Carbamate

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Chemical structure of carbamates

A carbamate is an organic compound derived from carbamic acid (NH2COOH). A carbamate group, carbamate ester (e.g., ethyl carbamate), and carbamic acids are functional groups that are inter-related structurally and often are interconverted chemically. Carbamate esters are also called urethanes.

Synthesis[edit]

Carbamic acids are unstable, but the salts of these elusive acids are well known. For example, ammonium carbamate is generate by treatment of ammonia with carbon dioxide

2 NH3 + CO2 → NH4[H2NCO2]

Carbamates also arise via hydrolysis of chloroformamides and subsequent esterification:

R2NC(O)Cl + H2O → R2NCO2H + HCl

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

RNCO + R′OH → RNHCO2R′

Applications and occurrence[edit]

Although most of this article concerns organic carbamates, the inorganic 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.

Carbamates in biochemistry[edit]

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).

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.[1]

CO2 capture by ribulose 1,5-bisphosphate carboxylase[edit]

Perhaps the most important carbamate is the one involved in the capture of CO2 by plants since this process is necessary for their growth. The enzyme ribulose 1,5-bisphosphate carboxylase/oxygenase 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.

Commercial carbamate compounds[edit]

Carbamate insecticides[edit]

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.[2] The organophosphate pesticides also inhibit this enzyme, although irreversibly, and cause a more severe form of cholinergic poisoning.[3]

Fenoxycarb has a carbamate group but acts as a juvenile hormone mimic, rather than inactivating acetylcholinesterase.[4]

The insect repellent icaridin is a substituted carbamate.

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.[5][6]

Polyurethanes[edit]

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.

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:

RN=C=O + R′OH → RNHC(O)OR′

Preservatives and cosmetics[edit]

Iodopropynyl butylcarbamate is a wood and paint preservative and used in cosmetics.[7]

Medicine[edit]

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.[8] It is occasionally used as a veterinary medicine.

In addition, some carbamates are used in human pharmacotherapy, for example, the acetylcholinesterase inhibitors neostigmine and rivastigmine, whose chemical structure is based on the natural alkaloid physostigmine. Other examples are meprobamate and its derivatives like carisoprodol, felbamate, mebutamate, and tybamate, a class of anxiolytic and muscle relaxant drugs widely used in the 1960s before the rise of benzodiazepines, and still used nowadays in some cases.

The protease inhibitor darunavir for HIV treatment also contains a carbamate functional group.

Toxicity[edit]

Carbamate insecticides target human melatonin receptors. [9]

Sulfur analogues[edit]

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.

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)
  • S-thiocarbamates (3), RSC(=O)NR2, where the R–O– group is replaced with an R–S– group

O-thiocarbamates can isomerise to S-thiocarbamates, for example in the Newman–Kwart rearrangement. Carbamates-thiocarbamates-dithiocarbamates-general-2D.png

See also[edit]

References[edit]

  1. ^ Bartoschek, S.; Vorholt, J. A.; Thauer, R. K.; Geierstanger, B. H.; Griesinger, C. (2001). "N-Carboxymethanofuran (carbamate) formation from methanofuran and CO2 in methanogenic archaea: Thermodynamics and kinetics of the spontaneous reaction". Eur. J. Biochem. 267 (11): 3130–3138. doi:10.1046/j.1432-1327.2000.01331.x. 
  2. ^ Fukuto, T. R. (1990). "Mechanism of action of organophosphorus and carbamate insecticides". Environmental Health Perspectives. 87: 245–254. PMC 1567830Freely accessible. 
  3. ^ Metcalf, Robert L. (2005), "Insect Control", Ullmann's Encyclopedia of Industrial Chemistry, Weinheim: Wiley-VCH, doi:10.1002/14356007.a14_263 
  4. ^ "Fenoxycarb". Cornell University. 
  5. ^ Gupta, Ramesh C (ed) (2015). Handbook of Toxicology of Chemical Warfare Agents. Cambridge, MA, USA: Academic Press. pp. 338–339. ISBN 9780128004944. 
  6. ^ Ellison DH. Handbook of Chemical and Biological Warfare Agents (2nd). CRC Press, 2008. pp 105-139. ISBN 9780849314346
  7. ^ Badreshia, S. (2002). "Iodopropynyl butylcarbamate". Am. J. Contact Dermatitis. 13 (2): 77–79. ISSN 1046-199X. doi:10.1053/ajcd.2002.30728. 
  8. ^ Holland, J. R.; Hosley, H.; Scharlau, C.; Carbone, P. P.; Frei, E., III; Brindley, C. O.; Hall, T. C.; Shnider, B. I.; Gold, G. L.; Lasagna, L.; Owens, A. H., Jr; Miller, S. P. (1 March 1966). "A controlled trial of urethane treatment in multiple myeloma" (free fulltext). Blood. 27 (3): 328–42. ISSN 0006-4971. PMID 5933438. 
  9. ^ Popovska-Gorevski, Chem Res Toxicol 2017 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318275/