developed a general procedure for N-nitroazetidines, applying similar nitration systems, using nitric acid and acetic anhydride with similar yield [60].

Scheme 6. Synthesis of N-nitroazetidines [59].

2.2. Base-Promoted N-Nitration Using Alkyl Nitrate

Early nitramine studies also investigated non-acidic methodologies and reported some of the earliest examples of alkaline nitration [61]. In base-promoted nitration, the amine is first deprotonated to generate a nucleophilic amide anion, which subsequently attacks an alkyl nitrate or related donor, affecting formal nitro-group transfer under non-acidic conditions. This pathway avoids nitronium ion chemistry and enables N-nitration of acid-sensitive substrates [62].

White et al. further developed such an alkaline nitration method where aromatic nitramines are synthesized from corresponding anilines with phenyl lithium as the base and amyl nitrate acts as nitration donors [62], see Scheme 7. Reaction yields were modest. Similar yields are reported by Fukuzumi when using butyllithium as the base and iso-butyl nitrate as the nitro-transfer agent [63].

Scheme 7. Example of generic base-promoted N-nitration of aromatic amine.

Daszkiewicz et al. revealed that secondary aryl amines can be treated with ethyl magnesium bromide, followed by nitro-transfer from ethyl nitrate [64]. Yields are listed as low to moderate. The same group later reported a similar procedure with NaH as the base, also with moderate yields [65].

Winters et al. devised this method suitable for alkyl amines, including primary amines, which are otherwise challenging to access synthetically [66]. In their protocol, butyllithium was employed as the base, and ethyl nitrate was employed as the nitrating agent, with reactions conducted at −78 °C. Yields were reported to be poor to moderate. However, later use of this method reported a slightly improved yield of tert-butyl nitramine by implementing slight modifications on the workup [67,68].

A clear advantage with this approach is that it is acid-free N-nitration: it avoids strongly acidic, oxidizing media (HNO₃, H₂SO₄), so substrates that are acid-sensitive or prone to protonation can be nitrated. Also, for anilines, this approach is selective for N-nitration, in contrast to fuming nitric acid, which often gives C-nitration too. Primary amines can also be used as substrates. However, reported yields are moderate compared to alternatives. Furthermore, it requires harsh reagents (e.g., organo lithium and alkyl nitrate esters) and cryogenic conditions. This reduces scalability.

2.3. Other Nitro-Transfer Agents

Beyond nitric acid-based routes and the base-promoted routes, several specialized reagents have been developed to deliver the nitro group under milder or more selective conditions. These nitro-transfer agents including species such as acetone cyanohydrin nitrate, 5-alkoxy-4-chloro-2-nitropyridazin-3-one, and fluoroalkyl nitrate derivatives—operate through transfer of the NO₂ group rather than free nitronium generation, not unlike the reagent used in base-promoted N-nitration. However, these are given a separate section, as the amine is not deprotonated prior to nitration.

These reagents’ design reflects a long-standing effort to overcome the intrinsic limitations of the previously mentioned methods. By embedding the electrophilic nitro functionality within an organic framework, these reagents provide neutral or weak polar media.

2.3.1. Cyanohydrin Nitrates

One example is the cyanohydrin nitrates—particularly acetone cyanohydrin nitrate [69], e.g., see nitration of amine 28 to give nitramine 29 in Scheme 8, while the scope and reported yields can be found in Table 2. This can be used as an effective type of nitration reaction, under mild, non-acidic conditions.

Scheme 8. Generic nitration with acetone cyanohydrin nitrate [69]. R groups can be found in Table 2.

Table 2. The different R groups used to illustrate the scope of the cyanohydrin nitrate [69].

Entry	R1	R2	Yield (%)
a	CH3	CH3	76
b	CH2CH3	CH2CH3	60
c	CH2CH2CH3	CH2CH2CH3	42
d	CH2CH2CH2CH3	CH2CH2CH2CH3	54
e	CH2CH(CH3)CH3	CH2CH(CH3)CH3	60
f	CH2CH2CH(CH3)CH3	CH2CH2CH(CH3)CH3	64
g	Mononitropiperazine		55
h	Nitropiperidine		62
i	Nitromorpholine		81
j	Nitropyrrolidine		60
k	CH2CH2CH3	H	50
l	CH2CH2CH2CH3	H	52
m	CH2CH(CH3)CH3	H	54
n	CH2CH(CH3)CH2CH3	H	55
o	CH2CH2CH(CH3)CH3	H	54

Using this reagent, nitration of primary and secondary amines gave yields of 42–81%. It is compatible with solvents such as tetrahydrofuran (THF) and acetonitrile or dissolved in the amine itself.

The reagent has recently been employed to synthesize mono-nitramine of piperazine (31) from piperazine hexahydrate (30) in 60% reaction yield, which was then applied as reference material in atmospheric studies of amines leaked from CCS systems [70], as depicted in Scheme 9.

Scheme 9. The synthesis of mono-nitramine of piperazine from piperazine hexahydrate [70].

2.3.2. 5-Alkoxy-4-Chloro-2-Nitropyridazin-3-One

Park et al. reported an efficient and mild method for the N-nitration of secondary amines employing 4-chloro-5-methoxy-2-nitropyridazin-3-one (33a) as a nitro-transfer reagent [71].

The nitrating agent was prepared by copper(II)nitrate-mediated nitration of 4-chloro-5-methoxypyridazin-3-one (32a) in acetic anhydride, see Scheme 10, while the scope and reported yields can be found in Table 3. Among the series of pyridazinone derivatives evaluated, the 5-methoxy and 5-ethoxy analogues exhibited the highest reactivity toward amines. Under neutral conditions, treatment of various secondary amines with the reagent afforded the corresponding N-nitramines in good to excellent yields.

Scheme 10. The preparation and use of 4-chloro-5-methoxy-2-nitropyridazin-3-one (or ethoxy analogue) as a nitro-transfer reagent [71]. R₂ and R₃ can be found in Table 3.

Table 3. The different R groups used by XX to illustrate the scope of the 5-alkoxy-4-chloro-2-nitropyridazin-3-one [71].

Entry	R2	R3	Yield (%)
a	Bn	(CH3)2CH	86
b	CH2CH3	CH2CH3	90
c	C6H11	C6H11	28
d	Morpholine		92
e	2,6-Dimethylmorpholine		74
f	3-Pyrroline		82
g	Homopiperazine		86
h	2-Piperazine		79
i	Decahydroquinoline		92

2.3.3. 2-(Trifluoromethyl)-2-Propyl Nitrate

Conventional alkyl nitrate esters are inert toward amine nitration under neutral conditions, thus needing strong bases, as seen previously. Schmitt, Bedford, and Bottaro demonstrated that suitably electron-deficient nitrate esters can function as direct N-nitration reagents for secondary amines. Of particular note is 2-(trifluoromethyl)-2-propyl nitrate, which efficiently converts a broad range of aliphatic secondary amines into the corresponding nitramines, typically in good to excellent yields [72].

2.3.4. N-Nitropyridinium Nitrate and Thionyl Nitrate

Thionyl nitrate and N-nitropyridininum can be applied as nitration agents, as shown in the syntheses of Bu-NENA [73,74]. Both reagents were used in two equivalents to the amine, and good yield (70% for thionyl nitrate, 75% for N-nitropyridinium nitrate) was obtained within hours on ice-bath.

Despite the good yields and relatively short reaction time, more experiments are needed to evaluate scope and limitations.

2.4. Dinitrogen Pentoxide as Nitrating Agents

Dinitrogen pentoxide (N₂O₅) is the anhydride of nitric acid and, in non-aqueous media, serves as a neutral, anhydrous nitrating agent capable of delivering the nitronium ion (NO₂⁺) in a manner similar to nitric acid methods, under controlled conditions [75,76].

Emmons and coworkers later applied the reagent to nitrate aliphatic amines efficiently under mild, non-aqueous conditions [77]. The reagent reacts cleanly with secondary amines, providing nitramines in high yields. However, primary amines generally give nitrate salts or undergo decomposition, as N₂O₅ readily oxidizes unstable primary nitramines [77]. These conditions are applicable to very sensitive substrates, such as the triazabicyclo[3.1.0]hexanes 36a and 36b [78], see Scheme 11.

Scheme 11. Dinitrogen pentoxide as nitrating agents on sensitive substrates [78].

In modern applications, N₂O₅ has found utility in the ring-opening nitration of strained heterocycles such as aziridines and azetidines, providing regioselective access to nitramine derivatives [79,80,81]. Golding demonstrated that such reactions proceed in aprotic solvents at low temperatures, with yields of 70–80% [80,81,82,83], see generic reaction in Scheme 12 and specific examples in Scheme 13 with R groups and yields listed in Table 4.

Scheme 12. Ring-opening nitration of strained heterocycles such as aziridines and azetidines [79].

Scheme 13. Specific examples of ring-opening nitration of strained heterocycles [79,82].

Table 4. The different R groups used in ring-opening nitration of strained heterocycles such as aziridines and azetidines [79].

Entry	n	R1	R2	Yield (%)
a	1	CH2CH2CN	CH3	70
b	1	CH2CH2CN	H	56
c	1	n-Bu	H	69
d	1	Picryl	H	76
e	1	EtO2C	H	82
f	2	CH2CH2CN	H	79
g	2	n-Bu	H	81
h	2	EtO2C	H	48

In the synthesis of 1,4,5,8-tetranitro-1,4,5,8-tetraazabicyclo-[4,4,0]-decane (TNAD), the combination of N₂O₅ and acidic liquid, [(CH₂)₄SO₃HMim]HSO₄, proved to be successful and high yielding [84]. This type of system needs more investigation to define scope and limitations.

Overall, N₂O₅ combines high reactivity and mild conditions with relative operational simplicity. Its main drawbacks remain limited compatibility with primary amines and strong oxidative potential, which restrict its use to well-controlled laboratory settings. Nevertheless, it remains one of the cleanest and most versatile non-acidic nitrating agents available for the synthesis of secondary nitramines and related compounds. Due to its potent nitrating ability, N₂O₅ is now recognized as a useful tool in the synthesis of energetic nitramines and other nitrogen-rich compounds [32].

2.5. Nitronium Salts as Nitrating Agents

Nitronium salts, such as nitronium tetrafluoroborate (NO₂BF₄) and nitronium triflate (NO₂OTf), represent highly selective electrophilic nitrating agents, see Scheme 14. Nitronium salts provide a preformed NO₂⁺ electrophile, allowing highly selective N-nitration in the absence of strong acids, albeit under strictly anhydrous and moisture-sensitive conditions. These methods offer great control over substrate scope and mild conditions. However, their practical application is restricted by high cost, moisture sensitivity, and safety concerns, which have limited their use primarily to laboratory-scale studies.

Scheme 14. Generic N-nitration with nitronium salt [85].

Olsen, Fish, and Hamel reported a procedure using NO₂⁺BF₄⁻ to obtain selective nitration, particularly for synthesizing secondary nitramines [85], see Scheme 14 and Table 5. The conditions work well on secondary amines of low-to-moderate basicity, giving the corresponding nitramines in good yields in relatively short reaction times [85,86]. Due to the slower reaction of more basic amines, the yields are lower, and more byproducts are produced [86].

Table 5. The different compounds (amines or amine-derived structures) used in N-nitration with nitronium salt [85].

Entry	R1	R2	Yield (%)
a	CH2CH2CH2CH3	CH2CH2CH2CH3	54
b	Morpholine		72
c	β,β′-bis(cyanoethyl)amine		62
d	Ethyl butylcarbamate		91
e	Butyl acetamide		40
f	Succinimide		43
g	Picramide		85

The conditions were found to give nitrate salts of primary amines rather than primary nitramines, with the exception of electron-poor primary aryl amines [85]. In Atkins work on polynitro anilines, they showed that NO₂⁺BF₄⁻ can be used to give the corresponding nitramines in moderate yields [28].

Adams et al. reported a convenient and anhydrous generation of a potent nitrating agent, NO₂OTf, see Scheme 15. This reagent can be used similarly to NO₂BF₃. It has been shown to be particularly effective on heterocyclic N-nitration. The conditions are mild and scalable and offer a safer, more selective alternative to traditional nitronium salts. However, the reagents are highly moisture sensitive and expensive, limiting the method to small-scale laboratory experiments. Moreover, the scope described in the paper is limited.

Scheme 15. Example of N-nitration using NO₂OTf [87].

2.6. Inorganic Nitrate Salts as Nitrating Agents

Ammonium nitrate/trifluoracetic acid has been used for N-nitration of amides and cyclic ureas, giving poor to good yield [88,89]. Dichloromethane and nitromethane can serve as solvents.

Bayat et al. used nitric acid and boric acid as a nitrating system. This was applied in their synthesis of Bu-NENA. The yield was excellent (95%), and reaction time was short [90]. Another advantage with this method is that it allows for a reduction in the amount of nitric acid to five equivalents, rather than huge excess.

Cu(NO₃)₂ in combination with acetic anhydride has been used to prepare acetic nitrate without involvement of nitric acid [91,92]; one example is depicted in Scheme 16. Nitration of carbamates 48 was successful. A comparison to nitric acid/acetic anhydride revealed that yields were comparable.

Scheme 16. Synthesis of 2-hydroxyetylnitramin [91].

Norris reported the synthesis of nitramines from the reaction of carbamyl chlorides and silver nitrate, shown in Scheme 17, with R groups and yields listed in Table 6. Nitramines are the direct end-product 53; without any separate hydrolysis, CO₂ is released, and AgCl is precipitated [93]. Carbamyl nitrate 52 is the postulated intermediate.

Scheme 17. The synthesis of nitramines from the reaction of carbamyl chlorides and silver nitrate. R groups and yields are listed in Table 6.

Table 6. The R groups and yields are obtained from reaction of carbamyl chlorides and silver nitrate. R₂ means that both side chains are equal or part of a ring system.

R2	Yield (%)
(CH3)2	48
(CH3CH2)2	28
[(CH3)2CH]2	49
(CH3CH2CH2)2	14
O(CH2CH2)2	22
(NCCH2CH2)2	30

Badgujar et al. reported microwave-assisted synthesis of an N-nitroaniline 55 from aniline 54 by employing a suspension pentahydrate of Bi(NO₃)₃ and THF absorbed on silica gel, see Scheme 18. Yields of nitramines are high to excellent in all reported cases [94]. This synthesis is also interesting as Bi(NO₃)₃ is a more environmentally friendly nitration reagent than most alternatives.

Scheme 18. Microwave-assisted synthesis of an N-nitroaniline by employing a suspension pentahydrate of Bi(NO₃)₃ and THF absorbed on silica gel [94].

3. Nitration of Protected Amines and Hydrolysis

To overcome the instability and poor selectivity sometimes encountered in direct nitration, protected amine derivatives, such as carbamates, ureas, and amides, have been employed as intermediates since the late 1800s.

These groups reduce the reactivity of nitrogen, enabling controlled nitration and subsequent hydrolysis, typically with ammonia or aqueous NaOH, to yield nitramines [95,96,97,98,99,100,101,102,103,104,105]. A classic example is the synthesis of methylnitramine (57) from oxalic amide 56, see Scheme 19 [95,96].

Scheme 19. Franchimont prepared methylnitramine (57) from nitration and hydrolysis of oxalic amides. No reaction yields were reported [95,96].

Moreover, these derivatives often exhibit enhanced stability under strongly acidic and oxidative conditions, in contrast to free amines that are prone to protonation or decomposition [77]. Derivatization strategies have proven particularly valuable for the preparation of otherwise unstable primary nitramines [91].

Despite its long history, this type of route remains an essential tool for the selective preparation of nitramines even today. This is largely due to systematic studies and reliable protocols, such as Curry and Mason’s predictable and reliable protocol for the synthesis of N-nitrocarbamates using nitric acid and acetic anhydride [106,107].

One example of a protection strategy from recent years is found in the preparation of methyl nitramine, synthesized for atmospheric studies of CCS systems [5,8]. In this synthesis, the amine was protected as a toluenesulfonylamide, as shown in Scheme 20. The reaction yield was high.

Scheme 20. Methyl nitramine is synthesized from methyl toluenesulfonylamide [5,8].

Another representative example is the preparation of dinitro-diaza plasticizer, DNDA-57 (61), where oxamides 60 are nitrated using a traditional nitric acid/sulfuric acid system, followed by deprotection using aminolysis to give nitramine 57. The resulting nitramines 57 are then reacted with paraformaldehyde to give DNDA-57 [108], see Scheme 21.

Scheme 21. Synthesis of DNDA-57 [108].

Most examples of synthesis of nitramines via amides, ureas, etc., use a traditional nitration method. However, other nitration methods can also be applied, e.g., efficient N-nitration with dinitrogen pentoxide in liquid CO₂, fluorinated solvents (see Scheme 22), or PEG-based media, achieving moderate to excellent yields while improving safety and waste management, have been reported as more environmentally friendly approaches [109,110,111,112].

Scheme 22. Synthesis of nitramines and dinitramines using DNP [111]. The method was used to synthesize compounds 57 and 61–64.

The main disadvantage with this type of route is the extra reaction steps in making the derived group and later removing it. The extra reactions affect the overall yield and affect the atom economy drastically. However, it is still seen as a cornerstone in nitramine synthesis for several reasons. First, it gives access to nitramines that would otherwise be unstable or unreactive under direct nitration conditions, e.g., primary amines. Second, it is less prone to detonation. In conclusion, this approach remains a useful but pragmatic compromise—favored when safety and selectivity outweigh efficiency.

4. Nitrolysis

Nitrolysis represents a historically important path to nitramines, bridging the chemistry of hydrolysis and nitration in a single transformation. In these reactions, a nitrogen–carbon or nitrogen–heteroatom bond is cleaved, while a new N–NO₂ bond is simultaneously formed, effectively coupling bond activation and nitration into one step.

Robson’s 1950s studies on the nitrolysis of N,N-dialkylamides revealed that a constellation of nitric acid and trifluoroacetic anhydride efficiently yields nitramines in variable yields [113,114]. This approach remains one of the foundational protocols for laboratory-scale nitrolysis. It has been widely applied, for instance, in the preparation of dimethyl nitramine (66) from dimethylformamide (65, DMF), as shown in Scheme 23, relevant to atmospheric and biological studies [5,115,116,117,118].

Scheme 23. Synthesis of dimethylnitramine (66) [5].

The same reagent system also converts nitrosamines to nitramines, as demonstrated by Archibald et al. with N-nitrosoazetidines, achieving high yields [119,120,121,122], see synthesis of nitroaziridine 69 from nitrosoaziridine 68, as depicted in Scheme 24. Despite appearing oxidative, isotope studies confirm that these reactions are nitrolysis [123]. Under similar conditions, nosyl groups, imides, and carbamates can also undergo nitrolysis [124,125,126].

Scheme 24. Nitrolysis of nitrosamine to nitramine [121].

Alternative systems employing N₂O₅ in liquid CO₂ have also been reported, typically affording moderate to good yields [127].

Tert-butylamines easily undergo nitrolysis, yielding nitramines in moderate to good yields [128]. The reaction may involve mixed or pure nitric acid, acetyl nitrate, or N₂H₅ [125,126].

Historically, nitrolysis has been central to industrial production of high-performance explosives such as RDX (1), commonly prepared from hexamethylenetetramine [129,130], see Scheme 25. The classical route is high yielding but requires large excesses of nitric acid and ammonium nitrate, generating substantial acid and nitrate waste. Thus, many various attempts have been made to make the reaction cleaner. Examples include applying catalytic ionic liquid, ([(CH₂)₄SO₃HPyr]NO₃, 3.0 mol%), used in the nitrolysis of hexamethylenetetramine [131] and fluorinated media such as perfluorodecalin with catalytic PfOS [132]. Both these approaches lead to reduced HNO₃ consumption and allow for milder (0–5 °C) conditions and shorter reaction times.

Scheme 25. Synthesis of RDX [130].

HMX (2) is a very powerful explosive, originally discovered as a byproduct from RDX (1) synthesis [129]. Its application has been limited by its high cost compared to RDX (1) [133]. Due to this, numerous attempts to synthesize this have been reported. Many of these are based on nitrolysis of hexamine, 3,7-dinitro-1,3,5,7-tetraazabicyclo[3,3,1]nonane (DPT) or other derivatives of hexamethylenetetramine [133,134,135,136], see example in Scheme 26. Analogous to RDX (1), many recent strategies focus on more benign conditions. Examples include the use of task-specific ionic liquids [136], N₂O₅/HNO₃ in PEG-200-DIAL [133], and a deep-eutectic catalytic system, [HMim]NO₃/ethylene, NaNO₂/HNO₃ [137]. All have improved yields and reduced nitric-acid demand versus traditional methods.

Scheme 26. Example of synthesis of HMX [133].

Hexanitrohexaazaisowurtzitane (6, CL-20) has been synthesized via nitrolysis routes from various hexabenzylhexaazaisowurtzitanes [138,139]. Recent attempts to make CL-20 (6) synthesis more efficient include using nitroguanidine or guanidinium nitrate as co-nitration agents [140], heteropolyacids as greener acid catalysts [141], and MHS as a solid acid [142], see examples in Scheme 27. The Brønsted-acidic ionic liquid [Hmim][HSO₄] also performed well, giving a 92% yield [143].

Scheme 27. Examples of synthesis of CL-20 [139,142].

Using microwave-assisted heating, Saikia et al. synthesized CL-20 (6) from 2,4,8,12-tetraacetyl-2,4,6,8,10,12-hexaazaisowurtzitane in 5 min at 75 °C, obtaining a 94% yield—an improvement compared to 240 min needed with conventional heating (90%) [144]. However, the method still relies on large excesses of nitric acid, and scaling is difficult.

The continued reliance on nitric acid-based systems underscores both their synthetic efficiency and their limitations: they are effective, scalable, and well-understood yet inherently hazardous and environmentally burdensome. The subsequent sections, therefore, examine how alternative reagents seek to capture the reactivity of nitric acid while mitigating its safety and sustainability drawbacks.

5. Oxidation of Nitrosamines

An alternative route to nitramines involves the oxidation of nitrosamines, a transformation that can proceed efficiently under a range of oxidative conditions. This approach is attractive because nitrosamines are often readily available, and oxidation can deliver nitramines in high yields. However, the carcinogenic nature of nitrosamines and the hazards of strong oxidants limit the practical utility of this strategy.

The oxidation of nitrosamines to nitramines has been studied since the mid-20th century, with both chemical and electrochemical methods employed to understand and optimize the process.

Some examples of transformation of nitrosamines to give nitramines have already been mentioned [139,145]. These are not listed as oxidations as it has been shown with isotope studies that they are, in fact, nitrolysis reactions [123].

An early example of oxidation of nitrosamine into nitramines is found in the work of Chute and coworkers: oxidation of nitrosamine 74 to yield nitramine 75, as depicted in Scheme 28 [51]. In their work, potassium persulfate in combination with nitric acid oxidizes the nitroso functionality into the nitramine.

Scheme 28. Early example of oxidation of nitrosamine to nitramine [51].

Later, a systematic study by Emmons et al. demonstrated that peroxytrifluoroacetic acid efficiently oxidizes dialkyl nitrosamines to nitramines in high yields [146]. Emmons et al. used a mixture of 90% H₂O₂ and peroxytrifluoroacetic anhydride in methylene chloride or a mixture of 90% H₂O₂ in trifluoroacetic acid to prepare peroxytrifluoroacetic acid.

Ease of work-up giving clean products is noted, though not ignoring the disadvantages regarding carcinogenicity and toxicity. Moreover, peroxytrifluoroacetic acid and 90% H₂O₂ are corrosive and unstable, making scale-up problematic.

However, due both to the hazard and availability of 90% H₂O₂, different research groups have successfully used 50% and 30% H₂O₂ in similar reactions [147,148,149,150], including oxidizing 1-nitrosopiperidine (77) to 1-nitropiperidine (78) in 87% isolated yield, see Scheme 29 [151].

Scheme 29. The synthesis of 1-nitropiperidine from 1-nitrosopiperidine to [151].

Wright and coworkers prepared RDX (1) by oxidation of nitrosamine 79 with H₂O₂/HNO₃, as shown in Scheme 30 [152].

Scheme 30. Synthesis of RDX (1) by oxidation of nitrosamine [152].

In the 1970s–1980s, researchers explored electrochemical oxidation of nitrosamines in the presence of oxygen to nitramines [153].

Ali et al. reported the electrochemical oxidation of nitrosamines to nitramines in flow chemistry [154]. The same group also reported a flow synthesis of nitrosamines [155]. The method was later improved by the same group to form nitramines from amines via NaNO₂/oxidant in a similar process. They found that mCPBA, MoO₃/H₂O₂, and Oxone can all serve as effective oxidants, but Oxone gave the highest yield [156]. See examples of reported nitramines in Scheme 31.

Scheme 31. Nitramine synthesis under nitric-acid-free conditions. (a) With NaNO₂ (3 equiv), HCl (2.2 equiv) in dichloromethane at 0 °C for 1 h. (b) With Oxone (2 equiv), in acetonitrile/H₂O (1:1.5) at 40 °C for 16 h [156].

6. Reduction of Nitroimines

Nitroimines can, under suitable conditions, be reduced to nitramines. Although it is less frequently used than the other listed strategies, this approach provides access to specific classes of compounds, such as steroidal nitramines and other specialized derivatives. However, its broader synthetic applicability is limited by competing reduction of the nitro group.

Reduction of nitroimines will give nitramines. Reduction agents such as NaBH₄ and LiAlH((O-tBu)₃ have been shown to work well [157,158,159,160,161,162]. The potential of reducing the nitro group itself limits the reagent and/or conditions that can be utilized. Most of the reported reductions of this type are on steroidal structures. According to Haire’s investigations, adding acetic acid increased the yield. The experiments were conducted on steroid-like compounds, see Scheme 32.

Scheme 32. An example of nitramine synthesis via reduction of nitroimine on steroid [157].

The synthesis has some other interesting features to be mentioned as well. The nitroalkene made from the alkene was transformed into an oxime (90), which is converted to the nitroimine (91). This was reduced to the corresponding nitramine (92), which can be further transformed to the nitroaziridine 93 (R² = Cl for this reaction), revealing the reaction potential of monosubstituted nitramines.

7. Nitramines as Intermediates and Rearrangements Giving Nitramines

Nitramines are most often found as end-products, with the N-nitration reaction being late in the synthetic sequence. This is because they are energetically hazardous, chemically less versatile, and synthetically inconvenient compared to other nitrogen functionalities (carbamates, nitroimines, nitrosamines).

However, there are examples of reactions where nitramines are formed early in the synthesis. In polymers containing nitramine functionality, this is typically the case [163,164,165], e.g., synthesis of dibromo nitramine 95, which is transformed into diazido nitramine 96 in Scheme 33. As described above, nitro groups from nitramines can migrate to aromatic ring systems under acidic conditions. Aromatic nitramines have also been shown to work well as leaving groups, as replacements for diazo groups often used [166].

Scheme 33. Example of the preparation of the building block from a nitramine containing polymer [164].

In azidonitramine plasticizers, a polymer that combines azido (-N₃) and nitramine (-NH-NO₂) groups, the nitramine functionality is often integrated early in the building blocks. A recent review summarizes synthesis and application progress [165]. Contrary to inert plasticizers, the energetic ones are considered improvements due to better softening and cleaner burning of the propellant binder contributing to the explosive/propulsive performance.

Due to the strong electron-withdrawing properties of the nitro group, the N–H on nitramines will function as weak acids instead of bases, like in regular amines. This will also affect their properties as synthetic intermediates.

Due to their polarity, nitramines can be alkylated. Examples include the use of the Mitsunobu type Reaction [167]. N-alkylate nitrourethane and N-nitrotoluenes can be alkylated with diazoalkanes [168] and electrophiles [169]. Lee et al. reported an electrochemical method for the α-C─H azolation of nitramines in continuous flow [156]}.

In a recent synthesis of the explosive compound BITE-101 (99), intra-molecular reactions of nitramine and nitroimine are one of the key reactions to give the target molecule, see Scheme 34 [170].

Scheme 34. Synthesis of BITE-101 [170].

Nitramines have also been prepared in a nitro-Ugi type reaction, where ammonium nitrate salts, isonitrile, and aldehydes are mixed in methanol. Migration of the nitro group gives nitramine 102 [171]. In this work, nitric acid reacts with isonitrile to give the nitrooxyimine 101, which is the tautomeric form of an amide. A rearrangement gives the nitramines. Yields range from poor to excellent, as shown in Scheme 35 and Table 7.

Scheme 35. Synthesis of nitramine by nitro-Ugi type reaction [171].

Table 7. The scope of the nitro-Ugi type reactions was tested on the listed molecules [171].

Entry	R1	R2	R3	Yield (%)
a	i-Bu	4-ClC6H4CH2	Cy-C6H11	89
b	PhCH2CH2	4-ClC6H4CH2	Cy-C6H11	93
c	PhCH2CH2	CH2=CHCH2	Cy-C6H11	71
d	PhCH2CH2	1H-indolyl	Cy-C6H11	43
e	4-ClC6H4	n-C6H13	Cy-C6H11	49
f	4-ClC6H4	4-ClC6H4CH2	Cy-C6H11	69
g	4-ClC6H4	Cy-C6H11	Cy-C6H11	21
h	4-ClC6H4	4-ClC6H4CH2	Cy-C6H11	27
i	3-Furyl	4-ClC6H4CH2	Cy-C6H11	32
j	3-Thiophenyl	4-ClC6H4CH2	Cy-C6H11	42
k	i-Bu	4-ClC6H4CH2	CH3CH2CH2CH2CH2	82
l	3-Thiophenyl	C6H4CH2	CH3CH2CH2CH2CH2	40
m	4-ClC6H4	Cy-C6H11CH2CH2	CH3CH2CH2CH2CH2	49
n	i-Bu	4-ClC6H4CH2	4-CH3OC6H4CH2	78
o	i-Bu	C6H4CH2	2,6-(CH3)2Ph	34
p	PhCH2CH2	4-ClC6H4CH2	EtO2CCH2	86
q	i-Bu	4-ClC6H4CH2	3,4-(CH3O)C6H4CH2CH2	84
r	i-Bu	CH2=CHCH2	3,4-(CH3O)C6H4CH2CH2	52

8. Concluding Remarks

The synthesis of nitramines remains one of the most chemically diverse yet operationally challenging areas of energetic materials chemistry. Over more than a century, methodologies have evolved from simple brute force nitric acid nitration to more sophisticated systems that prioritize safety, selectivity, and environmental responsibility. Despite this progress, direct nitration with nitric acid and its derivatives continues to dominate—not because it is ideal but because it is proven, accessible, and deeply integrated into both industrial and academic practice.

Modern research demonstrates that no single route offers a universal solution. Acidic, basic, and neutral nitration strategies each occupy distinct niches defined by substrate stability, scalability, and hazard profile. Reagents such as dinitrogen pentoxide and nitronium salts deliver exceptional selectivity and cleaner reactions, while base-promoted and nitro-transfer reactions expand access to otherwise inaccessible primary and acid-sensitive nitramines. Oxidative routes from nitrosamines have gained renewed attention in recent years, especially in flow chemistry and environmental studies, reflecting growing interest in safer and more controlled transformations.

Nitrolysis remains indispensable for large-scale synthesis of RDX (1), HMX (2), and CL-20 (6), though it continues to pose inherent safety challenges. Also, it is noteworthy that, even in studies motivated by environmental and health concerns, the synthesis of small nitramines continues to depend largely on classical nitric acid-derived protocols, underscoring a gap between sustainability goals and the practical realities of current synthetic chemistry.

However, the emerging trends are clear: flow chemistry, ionic liquids, and greener media (e.g., PEG or liquid CO₂) represent promising avenues for reconciling performance with safety and sustainability. At the same time, computational chemistry and mechanistic modeling are reshaping how nitramines are designed and evaluated, enabling predictive control over both energetic performance and environmental persistence.

Moving forward, the field’s priorities must align with contemporary chemical principles: reduced hazard, improved atom economy, and transparent environmental assessment. The comparative framework presented in this review—summarizing reagents, scope, and safety—illustrates how incremental innovation can collectively redefine old chemistry for a new era. Nitramine synthesis, once driven purely by military demands, is now guided by a broader mandate: advancing performance while, at the same time, protecting people and the planet.

Future

What will the next ten years be like within nitramine synthesis? The traditional methods still dominate in the more recently published papers. Most likely, this is because most of the recent papers on nitramines are aiming to prepare the compounds for a specific experiment rather than develop new methodologies.

Still, it is important to bear in mind that the HSE regulations today are vastly different from the ones in the early days of nitramine synthesis. One can argue that there has been continuous work on developing safer syntheses.

Although nitramine syntheses remain hazardous, significant progress is being made toward safer, more controlled, and more sustainable synthetic approaches. Regarding the more recent innovation in safety, there are a few papers on, e.g., continuous flow. This gives better control of temperature and thus reduces the risk of explosions. These include oxidation of nitrosamine to nitramines [154,156] and nitration to give NENA plasticizers [56,172]. A recent review paper describes innovations within continuous flow nitration, and there is huge potential for nitramine synthesis for further development [173].

Researchers develop new methodologies regarding nitration reagents, solvent systems, catalysts, etc. In recent years, the use of liquid or supercritical CO₂ for direct nitration and nitrolysis [109,110,127,174] has been applied. Others have investigated ionic liquids [131,133,136,143]. More experiments are welcomed as this is needed to define the scope and limitations.

In addition to synthesis itself, formulation safety can be improved by physical modification: for example, MOF encapsulation of RDX (1), HMX (2), and CL-20 (6) produced core–shell composites that altered decomposition behavior and markedly increased activation energies [175], and co-crystallization with tailored coformers has been used to reduce sensitivity while retaining energetic performance [176].

With the progress in computational chemistry in the last decades, it is not surprising that this finds its way to nitramine chemistry as well. FDT/ab initio modeling can be used to predict stability, decomposition pathways, and performance.

In environmental chemistry, computational chemistry has been used to predict degradational pathways for leaking amines or byproducts, combined with physical experiments [5,68,70,151,177,178,179].

Recent papers describe design and predictions of stability and performance of potential high-energy materials [180,181,182,183].

To help find safer and higher-performance energetic compounds for uses such as propellants and explosives, a machine learning approach that quickly predicts material properties and screens large numbers of candidates is highly advantageous [184,185]. Machine learning can also be useful in planning synthesis [186]. A recent paper describes the calculation of 1H NMR chemical shift prediction method employed for the first time on a variety of energetic materials using density functional theory (DFT) and gauge-independent atomic orbital (GIAO) [187].

Computational chemistry can make a significant contribution to laboratory safety and to the discovery of cleaner, more efficient reactions. However, it should be emphasized that these tools do not replace experimental chemistry—if anything, they enhance and guide it.