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Chemical structure of carbamates

In organic chemistry, a carbamate is a category of organic compounds with the general formula R2NC(O)OR and structure >N−C(=O)−O−, which are formally derived from carbamic acid (NH2COOH). The term includes organic compounds (e.g., the ester ethyl carbamate), formally obtained by replacing one or more of the hydrogen atoms by other organic functional groups; as well as salts with the carbamate anion H2NCOO− (e.g. ammonium carbamate).[1]

Polymers whose repeat units are joined by carbamate like groups −NH−C(=O)−O− are an important family of plastics, the polyurethanes. See § Etymology for clarification.

Properties

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While carbamic acids are unstable, many carbamate esters and salts are stable and well known.[2]

Equilibrium with carbonate and bicarbonate

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In water solutions, the carbamate anion slowly equilibrates with the ammonium NH+
4 cation and the carbonate CO2−
3 or bicarbonate HCO−
3 anions:[3][4][5]

H2NCO−2 + 2 H2O ⇌ NH+4 + HCO−3 + OH−
H2NCO−2 + H2O ⇌ NH+4 + CO2−3

Calcium carbamate is soluble in water, whereas calcium carbonate is not. Adding a calcium salt to an ammonium carbamate/carbonate solution will precipitate some calcium carbonate immediately, and then slowly precipitate more as the carbamate hydrolyzes.[3]

Synthesis

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Carbamate salts

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The salt ammonium carbamate is generated by treatment of ammonia with carbon dioxide:[6]

2 NH3 + CO2 → NH4[H2NCO2]

Carbamate esters

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Carbamate esters also arise via alcoholysis of carbamoyl chlorides:[1]

R2NC(O)Cl + R'OH → R2NCO2R' + HCl

Alternatively, carbamates can be formed from chloroformates and amines:[7]

R'OC(O)Cl + R2NH → R2NCO2R' + HCl

Carbamates may be formed from the Curtius rearrangement, where isocyanates formed are reacted with an alcohol.[7]

RCON3 → RNCO + N2
RNCO + R′OH → RNHCO2R′

Natural occurrence

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Within nature carbon dioxide can bind with neutral amine groups to form a carbamate, this post-translational modification is known as carbamylation. This modification is known to occur on several important proteins; see examples below.[8]

Hemoglobin

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The N-terminal amino groups of valine residues in the α- and β-chains of deoxyhemoglobin exist as carbamates. They help to stabilise the protein when it becomes deoxyhemoglobin, and increases the likelihood of the release of remaining oxygen molecules bound to the protein. This stabilizing effect should not be confused with the Bohr effect (an indirect effect caused by carbon dioxide).[9]

Urease and phosphotriesterase

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The ε-amino groups of the lysine residues in urease and phosphotriesterase also feature carbamate. The carbamate derived from aminoimidazole is an intermediate in the biosynthesis of inosine. Carbamoyl phosphate is generated from carboxyphosphate rather than CO2.[10]

CO2 capture by ribulose 1,5-bisphosphate carboxylase

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Perhaps the most prevalent carbamate is the one involved in the capture of CO2 by plants. This process is necessary for their growth. The enzyme ribulose 1,5-bisphosphate carboxylase/oxygenase (RuBisCO) fixes a molecule of carbon dioxide as phosphoglycerate in the Calvin cycle. At the active site of the enzyme, a Mg2+ ion is bound to glutamate and aspartate residues as well as a lysine carbamate. The carbamate is formed when an uncharged lysine side chain near the ion reacts with a carbon dioxide molecule from the air (not the substrate carbon dioxide molecule), which then renders it charged, and, therefore, able to bind the Mg2+ ion.[11]

Carbamate formation is a critical step in the formation of biomass from atmospheric carbon dioxide.

Applications

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Synthesis of urea

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Although not usually isolated as such, the salt ammonium carbamate is produced on a large scale as an intermediate in the production of the commodity chemical urea from ammonia and carbon dioxide.[1]

Polyurethane plastics

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Main article: Polyurethane

Polyurethanes contain multiple carbamate groups as part of their structure. The "urethane" in the name "polyurethane" refers to these carbamate groups; the term "urethane links" describe how carbamates polymerize. In contrast, the substance commonly called "urethane", ethyl carbamate, is neither a component of polyurethanes, nor is it used in their manufacture. Urethanes are usually formed by reaction of an alcohol with an isocyanate. Commonly, urethanes made by a non-isocyanate route are called carbamates.[citation needed]

Polyurethane polymers have a wide range of properties and are commercially available as foams, elastomers, and solids. Typically, polyurethane polymers are made by combining diisocyanates, e.g. toluene diisocyanate, and diols, where the carbamate groups are formed by reaction of the alcohols with the isocyanates:[12]

RN=C=O + R′OH → RNHC(O)OR′

Carbamate insecticides

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The carbamate insecticide Carbaryl.

The so-called carbamate insecticides feature the carbamate ester functional group. Included in this group are aldicarb (Temik), carbofuran (Furadan), carbaryl (Sevin), ethienocarb, fenobucarb, oxamyl, and methomyl. These insecticides kill insects by reversibly inactivating the enzyme acetylcholinesterase (AChE inhibition)[13] (IRAC mode of action 1a).[14] The organophosphate pesticides also inhibit this enzyme, although irreversibly, and cause a more severe form of cholinergic poisoning[15] (the similar IRAC MoA 1b).[14]

Fenoxycarb has a carbamate group but acts as a juvenile hormone mimic, rather than inactivating acetylcholinesterase.[16]

The insect repellent icaridin is a substituted carbamate.[17]

Besides their common use as arthropodocides/insecticides, they are also nematicidal.[18] One such is Oxamyl.[18]

Sales have declined dramatically over recent decades.[18]

Resistance

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Among insecticide resistance mutations in esterases, carbamate resistance most commonly involves acetylcholinesterase (AChE) desensitization, while organophosphate resistance most commonly is carboxylesterase metabolization.[19]

Carbamate nerve agents

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While the carbamate acetylcholinesterase inhibitors are commonly referred to as "carbamate insecticides" due to their generally high selectivity for insect acetylcholinesterase enzymes over the mammalian versions, the most potent compounds such as aldicarb and carbofuran are still capable of inhibiting mammalian acetylcholinesterase enzymes at low enough concentrations that they pose a significant risk of poisoning to humans, especially when used in large amounts for agricultural applications. Other carbamate based acetylcholinesterase inhibitors are known with even higher toxicity to humans, and some such as T-1123 and EA-3990 were investigated for potential military use as nerve agents. However, since all compounds of this type have a quaternary ammonium group with a permanent positive charge, they have poor blood–brain barrier penetration, and also are only stable as crystalline salts or aqueous solutions, and so were not considered to have suitable properties for weaponisation.[20][21]

Preservatives and cosmetics

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Iodopropynyl butylcarbamate is a wood and paint preservative and used in cosmetics.[22]

Chemical research

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Some of the most common amine protecting groups, such as Boc,[23] Fmoc,[24] benzyl chloroformate[25] and trichloroethyl chloroformate[26] are carbamates.

Medicine

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Ethyl carbamate

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Urethane (ethyl carbamate) was once produced commercially in the United States as a chemotherapy agent and for other medicinal purposes. It was found to be toxic and largely ineffective.[27] It is occasionally used in veterinary medicine in combination with other drugs to produce anesthesia.[28]

Carbamate derivatives

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Some carbamate derivatives are used in human pharmacotherapy:

  • Valmid or Valamin was a carbamate derivative chemically named ethinamate. It was withdrawn from the market in the U.S. and Netherlands around 1990.[30]

Toxicity

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Main article: Carbamate poisoning

Besides inhibiting human acetylcholinesterase[33] (although to a lesser degree than the insect enzyme), carbamate insecticides also target human melatonin receptors.[34] The human health effects of carbamates are well documented in the list of known endocrine disruptor compounds.[35] Clinical effects of carbamate exposure can vary from slightly toxic to highly toxic depending on a variety of factors including such as dose and route of exposure with ingestion and inhalation resulting in the most rapid clinical effects.[35] These clinical manifestations of carbamate intoxication are muscarinic signs, nicotinic signs, and in rare cases central nervous system signs.[35]

Sulfur analogues

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There are two oxygen atoms in a carbamate (1), ROC(=O)NR2, and either or both of them can be conceptually replaced by sulfur. Analogues of carbamates with only one of the oxygens replaced by sulfur are called thiocarbamates (2 and 3). Carbamates with both oxygens replaced by sulfur are called dithiocarbamates (4), RSC(=S)NR2.[36]

There are two different structurally isomeric types of thiocarbamate:

  • O-thiocarbamates (2), ROC(=S)NR2, where the carbonyl group (C=O) is replaced with a thiocarbonyl group (C=S)[37]
  • S-thiocarbamates (3), RSC(=O)NR2, where the R–O– group is replaced with an R–S– group[37]

O-thiocarbamates can isomerise to S-thiocarbamates, for example in the Newman–Kwart rearrangement.[38]

Etymology

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The etymology of the words "urethane" and "carbamate" are highly similar but not the same. The word "urethane" was first coined in 1833 by French chemist Jean-Baptiste Dumas.[39][40] Dumas states "Urethane. The new ether, brought into contact with liquid and concentrated ammonia, exerts on this substance a reaction so strong that the mixture boils, and sometimes even produces a sort of explosion. If the ammonia is in excess, all the ether disappears. It forms ammonium hydrochlorate and a new substance endowed with interesting properties."[40] Dumas appears to be naming this compound urethane. However, later Dumas states "While waiting for opinion to settle on the nature of this body, I propose to designate by the names of urethane and oxamethane the two materials which I have just studied, and which I regard as types of a new family, among nitrogenous substances. These names which, in my eyes, do not prejudge anything in the question of alcohol and ethers, will at least have the advantage of satisfying chemists who still refuse to accept our theory."[40] The word urethane is derived from the words "urea" and "ether" with the suffix "-ane" as a generic chemical suffix, making it specific for the R2NC(=O)OR' (R' not = H) bonding structure.[41]

The use of the word "carbamate" appears to come later only being traced back to at least 1849, in a description of Dumas's work by Henry Medlock.[42] Medlock states "It is well known that the action of ammonia on chloro-carbonate (phosgene) of ethyl gives rise to the formation of the substance which Dumas, the discoverer, called urethane, and which we are now in the habit of considering as the ether of carbamic acid."[42] This suggests that instead of continuing with the urethane family naming convention Dumas coined, they altered the naming convention to ethyl ether of carbamic acid. Carbamate is derived from the words "carbamide", otherwise known as urea, and "-ate" a suffix which indicates the salt or ester of an acid.[43][44]

Both words have roots deriving from urea. Carbamate is less-specific because the -ate suffix is ambiguous for either the salt or ester of a carbamic acid. However, the -ate suffix is also more specific because it suggests carbamates must be derived from the acid of carbamate, or carbamic acids. Although, a urethane has the same chemical structure as a carbamate ester moiety, a urethane not derived from a carbamic acid is not a carbamate ester. In other words, any synthesis of the R2NC(=O)OR' (R' not = H) moiety that does not derive from carbamic acids is not a carbamate ester but instead a urethane. Furthermore, carbamate esters are urethanes but not all urethanes are carbamate esters. This further suggests that polyurethanes are not simply polycarbamate-esters because polyurethanes are not typically synthesized using carbamic acids.

IUPAC states "The esters are often called urethanes or urethans, a usage that is strictly correct only for the ethyl esters."[45] But also states, "An alternative term for the compounds R2NC(=O)OR' (R' not = H), esters of carbamic acids, R,NC(=O)OH, in strict use limited to the ethyl esters, but widely used in the general sense".[46] IUPAC provides these statements without citation.

See also

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References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Carbamate

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from Grokipedia
In , carbamates are a class of compounds consisting of salts or esters of (NH₂C(O)OH) or its N-substituted derivatives (R₂NC(O)OH), featuring the characteristic –NH–C(O)–O–. This group arises from the formal reaction of an with or , and carbamate esters are sometimes referred to as urethanes, though the term is most accurately applied to the ethyl derivatives. Carbamates play a pivotal role in various industrial and biological applications due to their versatile reactivity and stability. In , N-methylcarbamate insecticides such as (1-naphthyl methylcarbamate) and are extensively used to control a broad spectrum of pests on crops, acting primarily by reversibly inhibiting the enzyme in , which disrupts function. These compounds are favored over organophosphates for their shorter environmental persistence and lower potential. In , the carbamate motif is a key structural element in numerous approved pharmaceuticals, enhancing stability, , and targeted delivery. Examples include the Alzheimer's treatment , a carbamate that acts as a to boost levels in the ; the anticancer agents and , where the carbamate contributes to their cytotoxic mechanisms; and antibiotics like , a featuring a cyclic carbamate for improved resistance. Carbamates also serve as linkages, enabling controlled release of active species . Beyond agrochemicals and pharmaceuticals, carbamates are fundamental to , forming the repeating –NH–C(O)–O– linkages in polyurethanes, which are synthesized via the reaction of diisocyanates with polyols and are widely employed in foams, coatings, adhesives, and elastomers due to their and versatility. Their presence in these diverse fields underscores the functional group's importance, though toxicity concerns from residues and synthesis hazards necessitate careful handling and ongoing research into safer alternatives.

Introduction

Definition and Nomenclature

Carbamates are organic compounds classified as esters or salts of , which has the molecular formula \ceH2NCO2H\ce{H2NCO2H}. The general formula for carbamates is \ceR2NC(O)OR′\ce{R2NC(O)OR'}, where the two R groups attached to the atom may be or hydrocarbyl substituents, and R' is typically an alkyl or for esters, or a cation (such as a metal ) for salts. This structure derives directly from , where one or both hydrogens on the amino group may be replaced by organic groups, and the acidic is substituted by an alkyl or cationic moiety. Carbamic acid is inherently unstable, readily decomposing into and , and computational studies indicate the neutral form \ceH2NCOOH\ce{H2NCOOH} is the most stable configuration, with the zwitterionic \ce+H3NCOO−\ce{^+H3NCOO^-} being significantly higher in energy. Despite this instability, carbamates themselves are often stable under standard conditions, forming the basis for various derivatives. A key distinction exists between carbamate salts and esters. Salts involve the carbamate anion \ce[NH2CO2]−\ce{[NH2CO2]-} paired with a cation, as in \ce(NH4)[NH2CO2]\ce{(NH4)[NH2CO2]}, a white crystalline solid used in fertilizers. Esters, on the other hand, replace the anionic charge with an alkoxy group, yielding structures like methyl carbamate \ceCH3OC(O)NH2\ce{CH3OC(O)NH2}, a simple compound with applications in . IUPAC nomenclature for carbamates emphasizes substitutive naming rooted in the parent . Unsubstituted esters are designated as alkyl carbamates, such as \ceCH3CH2OC(O)NH2\ce{CH3CH2OC(O)NH2}, commonly referred to as urethane—though "urethane" strictly applies only to the ethyl derivative, with broader use for similar esters historically termed urethans. For N-substituted variants, prefixes indicate the nitrogen substituents, e.g., N-phenylcarbamic acid methyl ester for \ceC6H5NHC(O)OCH3\ce{C6H5NHC(O)OCH3}. Salts follow ionic naming conventions, combining the cation name with "carbamate," as in potassium carbamate. These rules ensure systematic identification while accommodating structural variations.

Historical Development and Etymology

The study of carbamates originated in the early 19th century as part of broader investigations into nitrogenous compounds and the synthesis of organic molecules from inorganic precursors. A pivotal milestone occurred in 1828 when German chemist Friedrich Wöhler reported the synthesis of urea from ammonium cyanate, marking the first laboratory production of an organic compound previously thought to require a vital force. This discovery not only challenged the prevailing theory of vitalism but also spurred research into related structures, including ammonium carbamate, which decomposes to urea and water upon heating—a reaction later utilized in industrial processes. Wöhler's work revolutionized organic chemistry by establishing synthesis as a core method for exploring compound relationships and influenced subsequent research, including his later collaborations with Justus von Liebig. Further developments in the focused on the preparation and properties of , formed by the reaction of and . Although the compound was recognized in chemical literature by the mid-century, the direct conversion of to was first demonstrated in 1870 by Bassarov through heating in sealed tubes at 130–140 °C, providing insight into the equilibrium between these species. This finding built on earlier studies and highlighted carbamates' role in nitrogen chemistry, influencing subsequent applications in fertilizers and synthesis. The of "carbamate" derives from "," a term first recorded in English between and 1865, combining "carb-" from with "-amic" from to denote the NH₂COOH structure. The evolved to distinguish carbamates as salts or esters of this unstable acid. By the late , "carbamate" became standard in chemical terminology, reflecting the field's shift toward systematic naming influenced by figures like .

Chemical Properties

Structure and Bonding

Carbamates possess a with the general formula R₂N–C(=O)–OR', where the central carbonyl carbon is bonded to a atom and an alkoxy group, exhibiting hybrid characteristics of amides and esters. The molecular is stabilized by delocalization involving the and the carbonyl π-system, resulting in three primary contributors: one with a C=O and C–N , a second with charge separation on oxygen and , and a third emphasizing partial character in the C–N linkage. This delocalization imparts partial character to the C–N bond, restricting and leading to rotational barriers of approximately 12–16 kcal/mol, which is 3–4 kcal/mol lower than in typical amides due to the adjacent oxygen atom's electronic and steric influences. X-ray crystallographic studies of simple carbamates reveal characteristic bond lengths consistent with this stabilization. For instance, in ethyl N-phenylcarbamate, the C=O bond measures approximately 1.21 , indicative of strong character, while the C–N bond is shortened to about 1.35 compared to a typical single C–N bond of 1.47 , reflecting the partial nature. Bond angles around the carbonyl carbon are typically near 120–125° for the O=C–N and O=C–O angles, approaching planarity due to the sp² hybridization and effects. The carbamate group is highly polar, with the electronegative oxygen atoms in the carbonyl and alkoxy moieties creating a dipole moment that enhances in polar solvents. The N–H protons (in non-tertiary carbamates) enable hydrogen bonding as donors, while the C=O serves as an acceptor, facilitating intermolecular interactions such as dimer formation or association with or other protic . This polarity and hydrogen-bonding capability contribute to the group's stability and role in molecular recognition. Spectroscopic methods confirm these structural features. In infrared (IR) spectroscopy, the C=O stretching vibration appears as a strong absorption band around 1700 cm⁻¹, slightly higher than in amides due to reduced resonance donation from nitrogen influenced by the alkoxy group. In ¹³C nuclear magnetic resonance (NMR) spectroscopy, the carbonyl carbon resonates at approximately 155–165 ppm, shifted upfield relative to esters (170–180 ppm) owing to the electron-donating nitrogen.

Equilibrium with Carbonates and Bicarbonates

Carbamate salts, formed from the reaction of amines with , exist in equilibrium with and species in aqueous media. For primary or secondary amines (RNH₂ or R₂NH), the initial zwitterionic carbamate intermediate reacts further to form: 2 RNH₂ + CO₂ ⇌ RNH₃⁺ + RNHCOO⁻ The carbamate anion (RNHCOO⁻) is subject to : RNHCOO⁻ + H₂O ⇌ RNH₂ + HCO₃⁻ These equilibria determine the distribution of species in amine-based CO₂ absorption systems and influence the stability of carbamates under physiological conditions. The for carbamate formation (K_carb) for monoethanolamine, for example, is approximately 4.3 at 298 K, decreasing with temperature.

Synthesis

Carbamate Salts

Carbamate salts are ionic compounds formed by the protonation of (NH₂COOH) or its derivatives, typically consisting of or alkylammonium cations paired with carbamate anions (NH₂COO⁻ or RNHCOO⁻). These salts are prepared through several and industrial methods, primarily involving the direct reaction of with , which proceeds via the formation of an intermediate carbamic acid that subsequently deprotonates one amine molecule to yield the salt. A primary route for synthesizing carbamate salts is the reaction of ammonia or primary/secondary amines with CO₂. For ammonia, the process involves the absorption of CO₂ into liquid ammonia, leading to the formation of ammonium carbamate via the equilibrium 2NH₃ + CO₂ ⇌ NH₄[NH₂CO₂]; this reaction is exothermic and often conducted under pressure to favor salt formation, with yields exceeding 90% in industrial settings. Similarly, for alkylamines, the general reaction 2RNH₂ + CO₂ → [RNH₃][RNHCO₂] produces alkylammonium alkylcarbamates, typically carried out in anhydrous solvents or under supercritical CO₂ conditions to enhance solubility and selectivity, achieving up to 80% yields for primary aliphatic amines. These methods are distinct from ester synthesis, as they emphasize ionic product formation without alcohol involvement. Ammonium carbamate is specifically prepared by reacting gaseous CO₂ with excess , often in liquid as the medium to dissolve the reactants and precipitate the salt: NH₃ + CO₂ + NH₃ → NH₄[NH₂CO₂]. This approach is scalable for industrial use, particularly as an intermediate in production, where the salt is generated at 150–200 bar and 180–210°C before . An alternative laboratory method involves the of under pressure, where (NH₂)₂CO + H₂O → NH₂COOH + NH₃ occurs, followed by with a base to isolate the carbamate salt; this route is useful for generating in aqueous systems at elevated temperatures (around 120–150°C) and pressures (10–20 bar), with conversion efficiencies up to 70%. Purification of carbamate salts typically involves recrystallization from alcohols or from reaction mixtures, as they exhibit moderate in water and organic solvents. These salts are thermally unstable, decomposing reversibly above approximately 50–60°C to regenerate CO₂ and the parent amine, which limits their storage to cool, dry conditions; for instance, volatilizes around 60°C with an of decomposition of about 2000 kJ/kg.

Carbamate Esters

Carbamate esters, also known as urethanes, are commonly synthesized in the laboratory by the reaction of an with an alkyl (ROCOCl) in the presence of a base such as or triethylamine, which facilitates the nucleophilic attack by the amine on the carbonyl carbon to form RNHC(O)OR'. This method allows for the preparation of a wide variety of substituted carbamates under mild conditions, typically at in organic solvents like . In industrial applications, particularly for production, carbamate esters are formed by the addition of alcohols or polyols to isocyanates (RNCO), where the alcohol acts as a to yield the –NH–C(O)–O– linkage. This is catalyzed by bases or organometallic compounds and conducted at elevated temperatures (50–150°C) to control and . Alternative green methods have been developed to avoid toxic derivatives, including the direct of amines with CO₂ to form carbamate salts, followed by O-alkylation with alkyl halides or dialkyl under basic conditions. For example, primary amines react with CO₂ and ethyl iodide in the presence of cesium to produce ethyl carbamates in yields up to 90%. These approaches utilize supercritical CO₂ or ionic liquids to improve efficiency and sustainability.

Natural Occurrence

In Hemoglobin and CO2 Transport

In the physiological process of carbon dioxide (CO₂) transport in , carbamates play a crucial role through their formation with . Carbon dioxide reacts with the N-terminal amino groups of hemoglobin's chains, specifically the α-amino groups of the α- and β-subunits, to form via the reversible reaction:
\ceHb−NH2+CO2⇌Hb−NH−COOH\ce{Hb-NH2 + CO2 ⇌ Hb-NH-COOH}
This carbamate linkage occurs preferentially in deoxygenated hemoglobin, facilitating CO₂ carriage from tissues to the lungs. Carbaminohemoglobin accounts for approximately 20-25% of the total CO₂ transported in , with the majority (about 70%) carried as ions and the remainder (5-7%) dissolved directly in plasma. This proportion underscores the significance of carbamate formation in efficient , particularly under varying physiological conditions. The formation of carbamates is influenced by blood pH and oxygenation state, with enhanced binding in acidic, deoxygenated environments typical of peripheral tissues. This pH dependence aligns with the , where decreased (from elevated CO₂ levels) reduces hemoglobin's oxygen affinity, promoting deoxygenation and thereby increasing sites available for carbamate formation to aid CO₂ loading. In the lungs, the reverse occurs: higher and oxygenation favor carbamate dissociation, releasing CO₂ for . Structurally, the carbamate groups formed at the N-terminal residues of the chains contribute to stabilizing the tense (T) state of deoxyhemoglobin through additional salt bridges and electrostatic interactions, which further support the cooperative unloading of oxygen and loading of CO₂. This stabilization enhances the efficiency of respiratory gas transport without requiring enzymatic .

In Enzymes and Metabolic Pathways

Carbamates play crucial roles as intermediates or structural components in several enzymatic mechanisms across metabolic pathways. In the urease, a -dependent metalloenzyme found in , plants, and fungi, the of proceeds through a carbamate intermediate. initially binds to one of the two () via its carbonyl oxygen, polarizing the molecule. A -bound (derived from a bridging molecule deprotonated at Ni2) then acts as a , attacking the carbonyl carbon to form a tetrahedral intermediate. This intermediate collapses, releasing and generating a carbamate coordinated to Ni1, which subsequently decomposes to yield a second and . This mechanism enhances the by over 10^15-fold compared to the uncatalyzed process, facilitating recycling in and contributing to in ureolytic . In the Calvin-Benson-Bassham cycle of , ribulose-1,5-bisphosphate carboxylase/oxygenase (), the most abundant on , relies on carbamylation for activation and catalysis. A CO2 covalently modifies the ε-amino group of a conserved residue (Lys201 in higher ), forming a carbamate that coordinates Mg^2+ ions to stabilize the . This activated carbamylated then binds ribulose 1,5-bisphosphate (RuBP), enolizes it, and facilitates the addition of another CO2 to the C2 position of the enediol form of RuBP. The resulting 2-carboxy-3-keto intermediate is hydrated and cleaved to produce two molecules of 3-phosphoglycerate, incorporating the fixed carbon into sugars. This carbamylation step is essential, as uncarbamylated is inactive, and it underscores the 's dual role in CO2 fixation and oxygenation, with the latter leading to . Carbamoyl phosphate synthetase I (CPS1), the rate-limiting enzyme in the located in the of hepatocytes, generates as a key precursor for synthesis. The mechanism involves two ATP-dependent steps: first, is phosphorylated to form unstable carboxyphosphate, which reacts with to produce (the protonated form of carbamate). This carbamate intermediate is then phosphorylated by a second ATP to yield . Allosteric activation by N-acetylglutamate enhances CPS1 activity, linking detoxification to status. Disruptions in this pathway, such as CPS1 deficiencies, lead to , highlighting its centrality in . Phosphotriesterase (PTE), a zinc-dependent from like diminuta, features a carbamate bridge in its binuclear that supports the of esters, such as pesticides. The carbamate forms from CO2 reacting with the ε-amino group of Lys169, bridging the two Zn^2+ ions and stabilizing the metal center essential for . During , a Zn-bound attacks the atom of the substrate, proceeding through a pentacoordinate that facilitates cleavage of the P-O bond and release of the alcohol leaving group. This structural carbamate enhances metal affinity and catalytic efficiency, enabling PTE's promiscuous activity against a broad range of organophosphates.

Applications

Industrial Processes

The industrial production of represents one of the most significant applications of carbamates, where serves as a critical intermediate in the Bosch-Meiser process. In this process, and react under high pressure and temperature to form via the exothermic reaction 2NH3+CO2→NH2COONH42NH_3 + CO_2 \rightarrow NH_2COONH_4, typically at 170–220 °C and 12.5–25.0 MPa. This intermediate then undergoes dehydration in a subsequent endothermic step, NH2COONH4→(NH2)2CO+H2ONH_2COONH_4 \rightarrow (NH_2)_2CO + H_2O, yielding and , with overall single-pass conversions limited to around 10% due to kinetic barriers. Global production, reliant on this carbamate-mediated route, reached approximately 177 million metric tons in 2024, with capacity exceeding 240 million tons annually as of 2023 and over 90% directed toward agricultural fertilizers. The process is often integrated with synthesis plants to utilize CO₂ byproducts, enhancing efficiency in large-scale operations. Management of byproducts in urea plants focuses on unreacted to minimize waste and emissions. In total recycle configurations, such as the Monte-Catini process, carbamate decomposes in condensers or absorbers into and CO₂, which are then reintroduced to the , achieving near 100% recovery of these components and conversion efficiencies of 95–96%. Effluents containing residual carbamate are treated through and scrubbing to prevent environmental release, with byproducts removed via flash separation and to concentrate the urea solution. Beyond , carbamates play a role in the synthesis of solvents like (DMC), produced via alcoholysis routes involving methyl carbamate intermediates. In one approach, reacts with to form methyl carbamate, which then converts to DMC and over catalysts such as ZnO or compounds at temperatures above 407 K, with yields up to 56% under optimized conditions; this phosgene-free method supports DMC's use in separations and as a .

Polymers and Materials

Carbamates play a central role in as the foundational linkages in , which are synthesized through the reaction of diisocyanates with polyols. This process involves the of hydroxyl groups from polyols to the moieties, forming urethane (carbamate) bonds that constitute the polymer backbone. For instance, (MDI) reacted with (EG) produces flexible foams widely used in cushioning materials. Global production of polyurethanes exceeds 27 million metric tons annually as of , reflecting their versatility in applications such as flexible and rigid foams for furniture and insulation, coatings for surface protection, and elastomers for automotive components. This substantial market scale underscores the economic importance of carbamate-based polymers in modern . To address environmental concerns associated with traditional production involving , phosgene-free routes to polycarbamates have been developed, notably through non- polyurethane (NIPU) synthesis using (DMC). In this approach, DMC reacts with diols to form hydroxy-terminated carbamate oligomers, which are then coupled with diamines via or aminolysis, yielding linear poly(ether urethanes) without isocyanate intermediates. These methods promote by utilizing greener reagents and reducing toxic byproducts. The desirable mechanical and thermal properties of polyurethanes arise primarily from intermolecular hydrogen bonding between the carbamate NH and C=O groups, which enhances chain cohesion and between hard and soft segments. This hydrogen bonding network contributes to high tensile strengths, often exceeding 20 MPa in MDI-based variants, and improved thermal stability, with decomposition temperatures typically above 300°C under inert conditions. Such attributes enable polyurethanes to withstand mechanical stress and elevated temperatures in demanding applications like structural composites.

Pesticides and Insecticides

Carbamate-based pesticides function primarily as insecticides through the reversible inhibition of (AChE), an essential for nerve function in . By binding to the of AChE, carbamates prevent the of the , resulting in its accumulation at synapses. This leads to overstimulation of the , causing symptoms such as tremors, , and death in target pests. Unlike organophosphates, which form irreversible bonds, the carbamate-AChE complex spontaneously hydrolyzes, allowing for enzyme reactivation within hours, which contributes to the relatively lower persistence of these compounds in biological systems. Prominent examples of carbamate insecticides include (commonly known as Sevin), a 1-naphthyl N-methylcarbamate widely used for foliar application; (Temik), a systemic oxime carbamate effective against soil-dwelling pests, though its use has been banned or severely restricted in many countries due to toxicity concerns, including the since 2018; and (Lannate), another oxime carbamate valued for its contact and stomach poison properties. These compounds are typically applied in agricultural settings to control a variety of pests, such as , caterpillars, and beetles on crops including fruits, , and . The global carbamate insecticide market was valued at approximately USD 320 million in 2025, representing about 1.5% of the total market, with historical consumption estimates ranging from 20,000 to 35,000 tonnes annually in the late 1970s and early 1980s, particularly in regions like , , and . They are deployed via sprays, baits, or granular formulations on major crops to manage populations that threaten yield, though their use has declined in some areas due to regulatory restrictions and alternatives. Insecticide resistance to carbamates has been a challenge since the , primarily arising from in the AChE-encoding (ace-1 or ace-2), which reduce the enzyme's sensitivity to inhibition—for instance, the G119S substitution in mosquitoes like . These target-site , often combined with enhanced metabolic detoxification via esterases or cytochrome P450s, have been documented in over 50 , including vectors like mosquitoes and agricultural pests like . Effective management strategies include rotating carbamates with from different chemical classes to delay resistance development and preserve efficacy.

Pharmaceuticals and Medicine

Carbamates have played a significant role in pharmaceutical development, particularly as depressants and prodrugs. , also known as urethane, was historically employed as an and agent in s due to its properties. However, its clinical use has been severely restricted since the mid-20th century owing to its classification as a probable , with primarily occurring via enzymes to the more reactive vinyl carbamate, which contributes to its genotoxic effects. Several carbamate derivatives have been developed as therapeutic agents targeting neurological and musculoskeletal conditions. , introduced in the 1950s, functions as an by binding to the GABA-A receptor, thereby enhancing inhibitory neurotransmission similar to benzodiazepines, and also exhibits and effects. Ethinamate, a short-acting carbamate , was used as a for treating through its sedative- action on the . , an FDA-approved skeletal , alleviates acute musculoskeletal by acting as a ; its effects are largely attributed to its primary metabolite, , which modulates GABA-A receptors to produce sedation and muscle relaxation. The therapeutic mechanisms of many carbamate drugs involve modulation of systems or enzymatic processes. In and muscle relaxants like and , enhancement of GABA-A receptor activity increases chloride ion influx, leading to neuronal hyperpolarization and reduced excitability, which contributes to and relaxant effects. For pain relief, certain carbamates act as inhibitors of amide hydrolase (FAAH), an that degrades endocannabinoids; by blocking this enzyme, they elevate levels, providing effects in models of inflammatory and without the psychoactive side effects of direct agonists. This inhibition parallels the inhibition seen in carbamate insecticides, though adapted for selective therapeutic targeting in humans. Recent advancements since 2020 have expanded carbamate applications in targeted therapies. In , carbamate-based prodrugs and linkers have been incorporated into antibody-drug conjugates (ADCs) to improve stability and tumor-specific release; for instance, self-immolative carbamate linkers enable controlled activation upon lysosomal cleavage, enhancing efficacy against CD19-positive lymphomas while minimizing off-target toxicity. Additionally, , a carbamate converted to the active cytotoxic agent 5-fluorouracil via enzymatic hydrolysis, continues to be refined in combination regimens for and colorectal cancers, with post-2020 studies confirming its role in improving and reducing systemic exposure. In antivirals, carbamate derivatives targeting viral have shown promise; a carbamate-bearing cinnamic compound exhibited potent inhibition of main (Mpro) with an of 5.27 μM against , highlighting their potential for broad-spectrum coronavirus therapies. These developments underscore carbamates' versatility in design for enhanced pharmacokinetics and selectivity.

Toxicity and Environmental Impact

Human Health Effects

Carbamates exert their primary toxic effects on humans through reversible inhibition of (AChE), an critical for hydrolyzing the neurotransmitter acetylcholine, leading to its accumulation at cholinergic synapses and neuromuscular junctions. This overstimulation of muscarinic and nicotinic receptors manifests as the cholinergic toxidrome, commonly remembered by the mnemonic (salivation, lacrimation, urination, defecation, gastrointestinal distress, emesis), along with additional symptoms such as , , , muscle fasciculations, weakness, and in severe cases, or seizures. Acute poisoning typically onset within minutes to hours following high-level exposure, with symptoms often resolving within 24 hours due to the reversible nature of the inhibition, distinguishing carbamates from more persistent organophosphates. Treatment for acute carbamate poisoning focuses on supportive care and specific antidotes: atropine sulfate is administered intravenously to counteract muscarinic effects (initial dose 1-2 mg in adults, titrated to control secretions and ), while (2-PAM) may be used early to reactivate AChE, though its necessity is debated for carbamates alone due to spontaneous decarbamylation. Human exposure to carbamates primarily occurs via occupational routes, such as dermal contact or inhalation during in , and dietary intake through residues on fruits, , and grains. For example, , a common carbamate , has an acute oral LD50 in rats of approximately 300-500 mg/kg, indicating moderate , with human risks heightened by accidental ingestion or prolonged skin exposure. Chronic exposure to certain carbamates poses carcinogenic risks, notably ethyl carbamate (urethane), classified by the International Agency for Research on Cancer (IARC) as Group 2A (probably carcinogenic to humans) based on sufficient evidence in experimental animals and limited evidence in humans. This compound forms DNA adducts via metabolic activation to vinyl carbamate epoxide, a reactive intermediate that binds to DNA, potentially leading to mutations in target organs like the liver, lung, and esophagus. To mitigate health risks, the U.S. Environmental Protection Agency (EPA) establishes tolerance levels for carbamate residues in food, with ongoing assessments ensuring levels remain below thresholds that pose unacceptable risk; for instance, 2023 monitoring confirmed over 99% compliance with these tolerances in domestic produce samples.

Ecological and Environmental Concerns

Carbamate pesticides exhibit relatively low persistence in environmental compartments, with half-lives typically ranging from a few days to several weeks in and , depending on conditions such as , temperature, and microbial activity. For instance, the widely used carbamate has a half-life of 7-28 days and a half-life of approximately 10 days at neutral (7). Degradation primarily occurs via , where the carbamate ester bond cleaves to yield alcohols, amines, and (CO₂), often accelerated by alkaline conditions or microbial action. Bioaccumulation of carbamates is generally minimal owing to their moderate hydrophobicity, with log Kow values around 2 for many compounds (e.g., 2.36 for ), which limits partitioning into fatty tissues. Despite this, carbamates exert significant toxicity on aquatic ecosystems through (AChE) inhibition, disrupting nerve function in and at low concentrations (e.g., chronic exposure levels as low as 0.1 μg/L for some species). This mechanism parallels neurotoxic effects observed in wildlife, contributing to broader ecological disruptions beyond direct human parallels. Post-2020 regulatory developments in the have intensified focus on carbamates amid ongoing pollinator declines, particularly as alternatives to banned neonicotinoids. The 2018 EU ban on outdoor use of three neonicotinoids (, , ) due to bee toxicity has led to increased scrutiny of AChE-inhibiting substitutes like carbamates, with non-renewal of approvals for several, such as (expired 2019) and oxamyl (non-renewed 2023), based on risks to non-target insects including . Under the EU's Farm to Fork Strategy, targets for a 50% reduction in overall use by 2030 further emphasize evaluating carbamate impacts on . Mitigation strategies for carbamate pollution include , where soil bacteria such as and species degrade these compounds via enzymatic and mineralization pathways, achieving up to 90% removal in contaminated soils under optimized conditions. In agricultural settings, practices like establishing vegetated buffer strips along fields can reduce runoff by 50-90%, trapping carbamates in sediments and preventing their transport to surface waters.

Sulfur Analogues

Sulfur analogues of carbamates include thiocarbamates, characterized by the functional group –NH–C(S)–O–, which are used as herbicides and fungicides in , such as triallate and asulam. Dithiocarbamates, featuring –NH–C(S)–S–, serve as fungicides (e.g., maneb, ziram), rubber vulcanization accelerators, and metal chelators in and .

Carbamate Derivatives in Research

Carbamate derivatives continue to be a focal point in research due to their structural versatility, which allows for modulation of pharmacological properties such as stability, , and target specificity. These compounds mimic bonds and serve as prodrugs for amines or alcohols, enhancing hydrolytic stability and delaying first-pass . Recent studies emphasize their role in developing inhibitors for enzymes involved in neurological disorders, cancer, and viral infections, with carbamates integrated into scaffolds to improve potency and reduce . In research, carbamate derivatives have been extensively modified to target cholinesterases, particularly (BChE), as selective inhibitors to alleviate cognitive decline. Over the past decade, substituents like or groups have been appended to the carbamate core, yielding compounds with values in the nanomolar range against BChE while sparing . For instance, hybrids combining carbamates with moieties demonstrated neuroprotective effects in cellular models by reducing amyloid-beta aggregation and . Seminal work has highlighted multitarget-directed ligands, such as carbamate-thioamide hybrids, that inhibit BChE alongside , showing promise in transgenic mouse models of Alzheimer's with improved memory retention. Anticancer research leverages carbamate derivatives for their ability to disrupt dynamics or induce in tumor cells. Carbamate derivatives of melampomagnolide B exhibit potent against cell lines, with GI50 values below 1 μM (e.g., 0.62–0.68 μM for CCRF-CEM). Carbamate derivatives of show activity against colon cancer cells (e.g., ≈6–9 μM for HT-29). High-impact studies also explore carbamate-linked caged xanthones, which enhance drug-like properties and demonstrate submicromolar against cells through activation. In synthetic , O-carbamate groups have emerged as strategic directing metalation groups (DMGs) for regioselective C-H functionalization of aromatic systems. This approach facilitates (DoM) under milder conditions, enabling iterative assembly of polysubstituted arenes and biaryls via cross-coupling reactions like Suzuki-Miyaura. Recent advancements include nickel-catalyzed couplings of naphthyl O-carbamates with boronates, achieving quantitative yields and recyclability over multiple cycles, which streamlines synthesis of complex carbamate-embedded pharmaceuticals. Applications extend to anionic ortho-Fries rearrangements, producing salicylamides with high for downstream material and drug synthesis. Emerging research explores carbamate inhibitors of endocannabinoid-degrading enzymes, such as fatty acid amide hydrolase (FAAH) and (MAGL), for and neuroinflammatory conditions. Carbamate-based covalent inhibitors exhibit prolonged target engagement, with in vivo studies in models showing enhanced endocannabinoid tone and analgesia without psychoactive effects. Additionally, lupeol-3-carbamate derivatives have been synthesized for antitumor evaluation, displaying improved solubility and inhibitory effects on lines such as HepG2 (liver), with IC50 values in the low micromolar range (e.g., 3.13 μM), comparable to some standard agents. These developments underscore the ongoing innovation in carbamate chemistry for therapeutic applications.

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