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Imide

An imide is a functional group in organic chemistry consisting of a nitrogen atom bonded to two acyl groups, typically represented by the structure R-C(O)-NH-C(O)-R', where R and R' are organic substituents such as alkyl or aryl groups.^[1] This structure imparts resonance stabilization between the nitrogen lone pair and the adjacent carbonyl groups, resulting in planar geometry around the imide moiety.^[2] Imides are classified into two main types: acyclic imides, which have an open-chain structure like N-phenylsuccinimide, and cyclic imides, which incorporate the imide group within a ring, often five- or six-membered, such as succinimide (from succinic anhydride) or phthalimide (from phthalic anhydride).^[3] Cyclic imides are more common due to their stability and ease of synthesis from dicarboxylic acids or anhydrides.^[2] Physically, imides exhibit high thermal stability, with many withstanding temperatures up to 400–500°C, and they are generally soluble in polar solvents but insoluble in water.^[2] Chemically, they display weak acidity (pKa around 8–12 for the N-H proton), enabling deprotonation to form imide anions, and they resist hydrolysis under neutral conditions but can undergo ring-opening in basic or acidic media.^[3] Common preparation methods involve the condensation of dicarboxylic acids or their anhydrides with ammonia or primary amines at elevated temperatures (around 200°C), yielding water as a byproduct; for example, phthalic anhydride reacts with ammonia to produce phthalimide.^[2] Alternative routes include oxidation of primary amides or reactions of nitriles with water under catalytic conditions.^[3] Key reactions of imides include N-alkylation or N-arylation after deprotonation, as utilized in the Gabriel synthesis for primary amines (e.g., potassium phthalimide alkylated followed by hydrolysis), and halogenation to form N-haloimides like N-bromosuccinimide (NBS), which serves as a brominating agent in organic synthesis.^[3] They also participate in Diels-Alder reactions when unsaturated, such as maleimide acting as a dienophile.^[3] Imides find broad applications as intermediates in organic synthesis, in pharmaceuticals (e.g., thalidomide contains a glutarimide moiety), and notably in high-performance polymers like polyimides, which are synthesized from dianhydrides and diamines and exhibit exceptional thermal stability (decomposition above 500°C), mechanical strength, and chemical resistance for use in aerospace components, electronics, and flexible circuits.^[2]^[4]

Definition and Structure

Definition

Imides are a class of organic compounds characterized by a functional group in which two acyl groups are bound to a single nitrogen atom, typically represented by the general formula R-C(O)-NR'-C(O)-R'', where R and R'' are alkyl or aryl groups and R' is hydrogen or another substituent.^[1]^[5] This structure positions imides as nitrogen analogues of acid anhydrides, but the presence of the nitrogen bridge imparts greater resistance to hydrolysis compared to the oxygen-linked anhydrides, allowing some imides to withstand boiling water without decomposition.^[6] The term "imide" was coined in the mid-19th century by French chemist August Laurent, derived as an alteration of "amide" to reflect the replacement of two hydrogen atoms in ammonia with acyl groups.^[7] Imides have since gained prominence in materials science, particularly through their incorporation into polyimides, which are polymers valued for high thermal stability and mechanical strength in demanding applications such as aerospace components and electronics.^[8] In IUPAC nomenclature, acyclic imides are named as diacyl derivatives of azane (ammonia), while cyclic imides derived from dicarboxylic acids are systematically named by replacing the "-dioic acid" or "-ic acid" ending of the parent acid with "-imide," as seen in the common example of succinimide from succinic acid.^[9]

Structural Features

The imide functional group consists of two acyl groups attached to a central nitrogen atom, represented by the structural moiety -CO-NR-CO-, where R is hydrogen, alkyl, or aryl. This arrangement positions the nitrogen between two electron-withdrawing carbonyl groups, promoting electronic delocalization.^[10] The nitrogen atom in imides adopts sp² hybridization, resulting in a trigonal planar geometry around the C-N-C unit with bond angles approaching 120°. This hybridization facilitates the overlap of the nitrogen's p orbital with the π systems of the adjacent carbonyls. Resonance stabilization is a key feature, arising from the delocalization of the nitrogen lone pair into both carbonyl π* orbitals. The primary resonance structures depict the lone pair forming a double bond with one carbonyl carbon, placing a negative charge on the corresponding oxygen, while the other C-N bond retains single-bond character; a symmetric structure interchanges this for the second carbonyl. This delocalization imparts partial double-bond character to both C-N linkages, shortening them relative to typical single bonds and enhancing overall molecular stability. Cyclic imides, which incorporate the -CO-NR-CO- unit into five- or six-membered rings (such as in succinimide or glutarimide), are more common than acyclic variants due to their greater thermodynamic stability. This arises from minimal angle strain in these ring sizes, where the planar imide geometry aligns well with ideal tetrahedral and trigonal angles, avoiding the distortion seen in smaller or larger rings. Acyclic imides, while feasible, often exhibit reduced rigidity and are less prevalent in natural and synthetic contexts.^[11] Spectroscopic methods provide reliable identification of imide structures. In infrared (IR) spectroscopy, the carbonyl stretches appear as a single band at 1670–1740 cm⁻¹ for acyclic imides, reflecting symmetric conjugation; cyclic imides show two distinct bands at approximately 1680–1750 cm⁻¹ and 1735–1790 cm⁻¹ due to asymmetric coupling between the carbonyls. Unsubstituted imides additionally display an N-H stretch at 3200–3400 cm⁻¹. In ¹³C nuclear magnetic resonance (NMR) spectroscopy, the carbonyl carbons are deshielded by the electron-withdrawing nitrogen, resonating at 170–180 ppm, a range shifted downfield compared to simple amides or esters.^[5]^[12]

Examples

Acyclic Imides

Acyclic imides are organic compounds featuring two acyl groups attached to a nitrogen atom in an open-chain configuration, with the general formula R-C(O)-NR'-C(O)-R'', where R, R', and R'' can be hydrogen or various organic substituents.^[9] This structure positions them as diacyl derivatives of amines, distinct from their cyclic counterparts by the absence of a ring system.^[13] A representative example is diacetamide, with the formula CH₃C(O)NHC(O)CH₃, a symmetrical acyclic imide that demonstrates the basic motif and is often studied for its hydrogen-bonding capabilities in molecular recognition processes.^[14] Another notable class involves N-phenyl-substituted variants, such as N-phenyl-N-acetylbenzamide derivatives, which are employed in organic synthesis due to their tunable reactivity at the nitrogen center.^[15] Acyclic imides are typically prepared through the acylation of primary amides with acid chlorides or anhydrides, a method that allows for the formation of both symmetrical and unsymmetrical structures under controlled conditions.^[16] For instance, the reaction of acetamide with acetyl chloride yields diacetamide.^[13] These compounds exhibit greater molecular flexibility owing to their linear backbone, facilitating conformational adaptability in solution, and they undergo hydrolysis more readily than cyclic imides, which benefit from ring stabilization.^[2] This enhanced reactivity makes acyclic imides valuable intermediates in small-molecule synthesis, where selective cleavage of one acyl group can be exploited.^[17]

Cyclic Imides

Cyclic imides are characterized by the incorporation of the imide functional group (-CO-NH-CO-) into five- or six-membered rings, typically derived from the corresponding dicarboxylic acids or their anhydrides. These structures provide enhanced rigidity compared to their acyclic counterparts, which lack such constraints. A prototypical example is succinimide, formed by the reaction of succinic anhydride with ammonia, yielding a five-membered ring where the -CO-NH-CO- unit bridges two methylene groups.^[18] Prominent examples of cyclic imides include phthalimide, which features an aromatic benzene ring fused to the five-membered imide ring, conferring additional electronic delocalization. Maleimide represents an unsaturated variant with a carbon-carbon double bond within the five-membered ring, influencing its reactivity in conjugation reactions. In contrast, glutarimide adopts a six-membered piperidine-2,6-dione structure, offering a slightly more flexible ring while maintaining the core imide motif. N-substitution on the imide nitrogen is common in cyclic variants, altering their properties for specific applications. For instance, N-bromosuccinimide (NBS) is an N-bromo derivative of succinimide, widely employed as a brominating agent in organic synthesis due to its ability to deliver electrophilic bromine under controlled conditions. The stability of cyclic imides arises from their planar ring conformation, which facilitates resonance delocalization involving the nitrogen lone pair and the adjacent carbonyl groups, lowering the energy of the system and restricting rotation around the C-N bonds. This resonance stabilization is more pronounced in smaller rings like those in succinimide and phthalimide, contributing to their prevalence in synthetic and natural contexts.^[19]^[20]

Properties

Physical Properties

Imides exhibit polarity arising from their two adjacent carbonyl groups and the N-H bond, which facilitate intermolecular hydrogen bonding and interactions with polar environments.^[21] This structural feature imparts solubility in polar solvents, with small cyclic imides such as succinimide showing moderate water solubility of approximately 0.33 g/mL at ambient conditions and high solubility in dimethyl sulfoxide (DMSO). Larger cyclic imides like phthalimide display lower water solubility (360 mg/L) but dissolve readily in other polar media, including boiling acetic acid and aqueous alkali solutions.^[21] Cyclic imides typically possess elevated melting and boiling points due to extensive hydrogen bonding and molecular planarity, which enhance intermolecular cohesion. For example, phthalimide has a melting point of 238 °C and sublimes at 336 °C, while succinimide melts at 123–125 °C and boils at 285–290 °C.^[21]^[22] In crystalline forms, imides commonly assemble into hydrogen-bonded networks, featuring N–H···O interactions that form dimers, chains, or extended two-dimensional sheets, contributing to their structural rigidity.^[23]^[24] Imides are characterized by high thermal stability, with many monomeric examples resisting decomposition up to 280 °C or higher, a property stemming from the resilient C–N–C imide core.

Chemical Properties

Imides exhibit moderate hydrolytic stability, undergoing hydrolysis more slowly than acid anhydrides but more readily than simple amides, particularly under acidic conditions or for N-substituted imides under basic conditions.^[25]^[26] This resistance stems from the resonance stabilization of the imide carbonyls, which reduces their electrophilicity compared to anhydrides while still allowing cleavage to amides and carboxylates under forcing conditions.^[26] The N-H proton in imides confers notable acidity, with pKa values generally ranging from 8 to 12; for instance, maleimide has a pKa of approximately 10.^[25]^[26] This enhanced acidity relative to simple amides arises from effective resonance delocalization of the conjugate base's negative charge across the two adjacent carbonyl groups, stabilizing the anion.^[25] Imides serve as effective hydrogen bond donors via the N-H and acceptors through the carbonyl oxygens, enabling strong intermolecular interactions that enhance solubility in polar solvents and modulate reactivity in assemblies.^[27] These capabilities contribute to the polarity of imides, influencing their dissolution behavior without dominating over other factors.^[27] Imides demonstrate resistance to mild oxidizing agents, owing to the stability of their conjugated structure, which underpins their application in chemically demanding environments.^[28]

Natural Occurrence

In Biological Systems

Imides occur rarely in biological systems, primarily as post-translational modifications in proteins. C-terminal cyclic imides, formed spontaneously through intramolecular cyclization of asparagine or glutamine residues at protein termini, serve as natural degrons that target proteins for ubiquitination and degradation by the CRL4^CRBN E3 ubiquitin ligase complex.^[29] These modifications are regulated and can influence protein stability and cellular homeostasis, with recent studies identifying their genesis from deamidation and succinimide formation pathways.^[30] In the context of ubiquitin ligase modulation, cyclic imides play a key role in protein degradation pathways. Naturally occurring C-terminal aspartimides and aminoglutarimides are recognized by cereblon (CRBN), the substrate receptor of the CRL4^CRBN complex, facilitating targeted proteolysis.^[29] A prominent bioactive example of a natural imide is cycloheximide, a cyclic glutarimide produced by Streptomyces bacteria such as Streptomyces griseus. This compound acts as an antifungal agent by binding to the E-site of the 60S ribosomal subunit, thereby inhibiting eukaryotic translation elongation and protein synthesis.^[31] Its imide moiety contributes to its weakly acidic properties and biological activity, enabling selective disruption of fungal and eukaryotic protein production without affecting prokaryotic systems.^[32]

In Natural Products

Glutarimide alkaloids, characterized by a cyclic imide moiety, have been isolated from various plant species, particularly within the Euphorbiaceae family. For instance, julocrotine was identified from the leaves of Croton membranaceus, a shrub native to northeastern Brazil, showcasing the structural diversity of these compounds in tropical flora.^[33] Similarly, crotonimides A and B, along with a novel N-[2,6-dioxo-1-(2-phenylethyl)-3-piperidinyl]-acetamide, were extracted from the stem methanol extract of Croton pullei, another Amazonian plant, highlighting their occurrence in Croton genus species.^[34] These plant-derived imides often exhibit antimicrobial properties, though specific mycotoxic effects in plants remain less documented compared to fungal counterparts. In microbial sources, glutarimide-containing polyketides represent a prominent class of natural imides produced by actinobacteria. Streptimidone, a classic example, is biosynthesized by Streptomyces rimosus, demonstrating potent antifungal activity against plant pathogens such as Phytophthora capsici and Botrytis cinerea. Recent isolations include streptimidone from Streptomyces sp. MA37, with known cytotoxic potential against human tumor cell lines.^[35] These compounds underscore the role of soil and marine-derived microbes in generating imide-based metabolites with broad-spectrum bioactivity, distinct from synthetic analogs like captan. Cyclic imides, particularly diketopiperazines (2,5-DKPs), are abundant in marine environments, often from sponge-associated microorganisms. For example, cyclo(L-Pro-L-Tyr) was isolated from a Bacillus sp. linked to the Mediterranean sponge Spongia officinalis, displaying antimicrobial activity against Gram-positive bacteria including Staphylococcus aureus.^[36] Other DKPs, such as those from Aspergillus sydowii associated with the sponge Lissodendoryx isodictyalis, exhibit antifungal properties against Candida albicans.^[37] These sponge-derived imides contribute to ecological defense mechanisms, with their antimicrobial roles supporting biodiversity in marine ecosystems. Post-2011 biodiversity studies have revealed novel imide-based natural products, expanding the chemical repertoire from underrepresented sources. Streptoglutarimides A–J, isolated in 2021 from the marine actinobacterium Streptomyces sp. ZZ741 sourced from Chinese coastal mud, feature a conserved glutarimide core with varied side chains and show activity against methicillin-resistant Staphylococcus aureus (MRSA) and glioma cells.^[38] Additionally, between 2017 and 2021, marine actinobacteria yielded several glutarimide alkaloids with antibacterial and antifungal potential, emphasizing the value of targeted microbial screening in ocean biodiversity hotspots.^[39]

Synthesis

From Dicarboxylic Derivatives

The primary synthetic route to imides involves the condensation of dicarboxylic acids or their corresponding anhydrides with ammonia or primary amines, representing the most classical and widely employed method for preparing both acyclic and cyclic imides. In this process, the dicarboxylic derivative reacts with the nitrogen source to form an initial amide intermediate, followed by dehydration to yield the imide. A representative example is the reaction of phthalic anhydride with ammonia to produce phthalimide, as shown in the following equation:

\ce{(C6H4(CO)2O + NH3 -> C6H4(CO)2NH + H2O}

This transformation proceeds in high yield, typically 95-97%, under appropriate conditions. The mechanism begins with the nucleophilic attack of ammonia on one of the carbonyl carbons of the anhydride, leading to ring opening and formation of an amic acid (or amide-acid) intermediate. Subsequent dehydration, often facilitated by heat, closes the ring to form the imide structure, involving elimination of water from the adjacent carbonyl and amide groups. This stepwise nucleophilic acyl substitution is characteristic of anhydride reactivity with nucleophiles like ammonia. Typical reaction conditions involve heating the reactants at elevated temperatures of 150-200°C, often in solvent-free environments or using high-boiling solvents such as toluene or xylene to facilitate dehydration. Ammonia gas or aqueous ammonia can be used directly, though ammonium salts like urea or ammonium acetate serve as convenient ammonia equivalents to avoid handling gaseous ammonia, with the reaction monitored by cessation of gas evolution. For the synthesis of cyclic imides, this method is particularly efficient for five-membered rings, such as succinimides or phthalimides, due to the favorable thermodynamics of ring closure and the stability of the resulting planar imide moiety, often achieving yields of 50-98% under optimized heating. Larger rings form less readily and may require additional catalysts or modified conditions to improve selectivity.^[40]

Alternative Methods

Alternative methods for imide synthesis encompass oxidative transformations, rearrangement reactions, and catalytic couplings that diverge from traditional anhydride-based routes, often enabling access to specialized or chiral imides under milder or more sustainable conditions. One prominent approach involves the oxidation of primary or secondary amides to imides, leveraging hypervalent iodine reagents, metal catalysts, or peroxides to insert oxygen into the N-H bond. For instance, copper(I) bromide combined with Selectfluor oxidizes N-substituted amides to the corresponding imides in good yields, proceeding via a radical mechanism that tolerates various functional groups. Similarly, heterogeneous manganese oxide catalysts facilitate the peroxide-mediated oxidation of amides to imides under mild aqueous conditions, offering a scalable and environmentally benign alternative with up to 90% yields for aliphatic and aromatic substrates. These methods are particularly useful for late-stage functionalization in complex molecules, avoiding harsh conditions associated with classical syntheses.^[41]^[42] The Mumm rearrangement provides another versatile pathway, involving the migration of an acyl group from oxygen to nitrogen in O-acyl hydroxylamine derivatives, typically generated in situ from hydroxamic acids or via multicomponent reactions. This thermal or base-promoted process yields imides efficiently and has been adapted for asymmetric synthesis through integration with chiral auxiliaries or catalysts in Ugi-type reactions followed by rearrangement. Post-2011 developments include chiral phosphoric acid-catalyzed Ugi-Mumm sequences that produce enantioenriched imides with high diastereoselectivity, enabling the construction of chiral scaffolds for pharmaceuticals.^[43] Recent electrochemical variants further enhance sustainability; for example, a three-component cascade combining carboxylic acids, nitriles, and isocyanides under electrochemical conditions promotes decarboxylative Mumm rearrangement to afford diverse imides in moderate to excellent yields, minimizing waste and avoiding stoichiometric reagents. These advancements address limitations in stereocontrol and scalability of earlier Mumm protocols.^[44]^[45] Synthesis from nitriles and carboxylic acids represents a direct catalytic route, often involving Ritter-type mechanisms or multicomponent assemblies to form the imide core. Copper-catalyzed four-component reactions of nitriles, carboxylic acids, arylcyclopropanes, and N-fluorobenzenesulfonimide generate imides via ring-opening and nitrogen insertion, achieving up to 85% yields for unsymmetrical products under mild heating. For cyclic imides, a process reacting carboxylic diacids with dinitriles under acidic conditions yields polyimides or succinimides, suitable for polymer precursors. Metal-catalyzed variants from the 2020s, such as visible-light-promoted couplings of diazo compounds, nitriles, and carboxylic acids, proceed through nitrile ylide intermediates and Mumm-like rearrangements, providing a photoredox pathway with broad substrate scope and minimal byproducts. These methods highlight the potential for nitrile activation in imide assembly, contrasting with anhydride-dependent strategies.^[46]^[47]^[48] To promote sustainability, microwave-assisted and green chemistry routes have gained traction for imide preparation, reducing reaction times and solvent use. Microwave irradiation accelerates the condensation of amines with dicarboxylic acids or esters to cyclic imides, often in solvent-free conditions with yields exceeding 80% in minutes, as demonstrated for phthalimides and succinimides. For acyclic imides, p-toluenesulfonic acid-catalyzed reactions of nitriles with carboxylic anhydrides under microwave heating proceed cleanly, aligning with green principles by avoiding volatile organic solvents. These techniques not only enhance efficiency but also facilitate scale-up for industrial applications, filling gaps in classical methods by emphasizing energy efficiency and reduced environmental impact.^[49]^[16]

Reactions

Nucleophilic Behavior

Imides function as electrophiles in nucleophilic acyl substitution reactions, where nucleophiles primarily attack the carbonyl carbons through an addition-elimination mechanism. This behavior is characteristic of their structure, featuring two acyl groups attached to a nitrogen atom, rendering the carbonyls susceptible to ring-opening transformations under appropriate conditions.^[50] Base-catalyzed hydrolysis of imides proceeds via nucleophilic attack by hydroxide ion on one carbonyl group, leading to ring opening and formation of an amido carboxylate salt. For example, succinimide undergoes hydrolysis with OH⁻ to yield the sodium salt of 4-amino-4-oxobutanoic acid (HO₂CCH₂CH₂CONH₂ after acidification). This reaction is typically carried out under heating in aqueous base, reflecting the moderate reactivity of imides compared to more labile derivatives.^[51] The mechanism of this hydrolysis involves initial addition of OH⁻ to the electrophilic carbonyl carbon, generating a tetrahedral intermediate. Collapse of this intermediate expels the amide anion as the leaving group, opening the five-membered ring and producing the carboxylate-amide product. In neutral or acidic conditions, hydrolysis can occur via water addition, but base catalysis accelerates the process by enhancing nucleophile concentration and facilitating leaving group departure.^[51] Aminolysis of imides occurs similarly, with primary or secondary amines acting as nucleophiles to attack a carbonyl, resulting in ring opening and formation of diamides. For instance, phthalimide reacts with pyrrolidine in acetonitrile to produce N-(2-carboxybenzoyl)pyrrolidine, demonstrating the substitution at one acyl group. This reaction follows second-order kinetics, with the rate depending on both imide and amine concentrations, and is often studied in non-aqueous solvents to isolate kinetic behavior.^[52] The N-H bond in unsubstituted imides exhibits sufficient acidity (pK_a ≈ 8-12, depending on the structure) to allow deprotonation by strong bases, forming resonance-stabilized imide anions. Potassium phthalimide, prepared by treating phthalimide with KOH, exemplifies this salt formation and serves as a key intermediate in the Gabriel synthesis for primary amines.^[53] Imides display lower reactivity toward nucleophilic attack than acid anhydrides, with relative rates in hydrolysis and aminolysis orders of magnitude slower, due to resonance delocalization of the nitrogen lone pair across both carbonyl groups, which diminishes carbonyl electrophilicity and stabilizes the ground state. This resonance effect also contributes to the poor leaving group ability of the imide nitrogen in the tetrahedral intermediate compared to the carboxylate in anhydrides.^[50]

Electrophilic and Other Transformations

Imides are susceptible to electrophilic attack at the nitrogen atom, leading to N-halogenation products that serve as versatile reagents in synthetic chemistry. For instance, succinimide reacts with sodium hypochlorite in aqueous solution to afford N-chlorosuccinimide (NCS), a widely used chlorinating agent for allylic and benzylic positions as well as an oxidant in radical reactions. The mechanism proceeds via electrophilic chlorination, where hypochlorite generates a positive chlorine species that coordinates to the imide nitrogen, followed by deprotonation to yield the N-chloro derivative.^[54] Similar transformations apply to other halogens; for example, NCS can be further reacted with lithium bromide to produce N-bromosuccinimide (NBS) in high yield under mild conditions, enabling redox-neutral halogen exchange.^[54] These N-haloimides are bench-stable and facilitate selective halogenations without over-oxidation.^[54] Maleimides, as cyclic imides bearing an α,β-unsaturated system, act as highly reactive dienophiles in Diels-Alder cycloadditions due to the electron-withdrawing nature of the imide carbonyls, which lowers the LUMO energy and accelerates the [4+2] pericyclic reaction with electron-rich dienes such as furans.^[55] This reactivity is exemplified in the thermoreversible adduct formation between N-substituted maleimides and furan, occurring at approximately 60 °C forward and reversing above 110 °C, a property exploited in dynamic polymer networks and self-healing materials.^[55] The reaction's efficiency stems from the concerted mechanism, yielding endo-selective cycloadducts with high stereocontrol, and has been pivotal in sustainable synthesis using bio-derived furans.^[55] Rearrangements of imides provide access to amines and related derivatives through carbon-nitrogen bond migration. In the Hofmann rearrangement, cyclic imides undergo N-halogenation followed by base-mediated migration to form isocyanates, which hydrolyze to amino acids or amines with decarboxylation.^[56] For example, phthalimide treated with trichloroisocyanuric acid (TCCA) in water yields anthranilic acid in 77% yield on a multigram scale, proceeding via an in situ N-chloroimide intermediate and offering a green alternative to classical bromine-based methods with high atom economy.^[56] This transformation is particularly useful for synthesizing o-aminoaromatic acids from aromatic imides, with yields ranging from 69% to 83% for various cyclic substrates.^[56] Recent advances in photocatalysis have expanded imide transformations, particularly through radical pathways. For instance, N-hydroxyphthalimides serve as precursors for amidyl radicals under visible-light photoredox conditions, enabling selective C-H amination of arenes via phosphine-mediated N-O bond cleavage and hydrogen atom transfer.^[57] This metal-free approach achieves up to 90% yield for electron-rich arenes and highlights the role of imide derivatives in site-specific functionalizations without harsh oxidants.^[57] Additionally, the acidity of imides (pKa ≈ 9–12) allows salt formation with bases, which can modulate reactivity in these processes.^[57]

Applications

In Materials and Polymers

Polyimides represent a class of high-performance polymers renowned for their exceptional thermal stability, mechanical strength, and chemical resistance, making them indispensable in demanding engineering applications. These aromatic polymers are typically synthesized from dianhydrides and diamines, forming rigid imide linkages that confer glass transition temperatures (Tg) often exceeding 300°C and low dielectric constants around 3.0–3.5, enabling reliable performance in extreme environments.^[58]^[59] A prominent example is Kapton, a polyimide film produced by DuPont through the condensation of pyromellitic dianhydride and 4,4'-oxydianiline, which exhibits outstanding tensile strength (>230 MPa) and continuous use temperatures from -269°C to 400°C. This material is widely employed in aerospace for flexible circuits, insulation in spacecraft, and electronics for substrates in high-reliability components due to its low outgassing and radiation resistance.^[60]^[61]^[62] The synthesis of polyimides generally proceeds via step-growth polymerization, where dianhydride and diamine monomers react to form a soluble poly(amic acid) precursor, followed by thermal or chemical imidization to yield the final imide structure. This two-step process allows for solution casting or melt processing before cyclization at 200–400°C, ensuring high molecular weights and uniform films, though one-step high-temperature methods in solvents like m-cresol are also used for direct imide formation.^[4]^[63]^[64] In aerospace and electronics, polyimides serve as thermal insulators, dielectric layers, and structural composites, with their low coefficient of thermal expansion (often <20 ppm/°C) minimizing dimensional changes under heat stress. For instance, they are integral to satellite thermal control systems and flexible printed circuits in aircraft, where their hydrolytic stability and flame retardancy enhance safety and longevity.^[65]^[66]^[67] Recent advancements in the 2020s have expanded polyimide applications in flexible electronics, where colorless, optically transparent variants with Tg >350°C enable foldable displays and wearable sensors by integrating with organic semiconductors. Innovations in molecular engineering, such as incorporating fluorene or benzimidazole units, have improved solubility and processability without compromising thermal stability, facilitating roll-to-roll fabrication for active-matrix organic light-emitting diode (AMOLED) devices.^[68]^[69]^[59] For space applications, 3D-printed polyimides have emerged as lightweight, customizable components, leveraging direct ink writing or two-photon polymerization to produce aerogels with densities as low as 0.05 g/cm³ and thermal conductivities <0.02 W/m·K for insulation in satellites and habitats. These printed structures, often reinforced with cellulose nanocrystals, withstand atomic oxygen erosion and temperatures up to 500°C, supporting in-orbit manufacturing and reducing launch mass.^[70]^[71]^[72] Beyond full polymers, imide oligomers—short chains with reactive end-groups like phenylethynyl or anhydride—play a key role in adhesives and coatings, offering tunable melt viscosities and cure temperatures around 250–350°C for high-adhesion bonds in composites. These oligomers, such as bismaleimide-based systems, provide shear strengths >20 MPa at elevated temperatures and are used in aerospace adhesives for titanium-to-carbon fiber joints, as well as corrosion-resistant coatings on metals due to their low moisture absorption (<1%).^[73]^[74]^[75]

In Pharmaceuticals and Agrochemicals

Imides play a significant role in pharmaceutical applications, particularly through the class of immunomodulatory drugs known as IMiDs, which include thalidomide, lenalidomide, and pomalidomide. These cyclic imide derivatives are primarily used in the treatment of multiple myeloma, a hematologic malignancy, by modulating immune responses and directly targeting cancer cells. Thalidomide, the prototype IMiD, was reintroduced in the late 1990s for relapsed or refractory multiple myeloma after demonstrating efficacy in combination with dexamethasone, achieving response rates of around 50% in early trials.^[76] Its mechanism involves binding to cereblon, an E3 ubiquitin ligase component, leading to the degradation of transcription factors such as Ikaros and Aiolos, which suppresses myeloma cell growth and enhances T-cell and natural killer cell activity.^[77] Lenalidomide and pomalidomide, second- and third-generation analogs, exhibit improved potency and reduced toxicity compared to thalidomide; lenalidomide, for instance, is 50- to 2,000-fold more effective at inducing T-cell proliferation and is a standard first-line therapy in combination regimens, improving progression-free survival by over 50% in newly diagnosed patients.^[78] Pomalidomide is particularly effective in lenalidomide-resistant cases, with overall response rates of 30-40% in heavily pretreated populations.^[79] As of 2025, next-generation IMiDs like mezigdomide (CC-92480), a cereblon E3 ligase modulator (CELMoD), represent advancements in this class, offering higher cereblon binding affinity and greater degradation of target proteins, which remains investigational and not approved for treatment as of October 2025. Phase 1/2 trials have shown promising efficacy in relapsed/refractory multiple myeloma, with an objective response rate of 41% (95% CI, 31-51) in the dose-expansion cohort when combined with dexamethasone, and ongoing studies explore triplets with proteasome inhibitors like carfilzomib.^[80]^[81] These developments build on IMiD immunomodulation while addressing resistance mechanisms, such as mutations in cereblon or downstream pathways.^[82] In agrochemicals, cyclic imides are widely employed as fungicides, with notable examples including captan, folpet, and procymidone, which protect crops from fungal pathogens through disruption of cellular processes. Captan and folpet, both phthalimide derivatives, act as broad-spectrum protectants against diseases like apple scab and grape black rot by releasing thiophosgene upon decomposition, which reacts with thiol groups in fungal enzymes and proteins, inhibiting respiration and leading to cell death.^[83] This thiol-trapping mechanism is non-specific but highly effective at low doses, with captan applied at rates of 1-2 kg/ha for foliar protection.^[84] Procymidone, a dicarboximide fungicide, targets Botrytis cinerea and other gray molds in fruits and vegetables by inhibiting triglyceride synthesis and disrupting hyphal cell wall formation, providing both protective and curative action with residual efficacy lasting 7-14 days post-application.^[85]^[86] Beyond oncology and crop protection, cyclic imides serve as scaffolds for antivirals and anti-inflammatories, leveraging their ability to modulate biological targets. Certain N-substituted cyclic imides exhibit antiviral activity by interfering with viral replication enzymes, as seen in derivatives that inhibit HIV reverse transcriptase or hepatitis C polymerase in preclinical models.^[87] In anti-inflammatory applications, phthalimide-based compounds act as selective COX-2 inhibitors, reducing prostaglandin synthesis with potency comparable to celecoxib and selectivity indices over 50, making them candidates for treating arthritis and other inflammatory conditions without gastrointestinal side effects.^[88]^[89] The therapeutic use of imides, exemplified by thalidomide, underscores important toxicity considerations stemming from its historical tragedy in the 1950s-1960s, when it caused severe birth defects in over 10,000 children worldwide due to teratogenic effects on limb development during pregnancy.^[90] This event prompted the 1962 Kefauver-Harris Amendments to the Federal Food, Drug, and Cosmetic Act, mandating proof of both safety and efficacy for new drugs, rigorous clinical testing phases, and informed consent, fundamentally evolving global regulatory frameworks to prioritize risk assessment, especially for vulnerable populations.^[91] Modern IMiDs incorporate strict pregnancy prevention programs, such as iPLEDGE, to mitigate embryotoxicity while harnessing their benefits.^[92]

Isoimides

Structural Differences

Isoimides represent constitutional isomers of imides, characterized by a distinct rearrangement in atomic connectivity within the functional group. In imides, the nitrogen atom is directly bonded to two carbonyl carbon atoms, forming the motif - \ce{C(O)-NR-C(O)-} , which allows for effective resonance delocalization involving the nitrogen lone pair and both carbonyls. In contrast, isoimides adopt an O-acylated hydroxylamine-like structure, - \ce{C(O)-O-NR-C(O)-} , where the oxygen atom intervenes between one carbonyl carbon and the nitrogen, resulting in a higher-energy configuration with reduced resonance stabilization.^[93]^[94] This structural disparity imparts greater instability to isoimides relative to imides, positioning them as kinetically accessible but thermodynamically unfavorable species that frequently serve as transient intermediates in synthetic pathways. The altered connectivity disrupts the symmetric, planar geometry typical of imides, leading to a less planar arrangement in isoimides with bends or kinks, particularly evident in cyclic variants where the ring incorporates a lactone and exocyclic imine linkage. Such geometric features diminish conjugation and contribute to the enhanced solubility and processability of isoimides compared to the rigid imide framework.^[94] Isoimides are often denoted in nomenclature as variants of their parent imides, with the prefix "iso-" indicating the isomeric shift, and they are rarely isolated as stable entities outside specialized contexts like polymer precursors. Spectroscopic analysis provides a clear means of differentiation, as isoimides exhibit infrared carbonyl absorption bands shifted to higher wavenumbers (1790–1840 cm^{-1} for the ester-like C=O and 1680–1730 cm^{-1} for the imine C=N), contrasting with the characteristic imide bands at approximately 1780 cm^{-1} (asymmetric stretch) and 1710 cm^{-1} (symmetric stretch), along with a distinct imide N–C stretch near 1380 cm^{-1}. These spectral signatures arise from the unique vibrational modes of the isoimide's asymmetric connectivity and confirm its presence without ambiguity.^[94]

Synthesis and Interconversion

Isoimides are typically synthesized through O-acylation pathways, where the oxygen atom of an amide or related precursor is preferentially acylated under kinetic control. A common route involves the dehydration of amic acids or their derivatives using condensing agents such as N,N'-dicyclohexylcarbodiimide (DCC) or trifluoroacetic anhydride, leading to intramolecular O-acylation and formation of the isoimide as the kinetic product rather than the thermodynamic imide.^[95] This method is particularly effective for cyclic isoimides and has been applied to generate soluble polyisoimide precursors from polyamic acids.^[96] Alternative syntheses derive from hydroxylamine derivatives, such as N-acyl hydroxylamines, which undergo sulfonylation or acylation to yield isoimide structures via O-acylation of the hydroxyl group followed by rearrangement.^[97] The interconversion of isoimides to imides occurs readily upon heating, driven by a [1,3]-acyl shift that repositions the acyl group from oxygen to nitrogen. For small-molecule acyclic isoimides, this thermal rearrangement proceeds quantitatively at temperatures around 100-150°C, often in high yields without side products.^[98] In polymeric systems, higher temperatures of 250-300°C are typically required, followed by a final cure at 350-400°C to ensure complete conversion, with no volatile byproducts released during the process.^[95] This transformation enhances the thermal stability of the resulting imide while allowing initial processing advantages from the isoimide form. The mechanism of the isoimide-to-imide rearrangement involves either a concerted pericyclic [1,3]-shift through a four-membered transition state or a stepwise pathway via an ion pair intermediate, with the O-to-N acyl migration as the rate-determining step.^[99]^[100] The concerted mechanism is favored under thermal conditions for many substrates, as supported by substituent effects showing electron-donating groups accelerating the process.^[99] Isoimides function as protected forms of imides in organic synthesis, particularly in peptide assembly, where O-acyl isopeptides serve as stable, rearrangeable intermediates that convert to native peptide bonds under mild heating, avoiding epimerization.^[101] Post-2011 developments have highlighted their utility as precursors in advanced polymer materials, offering superior solubility in solvents like tetrahydrofuran and lower melt viscosities compared to direct imides. For example, acetylene-terminated polyisoimides synthesized via anhydride dehydration exhibit excellent processability for thermoset composites, rearranging thermally to high-performance polyimides with comparable mechanical and thermal properties.^[102]^[64]

Amides and Anhydrides

Imides are structurally distinguished from amides by the presence of two carbonyl groups flanking a single nitrogen atom, resulting in the core motif -C(O)-NR-C(O)-, where R can be hydrogen or an alkyl/aryl substituent. In contrast, amides feature only one carbonyl attached to nitrogen, as in the general form R-C(O)-NR'R''. This additional carbonyl in imides exerts a stronger electron-withdrawing effect, significantly increasing the acidity of the N-H bond; for instance, the pKa of phthalimide is 8.3, compared to approximately 16.8 for the N-H of acetamide.^[103]^[104] The enhanced acidity arises from the stabilization of the conjugate base by resonance involving both carbonyls, a feature less pronounced in simple amides.^[105] Relative to anhydrides, which possess the structure R-C(O)-O-C(O)-R', imides can be regarded as nitrogen analogs where the bridging oxygen is substituted by NR. This modification replaces the electrophilic oxygen with a more basic nitrogen lone pair, thereby enhancing the overall stability and reducing reactivity toward nucleophiles. Anhydrides are highly susceptible to hydrolysis, often proceeding rapidly even in neutral water, while imides hydrolyze more slowly under acidic or basic conditions with heating, and amides exhibit the slowest rates among these groups, requiring prolonged reflux in strong acid or base.^[106] The intermediate hydrolysis rate of imides reflects their partial resemblance to both anhydrides (in carbonyl adjacency) and amides (in N-acylation).^[2] A key synthetic interconversion linking these functional groups is the formation of imides from the reaction of anhydrides with primary amines, involving nucleophilic attack by the amine on one carbonyl of the anhydride, followed by dehydration to close the imide ring. This process is exemplified by the condensation of phthalic anhydride with ammonia to yield phthalimide, a reaction that proceeds under mild heating and is widely used in laboratory synthesis.^[106] Electronically, amides, anhydrides, and imides share conjugated C=O π bonds that enable resonance delocalization with the adjacent nitrogen or oxygen, contributing to planarity and rigidity in these motifs while modulating their electrophilicity.^[105]

Other Functional Groups

Carbodiimides, with the general structure R–N=C=N–R where R represents alkyl or aryl groups, feature an unsaturated cumulated diimide linkage that contrasts with the saturated nitrogen in imides (R–C(O)–NH–C(O)–R).^[107] These compounds serve as versatile coupling agents in organic synthesis, particularly for forming amide bonds in peptide and protein conjugation via activation of carboxylic acids.^[107] Unlike the hydrolysis-resistant imides, carbodiimides are reactive toward water, undergoing hydrolysis to form ureas, which limits their stability in aqueous environments but enables their use in controlled dehydration reactions.^[108] Inorganic imides, such as lithium imide (Li₂NH), represent a distinct class from organic counterparts, featuring metal-nitrogen-hydrogen frameworks with an anti-fluorite structure that supports ionic conductivity and compositional flexibility through solid solutions like Li₂₋ₓ(NH₂)ₓ(NH)₁₋ₓ.^[109] These materials are pivotal in hydrogen storage applications, enabling reversible uptake and release of H₂ via amide-imide interconversions, such as LiNH₂ + LiH ⇌ Li₂NH + H₂, with optimal performance at intermediate compositions that lower desorption temperatures.^[109] Ureas (R–NH–C(O)–NH–R) and sulfonamides (R–SO₂–NH–R) share NH-acidic character with imides as nitrogen-containing acyl derivatives but incorporate different central heteroatoms (carbonyl oxygen in ureas versus sulfur in sulfonamides), leading to variations in electronic properties and reactivity.^[110] Imides exhibit greater structural rigidity due to the flanking carbonyl groups that enforce planarity through extended conjugation, distinguishing them from the more flexible conformations typical of ureas and sulfonamides.^[19] Organic analogs like nitrones (R₂C=N⁺–O⁻) extend the scope of nitrogen-oxygen functional groups related to imides, serving as 1,3-dipoles in modern cycloaddition strategies akin to click chemistry for constructing complex nitrogen heterocycles.^[111] Strain-promoted alkyne-nitrone cycloadditions (SPANC) provide bioorthogonal ligation methods, offering rapid and selective alternatives to traditional copper-catalyzed reactions in bioconjugation.^[112] Nitrones also act as precursors to imides through catalyzed additions, such as with cyclopropenones, enabling efficient access to these motifs in synthesis.

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Apr 7, 2022 · Acetamide. -0.51. 4. Urea. 0.18. 4. Thiourea. -0.96. 4. Amidoximes. Ox-. 3.02 ... Phthalimide. 8.30. 18. N-trimethyl cysteine. 8.6. 23.
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https://pubchem.ncbi.nlm.nih.gov/compound/Acetamide#section=Chemical-and-Physical-Properties
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https://www.sciencedirect.com/science/article/pii/B9780444640000000147
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Theoretical and Experimental Study on Carbodiimide Formation - PMC
Jul 22, 2024 · Carbodiimides are important crosslinkers in organic synthesis and are used in the isocyanate industry as modifier additives.
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Carbodiimide - an overview | ScienceDirect Topics
Carbodiimides are one of the most important condensing reagents for preparing several functional groups, such as esters, amides, amidines, carboxylic acids, ...
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Compositional flexibility in Li–N–H materials - PubMed Central - NIH
The Li–N–H materials system consists of lithium salts of anions formed from nitrogen and/or hydrogen, and is most well-known for its favourable hydrogen storage ...
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Prodrugs of Amides, Imides and Other NH-acidic Compounds
The term 'NH-acidic compound,' in the context of this chapter, refers to amides, carbamates, ureas, imides, and sulfonamides (Figure 1).
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Synthesis and Transformations of Nitrones for Organic Synthesis
### Summary of Nitrones' Relation to Imides/Nitrogen Groups and Use in Click Chemistry/Modern Synthesis
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Strain-promoted cycloadditions involving nitrones and alkynes
SPANC reactions involving both acyclic and endocyclic nitrones have been demonstrated to be bioorthogonal click reactions that can serve as rapid alternatives.Missing: analogs imides