Carbamate
In organic chemistry, a carbamate is a category of organic compounds with the general formula Template:Chem2 and structure Template:Chem2, which are formally derived from carbamic acid (Template:Chem2). 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 Template:Chem2 (e.g. ammonium carbamate).<ref name= Jäger>Template:Ullmann</ref>
Polymers whose repeat units are joined by carbamate like groups Template:Chem2 are an important family of plastics, the polyurethanes. See Template:Section link for clarification.
Properties
While carbamic acids are unstable, many carbamate esters and salts are stable and well known.<ref>Template:Cite journal</ref>
Equilibrium with carbonate and bicarbonate
In water solutions, the carbamate anion slowly equilibrates with the ammonium Template:Chem cation and the carbonate Template:Chem or bicarbonate Template:Chem anions:<ref name=burr1912>Template:Cite journal</ref><ref name = clark>Template:Cite journal</ref><ref name=mani2006>Template:Cite journal</ref>
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.<ref name=burr1912/>
Synthesis
Carbamate salts
The salt ammonium carbamate is generated by treatment of ammonia with carbon dioxide:<ref name="Brooks1946">Template:Cite book</ref>
- 2 NH3 + CO2 → NH4[H2NCO2]
Carbamate esters
Carbamate esters also arise via alcoholysis of carbamoyl chlorides:<ref name= Jäger/>
- R2NC(O)Cl + R'OH → R2NCO2R' + HCl
Alternatively, carbamates can be formed from chloroformates and amines:<ref name="Chaturvedi2011">Template:Cite journal</ref>
- R'OC(O)Cl + R2NH → R2NCO2R' + HCl
Carbamates may be formed from the Curtius rearrangement, where isocyanates formed are reacted with an alcohol.<ref name="Chaturvedi2011"/>
- RCON3 → RNCO + N2
- RNCO + R′OH → RNHCO2R′
Natural occurrence
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.<ref>Template:Cite journal</ref>
Hemoglobin
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).<ref>Template:Cite journal</ref>
Urease and phosphotriesterase
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.<ref>Template:Cite journal</ref>
CO2 capture by ribulose 1,5-bisphosphate carboxylase
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.<ref>Template:Cite journal</ref>
Applications
Synthesis of urea
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.<ref name= Jäger/>
Polyurethane plastics
Template:Main 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.Template:Cn
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:<ref>Template:Ullmann</ref>
- RN=C=O + R′OH → RNHC(O)OR′
Carbamate insecticides
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)<ref>Template:Cite journal</ref> (IRAC mode of action 1a).<ref name="IRAC-MoAs-9.4" /> The organophosphate pesticides also inhibit this enzyme, although irreversibly, and cause a more severe form of cholinergic poisoning<ref name=Ullmann>Template:Ullmann</ref> (the similar IRAC MoA 1b).<ref name="IRAC-MoAs-9.4" />
Fenoxycarb has a carbamate group but acts as a juvenile hormone mimic, rather than inactivating acetylcholinesterase.<ref>Template:Cite web</ref>
The insect repellent icaridin is a substituted carbamate.<ref>Template:Cite web</ref>
Besides their common use as arthropodocides/insecticides, they are also nematicidal.<ref name="Updates" /> One such is Oxamyl.<ref name="Updates" />
Sales have declined dramatically over recent decades.<ref name="Updates">Template:Cite journal</ref>
Resistance
Among insecticide resistance mutations in esterases, carbamate resistance most commonly involves acetylcholinesterase (AChE) desensitization, while organophosphate resistance most commonly is carboxylesterase metabolization.<ref name="Comparing">Template:Cite journal</ref>
Carbamate nerve agents
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.<ref name="Handbook_of_Toxicology_of_Chemical_Warfare_Agents">Template:Cite book</ref><ref>Template:Cite book</ref>
Preservatives and cosmetics
Iodopropynyl butylcarbamate is a wood and paint preservative and used in cosmetics.<ref name="Badreshia2002">Template:Cite journal</ref>
Chemical research
Some of the most common amine protecting groups, such as Boc,<ref>Template:Cite book</ref> Fmoc,<ref>Template:Cite book</ref> benzyl chloroformate<ref>Template:Cite book</ref> and trichloroethyl chloroformate<ref>Template:Cite journal</ref> are carbamates.
Medicine
Ethyl carbamate
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.<ref>Template:Cite journal</ref> It is occasionally used in veterinary medicine in combination with other drugs to produce anesthesia.<ref>Template:Cite web</ref>
Carbamate derivatives
Some carbamate derivatives are used in human pharmacotherapy:
- The acetylcholinesterase inhibitor chemical class includes neostigmine and rivastigmine, both of which have a chemical structure based on the natural alkaloid physostigmine.Template:Citation needed
- The tranquilizer, sedative-hypnotic, and muscle relaxant, meprobamate (branded Miltown) was commonly prescribed from the 1950s through the 1970s.<ref>Carbachol Template:Drugs.com. Accessed 27 April 2021.</ref>Template:Failed verification
- Soma (carisoprodol) is a CNS depressant and a prodrug of meprobamate; initially acting primarily as a mildy-sedating muscle relaxant and muscle pain reliever; after 2-3 hours, 20-30% of initial dose converts into active metabolite meprobamate, synergistically working together to potentiate, or add on to/increase, the existing sedation and muscle relaxation and analgesia.Template:Citation needed
- Valmid or Valamin was a carbamate derivative chemically named ethinamate. It was withdrawn from the market in the U.S. and Netherlands around 1990.<ref>Template:Cite web</ref>
- The protease inhibitor darunavir for HIV treatment also contains a carbamate functional group.<ref>Template:DrugBank. Accessed 27 April 2021.</ref>
- Ephedroxane, an aminorex analogue used as a stimulant, also falls into the carbamate category.<ref>Template:Cite journal</ref>
Toxicity
Template:Main Besides inhibiting human acetylcholinesterase<ref>Template:Cite journal</ref> (although to a lesser degree than the insect enzyme), carbamate insecticides also target human melatonin receptors.<ref>Template:Cite journal</ref> The human health effects of carbamates are well documented in the list of known endocrine disruptor compounds.<ref name=":0">Template:Cite journal</ref> 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.<ref name=":0" /> These clinical manifestations of carbamate intoxication are muscarinic signs, nicotinic signs, and in rare cases central nervous system signs.<ref name=":0" />
Sulfur analogues
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.<ref>Template:Cite encyclopedia</ref>
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)<ref name="synth rev a">Template:Cite journal</ref>
- S-thiocarbamates (3), RSC(=O)NR2, where the R–O– group is replaced with an R–S– group<ref name="synth rev a" />
O-thiocarbamates can isomerise to S-thiocarbamates, for example in the Newman–Kwart rearrangement.<ref>Template:Cite journal</ref> File:Carbamates-thiocarbamates-dithiocarbamates-general-2D.png
Etymology
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.<ref>Template:Cite book</ref><ref name=":1">Template:Cite journal</ref> 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."<ref name=":1" /> 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."<ref name=":1" /> 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.<ref>Template:Cite web</ref>
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.<ref name=":2">Template:Cite journal</ref> 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."<ref name=":2" /> 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.<ref>Template:Cite web</ref><ref>Template:Cite journal</ref>
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."<ref>Template:Cite book</ref> 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".<ref>Template:Cite journal</ref> IUPAC provides these statements without citation.
See also
References
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