Inorganic chemistry, acarbamate is a category oforganic compounds with the generalformulaR2NC(O)OR andstructure>N−C(=O)−O−, which are formallyderived fromcarbamic acid (NH2COOH). The term includes organic compounds (e.g., theesterethyl carbamate), formally obtained by replacing one or more of thehydrogen atoms by other organicfunctional groups; as well assalts with the carbamateanionH2NCOO− (e.g.ammonium carbamate).[1]
Polymers whose repeat units are joined by carbamate like groups−NH−C(=O)−O− are an important family ofplastics, thepolyurethanes. See§ Etymology for clarification.
While carbamic acids are unstable, many carbamate esters andsalts are stable and well known.[2]
In water solutions, the carbamate anion slowly equilibrates with theammoniumNH+
4 cation and thecarbonateCO2−
3 orbicarbonateHCO−
3 anions:[3][4][5]
Calcium carbamate is soluble in water, whereascalcium carbonate is not. Adding acalcium salt to an ammonium carbamate/carbonate solution will precipitate some calcium carbonate immediately, and then slowly precipitate more as the carbamate hydrolyzes.[3]
The saltammonium carbamate is generated by treatment ofammonia withcarbon dioxide:[6]
Carbamate esters also arise via alcoholysis ofcarbamoyl chlorides:[1]
Alternatively, carbamates can be formed fromchloroformates andamines:[7]
Carbamates may be formed from theCurtius rearrangement, whereisocyanates formed are reacted with an alcohol.[7]
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]
The N-terminal amino groups ofvaline residues in the α- and β-chains ofdeoxyhemoglobin exist as carbamates. They help to stabilise the protein when it becomes deoxyhemoglobin, and increases the likelihood of the release of remainingoxygen molecules bound to the protein. This stabilizing effect should not be confused with theBohr effect (an indirect effect caused by carbon dioxide).[9]
The ε-amino groups of thelysine residues inurease andphosphotriesterase also feature carbamate. The carbamate derived from aminoimidazole is an intermediate in the biosynthesis ofinosine. Carbamoyl phosphate is generated from carboxyphosphaterather than CO2.[10]
Perhaps the most prevalent carbamate is the one involved in the capture ofCO2 by plants. This process is necessary for their growth. The enzymeribulose 1,5-bisphosphate carboxylase/oxygenase (RuBisCO) fixes a molecule of carbon dioxide as phosphoglycerate in theCalvin cycle. At the active site of the enzyme, aMg2+ ion is bound toglutamate andaspartate residues as well as a lysine carbamate. The carbamate is formed when an uncharged lysineside 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]
Although not usually isolated as such, the saltammonium carbamate is produced on a large scale as an intermediate in the production of the commodity chemicalurea fromammonia andcarbon dioxide.[1]
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 carbamatespolymerize. 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 analcohol with anisocyanate. Commonly, urethanes made by a non-isocyanate route are calledcarbamates.[citation needed]
Polyurethanepolymers 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, anddiols, where the carbamate groups are formed by reaction of the alcohols with theisocyanates:[12]
The so-called carbamateinsecticides feature the carbamate ester functional group. Included in this group arealdicarb (Temik),carbofuran (Furadan),carbaryl (Sevin),ethienocarb,fenobucarb,oxamyl, andmethomyl. These insecticides kill insects by reversibly inactivating the enzymeacetylcholinesterase (AChE inhibition)[13] (IRACmode of action 1a).[14] Theorganophosphate 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 ajuvenile hormone mimic, rather than inactivating acetylcholinesterase.[16]
The insect repellenticaridin is a substituted carbamate.[17]
Besides their common use as arthropodocides/insecticides, they are alsonematicidal.[18] One such isOxamyl.[18]
Sales have declined dramatically over recent decades.[18]
Amonginsecticide resistance mutations inesterases, carbamate resistance most commonly involvesacetylcholinesterase (AChE) desensitization, whileorganophosphate resistance most commonly iscarboxylesterase metabolization.[19]
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 asaldicarb andcarbofuran 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 asT-1123 andEA-3990 were investigated for potential military use asnerve agents. However, since all compounds of this type have aquaternary ammonium group with a permanent positive charge, they have poorblood–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]
Iodopropynyl butylcarbamate is a wood and paint preservative and used in cosmetics.[22]
Some of the most common amine protecting groups, such asBoc,[23]Fmoc,[24]benzyl chloroformate[25] andtrichloroethyl chloroformate[26] are carbamates.
Urethane (ethyl carbamate) was once produced commercially in the United States as achemotherapy 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 produceanesthesia.[28]
Some carbamate derivatives are used in humanpharmacotherapy:
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 knownendocrine 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]
There are two oxygen atoms in a carbamate (1), ROC(=O)NR2, and either or both of them can be conceptually replaced bysulfur.Analogues of carbamates with only one of the oxygens replaced by sulfur are calledthiocarbamates (2 and3). Carbamates with both oxygens replaced by sulfur are calleddithiocarbamates (4), RSC(=S)NR2.[36]
There are two differentstructurally isomeric types of thiocarbamate:
O-thiocarbamates canisomerise toS-thiocarbamates, for example in theNewman–Kwart rearrangement.[38]
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, andwhich 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 thatdoes 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.
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