2,4-Dichlorophenoxyacetic acid, Health effects, Cancer risk
A 1995 panel of 13 scientists reviewing studies on the carcinogenicity of 2,4-D had divided opinions. None of the scientists thought the weight of the evidence indicated that 2,4-D was a "known" or "probable" cause of human cancer. The predominant opinion indicated that it is possible that 2,4-D can cause cancer in humans,  although not all of the panelists believed the possibility was equally likely: one thought the possibility was strong, leaning toward probable, and five thought the possibility was remote, leaning toward unlikely. Two panelists believed it unlikely that 2,4-D can cause cancer in humans.


2,4-Dichlorophenoxyacetic acid, Health effects, Cancer risk
In a prior 1987 report the IARC classified some chlorphenoxy herbicides including 2,4-D, MCPA and 2,4,5-T as a group as class 2B carcinogens - "possibly carcinogenic to humans".


2,4-Dichlorophenoxyacetic acid, Health effects, Contaminants
A July 2013 Four Corners investigation found elevated levels of dioxins in a generic version of 2,4-D, one of Australia's most widely used herbicides. One scientist said the product tested by Four Corners, which was imported from China, had "one of the highest dioxin readings for 2,4-D in the last 10 to 20 years, and could pose potential health risks."


2,4-Dichlorophenoxyacetic acid, Metabolism
When radioactively labeled 2,4-D was fed to livestock, 90% or more of the total radioactive residue (TRR) was shed in urine unchanged or as conjugated forms of 2,4-D. A relatively small portion of 2,4-D was metabolized into dichlorophenol, dichloroanisole, 4-chlorophenoxyacetic acid (6.9% of the TRR in milk), and 2,4-dichlorophenol (5% of the TRR in milk; 7.3% of the TRR in eggs and 4% of the TRR in chicken liver). Residue levels in kidney were the highest.


2,4-Dichlorophenoxyacetic acid, Environmental behavior
Owing to the longevity and extent of use, 2,4-D has been evaluated several times by regulators and review committees.


2,4-Dichlorophenoxyacetic acid, Environmental behavior
2,4-D amine salts and esters are not persistent under most environmental conditions. The degradation of 2,4-D is rapid (half life of 6.2 days) in aerobic mineral soils. 2,4-D is broken down by microbes in soil, in processes that involve hydroxylation, cleavage of the acid side-chain, decarboxylation, and ring opening. The ethyl hexyl form of the compound is rapidly hydrolyzed in soil and water to form the 2,4-D acid. 2,4-D has a low binding affinity in mineral soils and sediment, and in those conditions is considered intermediately to highly mobile, and therefore likely to leach if not degraded.


2,4-Dichlorophenoxyacetic acid, Environmental behavior
In aerobic aquatic environments, the half life is 15 days, while in anaerobic aquatic environments, 2,4-D was moderately persistent to persistent (half life of = 41 to 333 days). 2,4-D has been detected in streams and shallow groundwater at low concentrations, in both rural and urban areas. Breakdown is pH dependent. Some ester forms are highly toxic to fish and other aquatic life.


2,4-Dichlorophenoxyacetic acid, Environmental behavior
"The ester forms of 2,4-D can be highly toxic to fish and other aquatic life. 2,4-D generally has moderate toxicity to birds and mammals, is slightly toxic to fish and aquatic invertebrates, and is practically nontoxic to honeybees" per EPA.


2,4-Dichlorophenoxyacetic acid, Environmental behavior, Microbial breakdown
A number of 2,4-D-degrading bacteria have been isolated and characterized from a variety of environmental habitats. Metabolic pathways for the compound’s degradation have been available for many years, and genes encoding 2,4-D catabolism have been identified for several organisms. As a result of the extensive metadata on environmental behavior, physiology, and genetics, 2,4-D was the first herbicide for which the bacteria actively responsible for in situ degradation were demonstrated. This was accomplished using the technique of DNA-based stable isotope probing, which enables a microbial function (activity), such as degrading a chemical, to be linked with the organism’s identity without the need to culture the organism involved.


2,4-Dichlorophenoxyacetic acid, Regulation
Maximum residue limits were first set in the EU in 2002 and re-evaluated in 2011 by the European Food Safety Authority, which concluded that the codex maximum residue limits were "not expected to be of concern for European consumers". The total chronic exposure represented less than 10% of the acceptable daily intake (ADI). 2,4-D is currently not approved for use on lawns and gardens in Denmark, Norway, Kuwait, and the Canadian provinces of Québec and Ontario. 2,4-D use is severely restricted in the country of Belize. In 2008, Dow AgroScience, LLC, sued the Canadian government for allowing Quebec to ban 2,4-D, but settled in 2011.


2,4-Dichlorophenoxyacetic acid, Regulation
In 2005, the US EPA approved the continued use of 2,4-D. On July 10, 2013, the Pest Management Regulatory Agency in Canada updated the re-evaluation notice of 2,4-D, stating that the 2,4-D registrants had provided it with required data and deemed them acceptable. On April 18, 2012, EPA denied the petition filed November 6, 2008, by the Natural Resources Defense Council  to revoke all tolerances and to cancel all registrations of 2,4-D. EPA stated that recent new study and EPA’s comprehensive review confirmed EPA’s previous finding that the 2,4-D tolerances are safe at anticipated exposure. The estimated annual use of 2,4-D in US agriculture is mapped by the US Geological Service.


2,4-Dichlorophenoxyacetic acid, Regulation
In October 2014, the US EPA registered Enlist Duo, an herbicide containing the less volatile 2,4-D choline salt, glyphosate, and an antidrift agent, for use in six states: Illinois, Indiana, Iowa, Ohio, South Dakota, and Wisconsin. In November 2015, the EPA attempted to withdraw its own approval of Enlist Duo, as a result of legal actions against both the agency and Dow by two U.S. groups. However, while it was implied that the approval was "gone" because of the action, in fact, Enlist Duo was still approved pending a decision by the courts. On January 25, 2016, the US Ninth Circuit Court of Appeals denied EPA's motion to vacate its Enlist Duo registration. Dow stated the product would be available in 15 US states and Canada for the 2016 crop season.


2,4-Dichlorophenoxyacetic acid, Regulation
On 21 August 2013, the Australian Pesticides and Veterinary Medicines Authority (APVMA) banned selected 2,4-D high volatile ester (HVE) products due to their environmental hazards. HVE 2,4-D products had already been banned in Europe and North America for 20 years; low volatile ester products continue to be available in Australia and worldwide. In July 2013 APVMA published their report findings.


2,4-Dichlorophenoxyacetic acid, Genetically modified crops
In 2010, Dow published that it had created genetically modified soybeans made resistant to 2,4-D by insertion of a bacterial aryloxyalkanoate dioxygenase gene, aad1. Dow intended it to be used as an alternative or complement to Roundup Ready crops due to the increasing prevalence of glyphosate-resistant weeds.


2,4-Dichlorophenoxyacetic acid, Genetically modified crops
As of April 2014, genetically modified maize and soybeans resistant to 2,4-D and glyphosate have been approved in Canada. In September 2014, the USDA also approved Dow's maize and soybeans, and in October, the EPA registered the "Enlist Duo" herbicide containing 2,4-D and glyphosate.


2,4-Dihydroxy-1,4-benzoxazin-3-one-glucoside dioxygenase
2,4-dihydroxy-1,4-benzoxazin-3-one-glucoside dioxygenase (EC , BX6 (gene), DIBOA- Glc dioxygenase) is an enzyme with systematic name (2R)-4-hydroxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl beta-D-glucopyranoside:oxygen oxidoreductase (7-hydroxylating). This enzyme catalyses the following chemical reaction


2,4-Dihydroxy-1,4-benzoxazin-3-one-glucoside dioxygenase
The enzyme is involved in the biosynthesis of protective and allelopathic benzoxazinoids in some plants.


2,4-Dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one 2 -D-glucosyltransferase
2,4-Dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one 2-D-glucosyltransferase (EC , uridine diphosphoglucose-2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one 2-glucosyltransferase, BX8, BX9, benzoxazinoid glucosyltransferase, DIMBOA glucosyltransferase) is an enzyme with systematic name UDP-alpha-D-glucose:2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one 2-beta-D-glucosyltransferase. This enzyme catalyses the following chemical reaction


2,4-Dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one 2 -D-glucosyltransferase
The enzyme is involved in the detoxification of the benzoxazinoids, DIBOA (2,4-dihydroxy-2H-1,4-benzoxazin-3(4H)-one) and DIMBOA (2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one).


2,4-Dihydroxybenzoic acid
As a resorcylic acid, it is one of the three isomeric crystalline acids that are both carboxyl derivatives of resorcinol and dihydroxy derivatives of benzoic acid.


2,4-Dihydroxybenzoic acid
It is a degradation product of cyanidin glycosides from tart cherries in cell cultures. It is also a metabolite found in human plasma after cranberry juice consumption.


2,4-Dimethoxybenzaldehyde
2,4-Dimethoxybenzaldehyde (DMBA) is a reagent used to specifically quantify phlorotannins. This product  reacts specifically with 1,3-and 1,3,5-substituted phenols (e.g., phlorotannins) to form a colored product.


2,4-Dimethyl-6-tert-butylphenol
2,4-Dimethyl-6-tert-butylphenol is the organic compound with the formula Me2(tert-Bu)C6H2OH (Me = methyl, tert-Bu = tertiary butyl). It is a colorless oil that is classified as an alkylated phenol.


2,4-Dimethyl-6-tert-butylphenol, Preparation, reactions, uses
It is used as an  antioxidant, e.g. to prevent gumming in fuels, and as an ultraviolet stabilizer. It is used in jet fuels, gasolines, and avgas.


2,4-Dimethyl-6-tert-butylphenol, Preparation, reactions, uses
It is prepared by alkylation of xylenol with isobutylene. This alkylation provides a means to separate 2,4-xylenol from 2,5-xylenol since 2,4-dimethyl-6-tert-butylphenol is insoluble in 10% NaOH but 2,5-dimethyl-6-tert-butylphenol is soluble. Subsequent to separation, the tert-butyl group can be removed in strong acid.


2,4-Dimethyl-6-tert-butylphenol, Tradenames
One of its trade names is Topanol A. It is found in antioxidant mixtures AO-30, AO-31, AO-32, IONOL K72, IONOL K78, IONOL K98, and others.


2,4-Dimethylpentane
2,4-Dimethylpentane is an  alkane with the chemical formula [(H3C)2CH]2CH2. This colorless hydrocarbon is produced in large quantities in oil refineries. It results from the alkylation of isobutane by propylene. Often referred to as "alkylate", it is blended with other gasoline components to give a high octane fuel. Unlike n-heptane, 2,4-dimethylpentane is a desirable fuel because its branched structure allows combustion without knocking.


2,4-Dinitroaniline
2,4-Dinitroaniline is a chemical compound with a formula of C6H5N3O4. It is used as an explosive and as a reagent to detect and characterize aldehydes and ketones.


2,4-Dinitroaniline, Preparation
2,4-Dinitroaniline can be prepared by reaction of 1-chloro-2,4-dinitrobenzene with ammonia.


2,4-Dinitroaniline, Preparation
It can be also prepared by the electrophilic aromatic substitution of aniline. Direct nitration should not be used due to the reactivity of aniline. (i.e. It can be protonated to anilinium or oxidized easily.) Instead the acetyl protection should be used.


2,4-Dinitroaniline, Basicity
Compared to aniline, the basicity of 2,4-dinitroaniline is even weaker. It is due to the electron-withdrawing nature of the nitro groups. This makes the pKa of conjugate acid of 2,4-dinitroaniline being even lower than that of hydronium ions, meaning that it is a strong acid.


2,4-Dinitroaniline, Basicity
The protons in the amino group is also much more acidic than that of aniline.


2,4-Dinitroaniline, Uses
2,4-Dinitroaniline is usually used as an explosive, although the material possess a negative oxygen balance and can be improved by combining it with an oxidizer such as ammonium nitrate. When in pure form, 2,4-Dinitroaniline has a VoD of 4,800 m/s at 1.61 g/cm3 molecular density.


2,4-Dinitroaniline, Uses
It is also used for the manufacture of certain azo dyes and disperse dyes, as well as in printing ink, toner, and the preparation of preservatives. The compound also finds applications as an intermediate in the synthesis of neutral dyes, sulfur dyes, and organic pigments.


2,4-Dinitroaniline, Safety
2,4-Dinitroaniline is moderately toxic, with a lethal dose of 285 mg/kg. However, the main danger is that it is explosive and flammable with heat or friction encouraging these properties.


2,4-Dinitroanisole
2,4-Dinitroanisole (DNAN) is a low sensitivity organic compound. It has an anisole (methoxybenzene) core, with two nitro groups (–NO2) attached.


2,4-Dinitroanisole
It is not explosive itself unless it is mixed with other explosive chemicals in certain ratios. Compared with TNT it has only 90% of the explosive power and is less dense with a higher melting point.


2,4-Dinitroanisole, Properties
2,4-Dinitroanisole crystallises in the monoclinic form. The unit cell has these sizes and angles: a=8.772 Å b=12.645 Å c=15.429 Å 81.89°, cell volume is V=1694 Å3, There are eight molecules in each unit cell, with four positions symmetric. The two asymmetric positions have the molecule bent in different ways. The methyl group can be rotated either at 5° or 13° out of the plane of the benzene ring. The ortho nitro group is rotated at 3° or 35°. The para nitro group is close to parallel with the ring plane.


2,4-Dinitroanisole, Properties
The specific heat of solid 2,4-dinitroanisole is given by Cp (Jmol−1K−1) = 0.3153 + 0.00265T (T in K). At 298.15 K. it is 219.02 Jmol−1K−1 The melting enthalpy is 20.2 kJmol−1 and solidification heat is 19.7 kJmol−1. These can differ so much as the liquid can be supercooled 22.8 °C. The initial decomposition temperature is 295 °C, and the explosion temperature is 312 °C. On explosion the adiabatic temperature rise is 4923 °C. Ignition temperature is 347 °C.


2,4-Dinitroanisole, Reactions
2,4-Dinitroanisole reacts without heat with a potassium cyanide solution to form a red coloured product via the isopurpuric acid reaction. In this cyanide is added in the meta position, and the ortho nitro group is reduced to -NHOH.


2,4-Dinitroanisole, Reactions
In alkaline conditions DNAN can be attacked at the methoxy position with nucleophiles to form Meisenheimer complexes. In these the ring develops a negative charge and another group is attached at the methoxy attachment point. So for example, sodium methoxide can produce the 6,6-dimethoxy-1,3-dinitro-1,3-cyclohexadiene anion.


2,4-Dinitroanisole, Reactions
When heated under pressure with water and ammonia DNAN is converted to 2,4-dinitroaniline.


2,4-Dinitroanisole, Reactions
With iron and acetic acid DNAN nitro groups can be reduced to amines forming 2,4-diaminoanisole.


2,4-Dinitroanisole, Formation
2,4-Dinitroanisole can be formed from p-nitroanisole or o-nitroanisole nitration. Also it can be formed from 1-chloro-2,4-dinitrobenzene by treatment with sodium methoxide (sodium in methanol) or sodium hydroxide with methanol.


2,4-Dinitroanisole, Formation
Over a period of days, alkalies will hydrolyse the ether bond to form 2,4-dinitrophenol.


2,4-Dinitroanisole, Use
2,4-Dinitroanisole is used as an explosive replacing TNT. It is used in explosive mixtures such as IMX-101, IMX-104, PAX-48, PAX-21 and PAX-41 in the spider grenade. It can be melted and cast more safely. It has also been used as a dye ingredient and insecticide.


2,4-Dinitroanisole, Environment
When mixed with soil, 2,4-dinitroanisole is modified by bacteria through the path 2-nitroso-4-nitroanisole, 2-hydroxyamino-4-nitroanisole to 2-amino-4-nitroanisole. This takes place on a time scale of a few weeks. In the human body it is converted to 2,4-dinitrophenol. Recent reports, demonstrated that a Nocardia sp. bacterium was able to mineralize 2, 4-dinitroanisole as a sole carbon source, via well established 2,4-dinitrophenol pathway.


2,4-Dinitrochlorobenzene
2,4-Dinitrochlorobenzene (DNCB) is an organic compound with the formula (O2N)2C6H3Cl. It is a yellow solid that is soluble in organic solvents. It is an important intermediate for the industrial production of other compounds.


2,4-Dinitrochlorobenzene
DNCB is produced commercially by the nitration of p-nitrochlorobenzene with a mixture of nitric and sulfuric acids. Other methods afford the compound less efficiently include the chlorination of dinitrobenzene, nitration of o-nitrochlorobenzene and the dinitration of chlorobenzene.


2,4-Dinitrochlorobenzene, Uses
By virtue of the two nitro groups, the chloride is susceptible to nucleophilic substitution. In this way, the compound is a precursor to many other compounds. Base gives the dinitrophenol, ammonia the dinitroaniline, methoxide the dinitroanisole, and amines the secondary amines.


2,4-Dinitrochlorobenzene, Uses, Laboratory use
DNCB is used as a substrate in GST enzyme activity assays. The molecule is conjugated to a single molecule of reduced glutathione which then absorbs at 340 nm. Affinity of CDNB for each class of GST varies and so it is not a good measure of activity for some forms (e.g. GSTT and GSTZ).


2,4-Dinitrochlorobenzene, Uses, Medical use
DNCB can be used to treat warts with an effective cure rate of 80%. DNCB induces an allergic immune response toward the wart-causing virus.


2,4-Dinitrochlorobenzene, Safety
DNCB induces a type IV hypersensitivity reaction in almost all people exposed to it, so it is used medically to assess the T cell activity in patients. This is a useful diagnostic test for immunocompromised patients. It can also be used to treat warts.


2,4-Dinitrophenol
2,4-Dinitrophenol (2,4-DNP or simply DNP) is an organic compound with the formula HOC6H3(NO2)2. It is a yellow, crystalline solid that has a sweet, musty odor. It sublimes, is volatile with steam, and is soluble in most organic solvents as well as aqueous alkaline solutions. When in a dry form, it is a high explosive and has an instantaneous explosion hazard. It is a precursor to other chemicals and is biochemically active, uncoupling oxidative phosphorylation from the electron transport chain in cells with mitochondria, by allowing protons to pass from the intermembrane space into the mitochondrial matrix.


2,4-Dinitrophenol
Oxidative phosphorylation is a highly regulated step in aerobic respiration that is inhibited, among other factors, by normal cellular levels of ATP. Uncoupling it results in chemical energy from diet and energy stores such as triglycerides being wasted as heat with minimal regulation, leading to dangerously high body temperatures that may develop into heatstroke. Its use as a dieting aid has been identified with severe side-effects, including a number of deaths.


2,4-Dinitrophenol, Uses
Commercially, DNP is used as an antiseptic and as a non-selective bioaccumulating pesticide.


2,4-Dinitrophenol, Uses
DNP is particularly useful as a herbicide alongside other closely related dinitrophenol herbicides like 2,4-dinitro-o-cresol (DNOC), dinoseb and dinoterb. Since 1998 DNP has been withdrawn from agricultural use. Currently, there are no actively registered pesticides containing DNP in the United States or Europe.


2,4-Dinitrophenol, Uses
It is a chemical intermediate in the production of sulfur dyes, wood preservatives and picric acid. DNP has also been used to make photographic developers and explosives (see shellite). DNP is classified as an explosive in the United Kingdom and the United States.


2,4-Dinitrophenol, Uses
Although DNP is widely considered too dangerous for clinical use, its mechanism of action remains under investigation as a potential approach for treating obesity. As of 2015, research is being conducted on uncoupling proteins naturally found in humans.


2,4-Dinitrophenol, Biochemistry
In living cells, DNP acts as a proton ionophore, an agent that can shuttle protons (hydrogen cations) across biological membranes. It dissipates the proton gradient across mitochondria membranes, collapsing the proton motive force that the cell uses to produce most of its ATP chemical energy. Instead of producing ATP, the energy of the proton gradient is lost as heat.


2,4-Dinitrophenol, Biochemistry
DNP is often used in biochemistry research to help explore the bioenergetics of chemiosmotic and other membrane transport processes.


2,4-Dinitrophenol, Biochemistry, Mechanism of action
DNP acts as a protonophore, allowing protons to leak across the inner mitochondrial membrane and thus bypass ATP synthase. This makes ATP energy production less efficient. In effect, part of the energy that is normally produced from cellular respiration is wasted as heat. The inefficiency is proportional to the dose of DNP that is taken. As the dose increases and energy production is made more inefficient, metabolic rate increases (and more fat is burned) in order to compensate for the inefficiency and to meet energy demands. DNP is probably the best known agent for uncoupling oxidative phosphorylation. The "phosphorylation" of adenosine diphosphate (ADP) by ATP synthase gets disconnected or "uncoupled" from oxidation.


2,4-Dinitrophenol, Biochemistry, Mechanism of action
From the Journal of Clinical Toxicology, Volume 44, Issue 3 (2006):


2,4-Dinitrophenol, Biochemistry, Mechanism of action
Dinitrophenol uncouples oxidative phosphorylation, causes release of calcium from mitochondrial stores and prevents calcium re-uptake. This leads to free intracellular calcium and causes muscle contraction and hyperthermia. Dantrolene inhibits calcium release from the sarcoplasmic reticulum which reduces intracellular calcium. The resulting muscle relaxation allows heat dissipation. There is little risk to dantrolene administration. Since dantrolene may be effective in reducing hyperthermia caused by agents that inhibit oxidative phosphorylation, early administration may improve outcome.


2,4-Dinitrophenol, Biochemistry, Pharmacokinetics
Information about pharmacokinetics of DNP in humans is limited. The ATSDR's Toxicological Profile for Dinitrophenols remarks that DNP elimination appears to be rapid except when liver function is impaired. The NEJM remarks that DNP appears to be eliminated in around three to four days, except possibly when the liver and kidneys are damaged. Other papers give a wide array of possible half-lives, ranging from 3 hours to 5–14 days, while still other, more recent papers maintain that the half-life in humans is unknown.


2,4-Dinitrophenol, Hazards, Toxicity
DNP is considered to have high acute toxicity. In March 2020 a UK judge stated "there is no antidote or remedy for DNP once taken. In consequence, DNP has a high mortality rate — of those who presented at hospital between 2007 and 2019 with a history of having taken DNP, 18% died. This puts DNP close to cyanide in terms of its toxicity." Other than increasing metabolic rate, acute oral exposure to DNP has resulted in nausea, vomiting, sweating, dizziness, headache, and loss of weight.


2,4-Dinitrophenol, Hazards, Toxicity
Chronic oral exposure to DNP can lead to the formation of cataracts and skin lesions and has caused effects on the bone marrow, central nervous system, and cardiovascular system. Contact with skin or inhalation can cause DNP poisoning. In 2009, an incident occurred in a Chinese chemical factory and 20 persons suffered acute DNP poisoning.


2,4-Dinitrophenol, Hazards, Toxicity
The factor that limits ever-increasing doses of DNP is not a lack of ATP energy production, but rather an excessive rise in body temperature due to the heat produced during uncoupling. Accordingly, DNP overdose will cause fatal hyperthermia, with body temperature rising to as high as 43.1 °C (109.6 °F) shortly before death. Case reports have shown that an acute administration of 10–20 milligrams per kilogram of body weight in humans can be lethal. The lowest published fatal ingested dose is 4.3 mg/kg. In the three separate publicly published medical management cases, a single dose of few tablets from an online retailer (tablet dose unknown) has proven fatal.


2,4-Dinitrophenol, Hazards, Toxicity
The United Kingdom's Food Standards Agency identifies DNP as "an industrial chemical known to have serious short-term and long-term effects, which can be extremely dangerous to human health" and advises "consumers not to take any product containing DNP at any level. This chemical is not suitable for human consumption." Since February 2017 DNP has been included in Australia SUSMP Schedule 10, "Substances of such a danger to health as to warrant prohibition of sale, supply and use" From December 2018 DNP has been classified as an "illegal poisonous substance" in Russia.


2,4-Dinitrophenol, Hazards, Chemical hazards
A dust explosion is possible with DNP in powder or granular form in the presence of air. DNP may explosively decompose when submitted to shock, friction or concussion, and may explode upon heating. DNP forms explosive salts with strong bases as well as ammonia, and emits toxic fumes of nitrogen dioxide when heated to decomposition. DNP's explosive strength is 81% that of TNT, based on the Trauzl lead block test. DNP was the cause of the 1916 Rainham Chemical Factory explosion which left 7 dead and 69 injured. DNP is listed on the Homeland Security Anti- Terrorism Chemicals of Interest list.


2,4-Dinitrophenol, Synthesis
DNP is produced by hydrolysis of 1-chloro-2,4-dinitrobenzene. Another route of DNP synthesis is by nitration of phenol with nitric acid.


2,4-Dinitrophenol, History and society
DNP was widely used in explosive mixtures around the world. Examples include Shellite in the UK, Tridite in the US, Tridita in Spain, MDPC/DD in France, MABT/ MBT in Italy, and DNP in the USSR. During World War I, 36 munition factory workers in France and 27 in the US lost their lives through DNP poisoning.


2,4-Dinitrophenol, History and society
Three fatalities were reported in dye factories, where DNP was used to make sulfur black dye.


2,4-Dinitrophenol, History and society
DNP was used extensively in diet pills from 1933 to 1938 after Cutting and Tainter at Stanford University made their first report on how the compound substantially increased metabolic rate. This effect occurs via DNP acting as a proton ionophore. After only its first year on the market, Tainter estimated that at least 100,000 people had been treated with DNP in the United States, in addition to many others abroad.


2,4-Dinitrophenol, History and society
In light of the adverse effects and fatal hyperthermia caused by DNP when it was used clinically, the dose was slowly titrated according to personal tolerance, which varies greatly. Concerns about dangerous side-effects and rapidly developing cataracts resulted in DNP being discontinued in the United States by the end of 1938. In 1938, the FDA included DNP in a list of drugs potentially so toxic that they should not be used even under a physician's supervision.


2,4-Dinitrophenol, History and society
"In studies of intermediate-duration oral exposure to 2,4-DNP, cases of death from agranulocytosis (described in the discussion of Hematological Effects) have been attributed to 2,4-DNP. These cases occurred during the usual dosing regimens for weight loss, employing increasing doses in one case from 2.9 to 4.3 mg/kg/day of 2,4-DNP for 6 weeks (Dameshek and Gargill 1934); a dose of 1.03 mg/kg/day 2,4-DNP for 46 days in another case (Goldman and Haber 1936); and in another, from 0.62 to 3.8 mg/kg/day 2,4-DNP as sodium 2,4-DNP for 41 days (Silver 1934). In all cases, the patients were under medical supervision."


2,4-Dinitrophenol, History and society
Back in 1952 UK enacted new  to control very dangerous poisons as DNP and DNOC.


2,4-Dinitrophenol, History and society
DNP, however, continues to be used by some bodybuilders and athletes to rapidly lose body fat. Fatal overdoses include cases of accidental exposure, suicide, and excessive intentional exposure (overdose). The substance's use as a dieting aid has also led to a number of accidental fatalities, including 31 confirmed DNP-related deaths in the UK since 2007. Annual Reports of the American Association of Poison Control Centers identify 22 DNP poisoning fatalities between 2013 and 2019 in the US. The Swedish Poisons Information Centre has reported three fatal DNP cases between June 2012 and May 2013. "Forensic analysis of DNP is not routinely performed so the true number of DNP deaths may be higher." DNP may not be detected in post mortem blood samples.


2,4-Dinitrophenol, History and society
In 2003, a vendor of DNP was sentenced to five years in prison for mail fraud, with the FDA's OCI investigators having gathered evidence that the vendor's encapsulation of DNP was neither accurate nor sanitary. One of his customers died and another was hospitalized in a coma for more than 10 days. In 2018, a seller in the United Kingdom was convicted of manslaughter for selling DNP as "fatburner" for human consumption. The conviction was sent to retrial in 2020 by the English Court of Appeal, where the seller was, once again, convicted of gross negligence manslaughter.


2,4-Dinitrophenol, History and society
In 2019, a company selling DNP in the UK was found "guilty of placing an unsafe food product on the market" and fined £100,000. The director of the company was given a suspended prison sentence. A seller in California was sentenced to three years in prison for selling DNP as diet pills. In 2020, a man from North Carolina was sentenced to the maximum sentence of seven years in prison after three of his customers died from DNP poisoning. In 2021 a woman from Texas was sentenced to 6 months in federal prison for selling DNP to consumers.


2,4-Dinitrophenylhydrazine
2,4-Dinitrophenylhydrazine (DNPH) is the organic compound C6H3(NO2)2NHNH2. Dinitrophenylhydrazine is a red to orange solid. It is a substituted hydrazine. The solid is relatively sensitive to shock and friction. For this reason dinitrophenylhydrazine is usually handled as a wet powder. DNPH is a precursor to the drug Sivifene.


2,4-Dinitrophenylhydrazine, Synthesis
It can be prepared by the reaction of hydrazine sulfate with 2,4-dinitrochlorobenzene:


2,4-Dinitrophenylhydrazine, DNP test
DNPH is a reagent in instructional laboratories on qualitative organic analysis. Brady's reagent or Borche's reagent,   is prepared by dissolving 2,4-dinitrophenylhydrazine in a solution containing methanol and some concentrated sulfuric acid. This  solution is used to detect ketones and aldehydes. A positive test is signalled by the formation of a yellow, orange or red precipitate of the dinitrophenylhydrazone. Aromatic carbonyls give red precipitates whereas aliphatic carbonyls give more yellow color. The reaction between 2,4-dinitrophenylhydrazine and a generic ketone to form a hydrazone is shown below:


2,4-Dinitrophenylhydrazine, DNP test
This reaction is, overall, a condensation reaction as two molecules joining together with loss of water. Mechanistically, it is an example of addition-elimination reaction: nucleophilic addition of the -NH2 group to the C=O carbonyl group, followed by the elimination of a H2O molecule:


2,4-Dinitrophenylhydrazine, DNP test
DNP-derived hydrazones have characteristic melting points, facilitating identification of the carbonyl. In particular, the use of 2,4-dinitrophenylhydrazine was developed by Brady and Elsmie. Modern spectroscopic and spectrometric techniques have superseded these techniques.


2,4-Dinitrophenylhydrazine, DNP test
Dinitrophenylhydrazine does not react with other carbonyl-containing functional groups such as carboxylic acids, amides, and esters, for which there is resonance-associated stability as a lone-pair of electrons interacts with the p orbital of the carbonyl carbon resulting in increased delocalization in the molecule. This stability would be lost by addition of a reagent to the carbonyl group. Hence, these compounds are more resistant to addition reactions. Also, with carboxylic acids, there is the effect of the compound acting as a base, leaving the resulting carboxylate negatively charged and hence no longer vulnerable to nucleophilic attack.


2,4-Dinitrophenylmorphine
2,4-Dinitrophenylmorphine is an analog of morphine in which a hydroxyl group is substituted with a dinitro phenoxy group.


2,4-Dinitrophenylmorphine, Properties
Being an analog of morphine, it would be expected to have the same effects on the body as a typical opioid. Also, as dinitrophenol is a metabolic and respiratory stimulant, this morphine derivative was invented in Austria in 1931 as a narcotic analgesic with less potential to depress respiration.


2,4-Dinitrotoluene
2,4-Dinitrotoluene (DNT) or dinitro is an organic compound with the formula C7H6N2O4. This pale yellow crystalline solid is well known as a precursor to trinitrotoluene (TNT) but is mainly produced as a precursor to toluene diisocyanate.


2,4-Dinitrotoluene, Isomers of dinitrotoluene
Six positional isomers are possible for dinitrotoluene. The most common one is 2,4-dinitrotoluene. The nitration of toluene gives sequentially mononitrotoluene, DNT, and finally TNT. 2,4-DNT is the principal product from dinitration, the other main product being about 30% 1,3-DN2-T. The nitration of 4-nitrotoluene gives 2,4-DNT.


2,4-Dinitrotoluene, Applications
Most DNT is used in the production of toluene diisocyanate, which is used to produce flexible polyurethane foams. DNT is hydrogenated to produce 2,4-toluenediamine, which in turn is phosgenated to give toluene diisocyanate. In this way, about 1.4 billion kilograms are produced annually, as of the years 1999–2000. Other uses include the explosives industry. It is not used by itself as an explosive, but some of the production is converted to TNT.


2,4-Dinitrotoluene, Applications
Dinitrotoluene is frequently used as a plasticizer, deterrent coating, and burn rate modifier in propellants (e.g., smokeless gunpowders). As it is carcinogenic and toxic, modern formulations tend to avoid its use. In this application it is often used together with dibutyl phthalate.


2,4-Dinitrotoluene, Toxicity
Dinitrotoluenes are highly toxic with a threshold limit value (TLV) of 1.5 mg/m3. It converts hemoglobin into methemoglobin.


2,4-Dinitrotoluene, Toxicity
2,4-Dinitrotoluene is also a listed hazardous waste under 40 CFR 261.30. Its United States Environmental Protection Agency (EPA) Hazardous Waste Number is D030. The maximum concentration that may be contained to not have toxic characteristics is 0.13 mg/L.


2,4-Dithiapentane
2,4-Dithiapentane is an organosulfur compound. It is a colorless liquid with a strong odor.


2,4-Dithiapentane
2,4-Dithiapentane is the dimethyldithioacetal of formaldehyde. It is prepared by the acid-catalyzed condensation of methyl mercaptan, the main aromatic compound in both halitosis and foot odor and a secondary compound in flatulence, with formaldehyde.


2,4-Dithiapentane
2,4-Dithiapentane is found as an aromatic component in some truffle varietals. A synthetic version is used as the primary aromatic additive in commercial truffle products, such as truffle oil, truffle butter, truffle salt, pastes, etc. It has also been found to occur naturally in rotting wood of some species in genus Lecythis.


2,4-Dithiapentane, Notes and references
This article about an organic compound is a stub. You can help Wikipedia by .


2,4-Lutidine
2,4-Lutidine is a heterocyclic organic compound with the formula (CH3)2C5H3N. It is one of several dimethyl-substituted derivatives of pyridine, all of which are referred to as lutidines. It is a colorless liquid with mildly basic properties and a pungent, noxious odor. The compound has few uses.


2,4-Lutidine, Biodegradation
The biodegradation of pyridines proceeds via multiple pathways. Although pyridine is an excellent source of carbon, nitrogen, and energy for certain microorganisms, methylation significantly retards degradation of the pyridine ring.


2,4-Xylidine
2,4-Xylidine is an organic compound with the formula C6H3(CH3)2NH2. It is one of several isomeric xylidines. It is a colorless viscous liquid. Commercially significant derivatives include the veterinary drug cymiazole and the colorant Pigment Yellow 81.


2,4-Xylidine
It is prepared by nitration of m-xylene followed by hydrogenation.


2,4-diaminopentanoate dehydrogenase
In enzymology, a 2,4-diaminopentanoate dehydrogenase (EC ) is an enzyme that catalyzes the chemical reaction


2,4-diaminopentanoate dehydrogenase
The 4 substrates of this enzyme are 2,4-diaminopentanoate, H2O, NAD+, and NADP+, whereas its 5 products are 2-amino-4-oxopentanoate, NH3, NADH, NADPH, and H+.


2,4-diaminopentanoate dehydrogenase
This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-NH2 group of donors with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is 2,4-diaminopentanoate:NAD(P)+ oxidoreductase (deaminating). This enzyme is also called 2,4-diaminopentanoic acid C4 dehydrogenase. This enzyme participates in 3 metabolic pathways: lysine degradation, arginine and proline metabolism, and d-arginine and d-ornithine metabolism.


2,4-dichlorobenzoyl-CoA reductase
In enzymology, a 2,4-dichlorobenzoyl-CoA reductase (EC ) is an enzyme that catalyzes the chemical reaction


2,4-dichlorobenzoyl-CoA reductase
The 3 substrates of this enzyme are 4-chlorobenzoyl-CoA, NADP+, and HCl, whereas its 3 products are 2,4-dichlorobenzoyl-CoA, NADPH, and H+.


2,4-dichlorobenzoyl-CoA reductase
This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-CH group of donor with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is 4-chlorobenzoyl-CoA:NADP+ oxidoreductase (halogenating). This enzyme participates in 2,4-dichlorobenzoate degradation.


2,4-dichlorophenol 6-monooxygenase
In enzymology, a 2,4-dichlorophenol 6-monooxygenase (EC ) is an enzyme that catalyzes the chemical reaction


2,4-dichlorophenol 6-monooxygenase
The 4 substrates of this enzyme are 2,4-dichlorophenol, NADPH, H+, and O2, whereas its 3 products are 3,5-dichlorocatechol, NADP+, and H2O.


2,4-dichlorophenol 6-monooxygenase
This enzyme belongs to the family of oxidoreductases, specifically those acting on paired donors, with O2 as oxidant and incorporation or reduction of oxygen. The oxygen incorporated need not be derived from O2 with NADH or NADPH as one donor, and incorporation of one atom o oxygen into the other donor. The systematic name of this enzyme class is 2,4-dichlorophenol,NADPH:oxygen oxidoreductase (6-hydroxylating). Other names in common use include 2,4-dichlorophenol hydroxylase, and 2,4-dichlorophenol monooxygenase. This enzyme participates in 1,4-dichlorobenzene degradation. It employs one cofactor, FAD.


2,4-dienoyl-CoA reductase 1
2,4-dienoyl-CoA reductase 1 is a protein that in humans is encoded by the DECR1 gene.


2,4-dienoyl-CoA reductase 1, Function
This gene encodes an accessory enzyme which participates in the beta-oxidation and metabolism of unsaturated fatty enoyl-CoA esters.


2,4-dienoyl-CoA reductase 1, Further reading
This article incorporates text from the United States National Library of Medicine, which is in the public domain.


2,4-dienoyl-CoA reductase 1, Further reading
This article on a gene on human chromosome 8 is a stub. You can help Wikipedia by .


2,5-Bis(hydroxymethyl)furan
2,5-Bis(hydroxymethyl)furan (BHMF) is a heterocyclic organic compound, and is a derivative of a broader class of compounds known as furans. It is produced from cellulose and has received attention as a biofeedstock. It is a white solid, although commercial samples can appear yellowish or tan.


2,5-Bis(hydroxymethyl)furan, Synthesis
2,5-BHMF may be obtained from the reduction of the formyl group of 5-hydroxymethylfurfural (HMF). HMF is the product of acid-catalyzed dehydration of fructose. Fructose is both an isomer of and a derivative of glucose, which can be derived from the hydrolysis of cellulose. The reduction is catalyzed by nickel, copper chromite, platinum oxide, cobalt oxide, or molybdenum oxide, and sodium amalgam, under high temperatures and high hydrogen pressure. Hydrogenation in the presence of a copper or platinum catalyst in an aqueous environment gives 2,5-BHMF as the main product. Under more forcing conditions, the furan ring is reduced as well, resulting in 2,5-bis(hydroxymethyl)tetrahydrofuran.


2,5-Bis(hydroxymethyl)furan, Applications
Functioning as a diol, 2,5-BHF has applications in the manufacture of polyurethane foams and polyesters.


2,5-Bis(hydroxymethyl)pyrrole
2,5-Bis(hydroxymethyl)pyrrole is an organic chemical compound with formula C6H9O2N, or (HOCH2)2(C4H3N). Its molecule can be described as that of pyrrole C4H5N with hydroxymethyl groups HO−CH2− replacing the two hydrogen atoms adjacent to the nitrogen atom.


2,5-Bis(hydroxymethyl)pyrrole
The compound is a white solid, soluble in water and acetone. It is stable in alkaline solutions, but otherwise tends to polymerize by self-condensation. The compound was used as an intermediate in the synthesis of hexahydroporphine ("unsubstituted porphyrinogen"), the core of uroporphyrinogen III, precursor of many critically important biological products such as hemoglobin and chlorophyll.


2,5-Bis(hydroxymethyl)pyrrole, Preparation
The compound can be synthesized by formylation of pyrrole followed by reduction of the resulting pyrrolecarboxaldehyde.


2,5-Diamino-6-hydroxy-4-(5-phosphoribosylamino)pyrimidine
2,5-diamino-6-hydroxy-4-(5-phosphoribosylamino)pyrimidine is a metabolite in the purine metabolism, formed by the hydrolysis of GTP by GTP cyclohydrolase II. Alternatively two separate enzymes can carry out this reaction, initially GTP cyclohydrolase IIa hydrolyses the 8,9 bond to form 2-Amino-5-formylamino-6-(5-phospho-D-ribosylamino)pyrimidin-4(3H)-one, followed by de-formylation by 2-amino-5-formylamino-6-ribosylaminopyrimidin-4(3H)-one 5'-monophosphate deformylase. 2,5-diamino-6-hydroxy-4-(5-phosphoribosylamino)pyrimidine is deaminated by Diaminohydroxyphosphoribosylaminopyrimidine deaminase to form 5-amino-6-(5-phosphoribosylamino)uracil.


2,5-Diaminotoluene
2,5-Diaminotoluene is an organic compound with the formula C6H3(NH2)2CH3. It is one isomer of six with this formula. 2,5-Diaminotoluene is a colorless crystalline solid, although commercial samples are often colored owing to air oxidation. It is commonly used in hair coloring.


2,5-Diaminotoluene, Formation and use
2,5-Diaminotoluene is prepared through electrolytic reduction of 2,5-dinitrotoluene. Other methods include the reductive cleavage of 4-amino-2,3'-dimethylazobenzene as well as the condensation of 2-amino-1-methylbenzene and toluene-4-sulphonyl chloride to produce 4-toluenesulphono-2-toluidide which is then coupled with diazotized aminobenzenesulphonic acid and reduced.


2,5-Diaminotoluene, Formation and use
2,5-Diaminotoluene is a substitute for phenylenediamine (1,4-diaminobenzene) in commercial hair dyes. It is preferred because of its lower toxicity. However, many home hair dyes still use phenylenediamine. In these applications, these diamines function as a primary intermediate, which means that it is first oxidized with hydrogen peroxide and then combined with a coupler to form the hair dye. 2,5-Diaminotoluene is commonly used to produce black, drab and warm browns, and shades of blonde and gray hair dyes.


2,5-Diaminotoluene, Formation and use
2,5-Diaminotoluene is also known to be used in the production of dyes for textiles, furs, leathers, biological stains and indicators, wood stains, and pigments. Two examples of dyes produced by 2,5-diaminotoluene are Cl Basic Red 2 and Cl Acid Brown 103.


2,5-Dichloroaniline
2,5-Dichloroaniline is an organic compound with the formula C6H3Cl2NH2. One of six isomers of dichloroaniline, it is a colorless solid that is insoluble in water. It is produced by hydrogenation of 1,4-dichloro-2-nitrobenzene. It is a precursor to dyes and pigments, e.g., Pigment Yellow 10.


2,5-Dihydrofuran
2,5-Dihydrofuran is an organic compound classified as a monounsaturated derivative of furan. It is a colorless, volatile liquid. It can be produced by the rearrangement of the epoxide of butadiene.


2,5-Dihydroxy-1,4-benzoquinone
2,5-Dihydroxy-1,4-benzoquinone or 2,5-dihydroxy-para-benzoquinone is an organic compound with formula C6H4O4, formally derived from 1,4-benzoquinone by replacing two hydrogen atoms with hydroxyl (OH) groups. It is one of seven dihydroxybenzoquinone isomers. It is a yellow solid with planar molecules that exhibits ferroelectric properties.


2,5-Dihydroxy-1,4-benzoquinone
The compound is a weak acid: one or both hydroxyls can lose a proton to yield the anions C6H3O−4 (pKa1 = 2.95) and C6H2O2−4 (pKa2 = 4.87), respectively. The latter forms a variety of metal complexes, functioning as a binucleating ligand.


2,5-Dihydroxy-1,4-benzoquinone
The compound has been identified as partly responsible for the color of aged cellulosic materials.


2,5-Dihydroxycinnamic acid
2,5-Dihydroxycinnamic acid is a hydroxycinnamic acid. It is an isomer of caffeic acid.


2,5-Dihydroxycinnamic acid, Preparation
2,5-Dihydroxycinnamic acid is produced by Elbs persulfate oxidation of o-Coumaric acid.


2,5-Diketopiperazine
2,5-Diketopiperazine, also known as piperazine-2,5-dione and as the cyclodipeptide cyclo(Gly-Gly), is an organic compound and the smallest cyclic dipeptide that consists of a six-membered ring containing two amide linkages where the two nitrogen atoms and the two carbonyls are at opposite positions in the ring. It was first synthesized by Curtius and Gloebel in 1888 and was the first compound containing a peptide bond to be studied by X-ray crystallography in 1938. It occurs in cocoa and bread and has a metallic and bitter taste.


2,5-Diketopiperazine
2,5-Diketopiperazines (2,5-DKPs) which include mono- and disubstituted 2,5-diketopiperazines, their annulated, spiro-annulated and bridged derivatives are amongst the most ubiquitous peptide derivatives found in nature. They are found in fermentation broths and yeast cultures and this subunit is often found alone or embedded in larger more complex architectures in a variety of natural products isolated from fungi, bacteria, plants, and mammals, and their core structure occurs in several drugs. In addition, they are often produced as degradation products of polypeptides, especially in processed food and beverages, and  have been identified in the contents of comets.


2,5-Diketopiperazine, Occurrence as natural products
There is a widespread occurrence of the 2,5-diketopiperazine core in biologically active natural products. The most structurally diverse 2,5-diketopiperazine natural products are based on tryptophan and proline modified by heterocyclisation and isoprenyl addition. These range from the hepatoxic brevianamide F (cyclo(L-Trp-L-Pro)) to the annulated tremorogenic verruculogen and the spiro-annulated spirotryprostatin B which represent a promising class of antimitotic arrest agents, to the structurally complex (+)-stephacidin A, a bridged 2,5-diketopiperazine that possess a unique bicyclo[2.2.2]diazaoctane core ring system and is active against the human colon HCT-116 cell line.


2,5-Diketopiperazine, Occurrence as natural products
Other bridged 2,5-diketopiperazines include bicyclomycin, an antibacterial agent used as food additives to prevent diarrhea in animals while the thio derivatives such as the cytotoxic bridged epipolythiodioxopiperazine are represented by gliotoxin. The unsaturated derivatives are illustrated by phenylahistin the anti-cancer microtubule binding agent, and the mycotoxin roquefortine C found in blue cheeses.


2,5-Diketopiperazine, Occurrence in foods and beverages
2,5-Diketopiperazines are often formed during chemical and thermal processing of food and beverages as the degradation products of polypeptides. They have been detected in stewed beef, beer, bread, Awamori spirits, cocoa, chicken essence, roasted coffee, Comte cheese, dried squid, aged saki and yeast extract. In food systems, 2,5-diketopiperazines have been shown to be important sensory compounds contributing to the taste of the final products and being perceived as astringent, salty, grainy, metallic or bitter. Although these range from proline, aromatic, aliphatic to polar 2,5-diketopiperazines, the proline 2,5-diketopiperazines are the most abundant and structurally diverse 2,5-diketopiperazines found in food.


2,5-Diketopiperazine, Occurrence in foods and beverages
The valine derivative cyclo(L-Val-L-Pro) at a concentration of 1742 ppm, was identified as the most important bitter 2,5-diketopiperazine contributing to the bitter taste of roasted cocoa. It has also been found as one of the major 2,5-diketopiperazines in autolyzed yeast extract and stewed beef and is also present in chicken essence and coffee. It has also been isolated from a variety of marine microorganisms and has been identified as an active LasI quorum-sensing signal molecule important for the plant growth promotion by Pseudomonas aeruginosa.


2,5-Diketopiperazine, Occurrence in foods and beverages
The most studied of all the simple 2,5-diketopiperazines is the histidyl-proline 2,5-diketopiperazine cyclo(L-His-L-Pro) which is found in a variety of foods, with particularly high concentrations in fish and fish products. It is well absorbed orally, and crosses the blood–brain barrier via a non-saturable mechanism. It also occurs in humans as a metabolite from the thyrotropin-releasing hormone (TRH) and exhibits a wide variety of central nervous system, endocrine, electrophysiological, and cardiovascular effects. Derivatives of cyclo(L-His-L-Pro) have been studied extensively to develop therapeutic agents for neurodegeneration.


2,5-Diketopiperazine, Structure and conformation
The 2,5-diketopiperazines (2,5-DKPs) are the smallest possible cyclic peptides, which are peptidomimetic in nature and bear resemblance with a constrained protein beta turn. These cyclic dipeptides incorporate both donor and acceptor groups for hydrogen bonding and are small, conformationally constrained heterocyclic scaffolds in which diversity can be introduced at up to six positions and stereochemistry controlled at up to four positions, and they are stable to proteolysis. These characteristics enable them to bind to a wide range of receptors which result in a widespread class of biologically active natural compounds. They have a rigid backbone, which can mimic a preferential peptide conformation and contain constrained amino acids embedded within their structures without the unwanted physical and metabolite properties of peptides. This improves their bioavailability and resistance to enzymatic degradation in comparison to their linear analogues.


2,5-Diketopiperazine, Structure and conformation
These conformationally constrained heterocycles are flexible because the six-membered ring can exist in an essentially flat conformation 1 or a slightly puckered boat form 2, with only a few kcal/mol difference in energy between the boat and planar forms. In addition, the 2,5-DKPs can be configured as both cis and trans isomers. As a consequence of their predominant biosynthetic origin from L-α-amino acids most naturally occurring 2,5-DKPs are cis configured as the cyclo(L-Xaa-L-Yaa) isomers. However, 2,5-DKPs epimerize under basic, acidic and thermal conditions.


2,5-Diketopiperazine, Structure and conformation
The composition of the cis and trans isomers in the equilibrium state varies widely depending on the bulk of the side chains, if a ring (e.g. proline) is present, or if the nitrogen atoms are alkylated . Although epimerization was historically an issue in the synthesis of 2,5-DKPs, several mild methods have been developed recently that avoid epimerization.


2,5-Diketopiperazine, Synthesis
In the synthesis of 2,5-diketopiperazines there are essentially three methods of ring closure: amide bond formation, N-alkylation and C-acylation.


2,5-Diketopiperazine, Synthesis, Amide bond formation
The most commonly used synthesis of 2,5-diketopiperazines 3 is amide bond formation by cyclisation of dipeptide 1 or 2. These dipeptides can be formed by coupling two amino acids together by the many methods of peptide synthesis or by using the Ugi reaction of an isonitrile, amino acid, aldehyde and amine, followed by deprotection.


2,5-Diketopiperazine, Synthesis, Amide bond formation
Dipeptides substituted with an amine at one terminus and an ester at the other 1 can spontaneously cyclize to form a 2,5-diketopiperazine at a range of pHs. However, careful selection of reaction conditions is required to limit racemization. This has been achieved in a general, efficient, and environmentally benign solution-phase synthesis of 2,5-diketopiperazines using microwave-assisted heating in water, which in contrast to other published methods is independent of the amino acid sequence, and no epimerization was seen.


2,5-Diketopiperazine, Synthesis, Amide bond formation
The Ugi reaction using an isonitrile, amino acid, aldehyde and amine, can produce a dipeptide in equally high yield and optical purity, to that formed by standard peptide couplings. Commonly, an isonitrile is chosen to give a labile terminal amide to enable cyclization. For example, the direct 2,5-DKP ring formation via such an activated leaving group using the stable, easily accessible and versatile convertible isonitrile 1-isocyano-2-(2,2-dimethoxyethyl)-benzene 4 gave a one-pot synthesis of N-substituted 2,5-diketopiperazine's 7.


2,5-Diketopiperazine, Synthesis, Amide bond formation
The mild acidic and chemoselective post Ugi activation of 5 involving simultaneous indolamide formation and tert-butoxycarbonyl (Boc) removal gives the active amide 6 which allows cyclization to 7 without affecting other peptidic or even ester moieties and with stereochemical retention of the chiral centers.


2,5-Diketopiperazine, Synthesis, N-Alkylation
Intramolecular amide N-alkylation of alpha-haloacetamide amides 8 with ethanolic potassium hydroxide using ultrasonication gave the 2,5-diketopiperazines 9, where 8 was obtained by an Ugi reaction between amines, aldehydes, isocyanides, and chloroacetic acid. However this route is limited by epimerization at the stereogenic centre and failure to obtain the 2,5-diketopiperazine ring if R1 = Alkyl.


2,5-Diketopiperazine, Synthesis, C-Acylation
Formation of the 2,5-diketopiperazine ring by enolate acylation  was used in the construction of the 2,5-diketopiperazine ring in 11 by intramolecular cyclization of the enolate of 10 onto the carbonyl of the phenyl carbamate to give 11 in 90% yield.


2,5-Diketopiperazine, Reactions, Reactivity at carbon (C-3 and C-6)
Regio- and sterocontrolled C-functionalization of 2,5-diketopiperazines at C-3 and C-6 involve enolate, radical and cationic precursors (and N-acyliminium ion) and are sensitive to polar and steric effects.


2,5-Diketopiperazine, Reactions, Reactivity at carbon (C-3 and C-6), Alkylation of enolates
Alkylation of the bis-paramethoxybenzyl (pMB) protected 2,5-DKP 1 using the base LHMDS and an alkyl bromide R1Br, gave the mono-alkylated derivative 2, which on further alkylation gave the symmetrical trans-disubstituted derivative 3


2,5-Diketopiperazine, Reactions, Reactivity at carbon (C-3 and C-6), Halogenation and displacement
The 3-monobromides 6 and the 3,6-dibromides 5 are prepared from the benzyl protected 2,5-DKP 4 by radical halogenation with N-bromosuccinimide in carbon tetrachloride. Displacement of these labile bromides readily occurs with a range of nucleophiles SR, OR, NR2, alkyl and aryl to give 7 .


2,5-Diketopiperazine, Reactions, Reactivity at carbon (C-3 and C-6), Aldol addition
A one- or two-fold aldol condensation of N-acetylated 2,5-DKP 8 gives access to 3-dehydro-2,5-diketopiperazines 9 and 3,6-didehydro-2,5-diketopiperazines 10 and the condensation of 8 can controlled in a stepwise fashion using triethylamine in dimethylformamide to give the unsymmetrical 3,6-didehydro-2,5-diketopiperazines 10  (R1 = Ar1, R2 = Ar2).


2,5-Diketopiperazine, Reactions, Reactivity at nitrogen, Alkylation
The most common method for alkylation of the lactam nitrogen of 2,5-diketopiperazines is based on the use of sodium hydride as base. However epimerisation can occur especially with proline-fused 2,5-diketopiperazines, even with milder methods such as under phase-transfer catalyst conditions for example 1 to 2.


2,5-Diketopiperazine, Reactions, Reactivity at carbonyl carbons (C-2 and C-5), Reduction
Reduction of the carbonyl groups of chiral 2,5-diketopiperazine with lithium aluminium hydride (LiAlH4) cleanly gives the corresponding chiral piperazines. For example, cyclo(L-Phe-L-Phe) 1 gives the chiral piperazine (2S,5S)-dibenzylpiperazine 2.


2,5-Diketopiperazine, Reactions, Reactivity at carbonyl carbons (C-2 and C-5), Dihydropyrazine and pyrazine synthesis
Reaction of the lactam-derived enol phosphates 4 of 2,5-diketopiperazines with palladium catalyzed reactions (reduction, Suzuki and Stille cross-coupling reactions) enables the synthesis of a range of functionalised 1,4-dihydropyrazines 5 which can be aromatized to 1,4-pyrazines 6 in the presence of acid.


2,5-Diketopiperazine, Applications, Therapeutics
There are numerous bioactive molecules containing the 2,5-DKP core template in the literature arising from natural products and available from combinatorial libraries. These small, conformationally rigid, chiral templates have multiple H-bond acceptor and donor functionality and have multiple sites for structural elaboration of diverse functional groups with defined stereochemistry. These characteristics not only enable them to bind with high affinity to a large variety of receptors, showing a broad range of biological activities, but also allow the development of the drug-like physicochemical properties required for the multiobjective optimization process of transforming a lead to a drug product.


2,5-Diketopiperazine, Applications, Therapeutics
The structure–activity relationship (SAR) has been explored for many of these 2,5-DKP templates, and several  have been developed into clinical drugs. These include tadalafil (a PDE5 inhibitor for erectile dysfunction), retosiban (an oxytocin antagonist for preterm labor), aplaviroc (a CCR5 antagonists for HIV), epelsiban (an oxytocin antagonist for premature ejaculation) and the experimental cancer drug plinabulin (NPI-2358/KPU-2) that is active in multidrug-resistant (MDR) tumor cell lines.


2,5-Diketopiperazine, Applications, Reagents
The diketopiperazine obtains from glycylserine is a reagent for the preparation of C-alkylated derivatives of glycine. This approach is useful for the production of unnatural amino acids with stereochemical control. The diketopiperazine skeleton protects both the N and O termini of the glycine. For this application, the diketopiperazine is O-alkylated with concomitant N-deprotonation to give what is called the Schöllkopf reagent.


2,5-Dimethoxy-4-(2-fluoroethyl)amphetamine
2,5-Dimethoxy-4-(2-fluoroethyl)amphetamine (DOEF; also known as dimethoxyfluoroethylamphetamine) is a lesser-known psychedelic drug and member of the DOx class. DOEF was first synthesized by Alexander Shulgin. In his book PiHKAL, the dosage range is listed as 2–3.5 mg, and the duration is listed as 12–16 hours. Very little data exists about the pharmacological properties, metabolism, and toxicity of DOEF.


2,5-Dimethoxy-4-amylamphetamine
Dimethoxy-4-amylamphetamine (DOAM) is a lesser-known psychedelic drug and a substituted amphetamine. DOAM was first synthesized by Alexander Shulgin. In his book PiHKAL (Phenethylamines i Have Known And Loved), the minimum dosage is listed as 10 mg, and the duration is unknown. DOAM produces a bare threshold and tenseness.


2,5-Dimethoxy-4-amylamphetamine
As the 4-alkyl chain length is increased from shorter homologues such as DOM, DOET, DOPR, and DOBU which are all potent hallucinogens, the 5-HT2 binding affinity increases, rising to a maximum with the 4-(n-hexyl) derivative before falling again with even longer chains, but compounds with chain length longer than n-propyl, or with other bulky groups such as isopropyl, t-butyl or γ-phenylpropyl at the 4- position, fail to substitute for hallucinogens in animals or produce hallucinogenic effects in humans, suggesting these have low efficacy and are thus antagonists or weak partial agonists at the 5-HT2A receptor.


2,5-Dimethoxy-4-bromoamphetamine
Dimethoxybromoamphetamine (DOB), also known as brolamfetamine (INN) and bromo-DMA, is a psychedelic drug and substituted amphetamine of the phenethylamine class of compounds. DOB was first synthesized by Alexander Shulgin in 1967. Its synthesis and effects are documented in Shulgin's book PiHKAL: A Chemical Love Story.


2,5-Dimethoxy-4-bromoamphetamine, Chemistry
The full name of the chemical is 2,5-dimethoxy-4-bromoamphetamine. DOB has a stereocenter and R-(–)-DOB is the eutomer. This is an important finding as it is suggestive that it is targeting different receptors relative to most other phenethylamines (e.g. MDMA) where the R-isomer serves as the distomer. The toxicity of DOB is not fully known, although high doses may cause serious vasoconstriction of the extremities.


2,5-Dimethoxy-4-bromoamphetamine, Chemistry
DOB is one of the most potent compounds in PiHKAL; while the active dose is similar to that of DOI, another psychedelic amphetamine, DOB has been shown to have a higher efficacy in triggering downstream effects mediated by 5-HT2 receptors, making it likely to be slightly more dangerous than DOI in overdose, due to greater vasoconstrictive action. Omission of the amphetamine related α-methyl leads to 2C-B, a compound that possesses a lower affinity for the 5-HT2A receptor and is a weaker receptor agonist which results in drastically reduced vasoconstriction.


2,5-Dimethoxy-4-bromoamphetamine, Pharmacology
DOB is a 5-HT2A, 5-HT2B, and 5-HT2C receptor agonist or partial agonist. Its psychedelic effects are mediated by its agonistic properties at the 5-HT2A receptor. Due to its selectivity, DOB is often used in scientific research when studying the 5-HT2 receptor subfamily. It is an agonist of human TAAR1.


2,5-Dimethoxy-4-bromoamphetamine, Pharmacology
It has been suggested that DOB is a prodrug metabolized in the lungs.


2,5-Dimethoxy-4-bromoamphetamine, Pharmacology
Excessively high doses of this hallucinogen may cause diffuse arterial spasm. The vasospasm responded readily to intra-arterial and intravenous vasodilators, such as tolazoline.


2,5-Dimethoxy-4-bromoamphetamine, Legal status
Internationally DOB is a Schedule I substance under the Convention on Psychotropic Substances and the drug it's legal only for medical, industrial or scientific purposes.


2,5-Dimethoxy-4-bromoamphetamine, Legal status, Canada
Listed as a Schedule 1 as it is an analogue of amphetamine.


2,5-Dimethoxy-4-bromoamphetamine, Legal status, Australia
DOB is considered a Schedule 9 prohibited substance in Australia under the Poisons Standard (February 2017). A Schedule 9 substance is a substance which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities.


2,5-Dimethoxy-4-bromoamphetamine, Legal status, Russia
Schedule I, possession of at least 10 mg is a criminal offence.


2,5-Dimethoxy-4-butylamphetamine
2,5-Dimethoxy-4-butylamphetamine (DOBU) is a lesser-known psychedelic drug and a substituted Amphetamine. DOBU was first synthesized by Alexander Shulgin. In his book PiHKAL (Phenethylamines i Have Known And Loved), only low dosages of 2–3 mg were tested, with the duration simply listed as "very long". DOBU produces paresthesia and difficulty sleeping, but with few other effects.


2,5-Dimethoxy-4-butylamphetamine
Compared to shorter chain homologues such as DOM, DOET and DOPR which are all potent hallucinogens, DOBU has an even stronger 5-HT2 binding affinity but fails to substitute for hallucinogens in animals or produce hallucinogenic effects in humans, suggesting it has low efficacy and is thus an antagonist or weak partial agonist at the 5-HT2A receptor.


2,5-Dimethoxy-4-butylamphetamine, Isomers
Alternative isomers of DOBU can also be produced, where the 4-(n-butyl) group of DOBU is replaced with any of the three other butyl isomers, the iso-butyl, sec-butyl and tert-butyl compounds being called DOIB, DOSB and DOTB respectively. All are significantly less potent than DOBU, with DOIB being active at around 10–15 mg, and DOSB at 25–30 mg, and both being primarily stimulant in action with little or no psychedelic effects. The most highly branched isomer DOTB was completely inactive in both animal and human trials.


2,5-Dimethoxy-4-chloroamphetamine
2,5-Dimethoxy-4-chloroamphetamine (DOC) is a psychedelic drug of the phenethylamine and amphetamine chemical classes. It was presumably first synthesized by Alexander Shulgin, and was described in his book PiHKAL (Phenethylamines i Have Known And Loved).


2,5-Dimethoxy-4-chloroamphetamine, Chemistry
DOC is a substituted alpha-methylated phenethylamine, a class of compounds commonly known as amphetamines. The phenethylamine equivalent (lacking the alpha-methyl group) is 2C-C. DOC has a stereocenter and (R)-(−)-DOC is the more active stereoisomer.


2,5-Dimethoxy-4-chloroamphetamine, Pharmacology
DOC acts as a selective 5-HT2A, 5-HT2B, and 5-HT2C receptor partial agonist. Its psychedelic effects are mediated via its actions on the 5-HT2A receptor.


2,5-Dimethoxy-4-chloroamphetamine, Dosage
A normal average dose of DOC ranges from 0.5–7.0 mg the former producing threshold effects, and the latter producing extremely strong effects. Onset of the drug is 1–3 hours, peak and plateau at 4–8 hours, and a gradual come down with residual stimulation at 9-20h. After effects can last well into the next day.


2,5-Dimethoxy-4-chloroamphetamine, Effects
Unlike simple amphetamines, DOC is considered a chemical that influences cognitive and perception processes of the brain. The strongest supposed effects include open and closed eye visuals, increased awareness of sound and movement, and euphoria. In the autobiography PiHKAL, Alexander Shulgin included a description of DOC as "an archetypal psychedelic" (#64); its presumed full-range visual, audio, physical, and mental effects show exhilarating clarity, and some overwhelming, humbling, and "composting"/interweaving effects.


2,5-Dimethoxy-4-chloroamphetamine, Dangers
Very little data exists about the toxicity of DOC. In April 2013, a case of death due to DOC was reported. The source does not specify whether the drug alone caused the death. In 2014, a death was reported in which DOC was directly implicated as the sole causative agent in the death of a user. The autopsy indicated pulmonary edema and a subgaleal hemorrhage.


2,5-Dimethoxy-4-chloroamphetamine, Detection in biological specimens
DOC may be quantitated in blood, plasma or urine by gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry to confirm a diagnosis of poisoning in hospitalized patients or to provide evidence in a medicolegal death investigation. Blood or plasma DOC concentrations are expected to be in a range of 1–10 μg/L in persons using the drug recreationally, >20 μg/L in intoxicated patients and >100 μg/L in victims of acute overdosage.


2,5-Dimethoxy-4-chloroamphetamine, Popularity
Although rare on the black market, it has been available in bulk and shipped worldwide by select elite "Grey Market" Research Chemical suppliers for several years. Sales of DOC on blotting paper and in capsules was reported in late 2005 and again in late 2007. According to the DEA's Microgram from December 2007, the Concord Police Department in Contra Costa County, California, in the US, seized "a small piece of crudely lined white blotter paper without any design, suspected LSD 'blotter acid'".


2,5-Dimethoxy-4-chloroamphetamine, Popularity
They added "Unusually, the paper appeared to be hand-lined using two pens, in squares measuring approximately 6 x 6 millimeters. The paper displayed fluorescence when irradiated at 365 nanometers; however, color testing for LSD with para-dimethylaminobenzaldehyde (Ehrlich's reagent) was negative. Analysis of a methanol extract by GC/MS indicated not LSD but rather DOC (not quantitated but a high loading based on the TIC)". DOC is sometimes misrepresented as LSD by unscrupulous dealers. This is particularly dangerous, as DOC is not known to have the safety profile of LSD. It can be particularly unsafe, in comparison to LSD, for those suffering from hypertension, as amphetamine compounds are known to cause sharp increases in systolic blood pressure.


2,5-Dimethoxy-4-chloroamphetamine, Drug prohibition laws, Canada
Listed as a Schedule 1 as it is an analogue of amphetamine. The CDSA was updated as a result of the Safe Streets Act changing amphetamines from Schedule 3 to Schedule 1.


2,5-Dimethoxy-4-chloroamphetamine, Drug prohibition laws, Australia
Unscheduled but can be controlled as schedule II as an analogue of DOB.


2,5-Dimethoxy-4-chloroamphetamine, Drug prohibition laws, China
As of October 2015 DOC is a controlled substance in China.


2,5-Dimethoxy-4-chloroamphetamine, Drug prohibition laws, Denmark
Denmark added DOC to the list of Schedule I controlled substances as of 8.4.2007.


2,5-Dimethoxy-4-chloroamphetamine, Drug prohibition laws, Sweden
Sveriges riksdag added DOC to schedule I ("substances, plant materials and fungi which normally do not have medical use") as narcotics in Sweden as of Aug 30, 2007,  published by Medical Products Agency in their regulation LVFS 2007:10 listed as DOC, 4-klor-2,5-dimetoxi-amfetamin. DOC was first classified by Sveriges riksdags health ministry Statens folkhälsoinstitut as "health hazard" under the act Lagen om förbud mot vissa hälsofarliga varor (translated Act on the Prohibition of Certain Goods Dangerous to Health) as of Jul 1, 2004,  in their regulation SFS 2004:486 listed as 4-klor-2,5-dimetoxiamfetamin (DOC).


2,5-Dimethoxy-4-chloroamphetamine, Drug prohibition laws, United States
DOC is not scheduled or controlled at the federal level in the United States, but the Department of Justice considers it to be an analogue of DOB and, as such, possession or sale could be prosecuted under the Federal Analogue Act. In the United States, the analogues DMA, DOB, and DOM are Schedule I controlled substances.


2,5-Dimethoxy-4-chloroamphetamine, Drug prohibition laws, United States, US State of Florida
DOC is a Schedule I controlled substance in the state of Florida making it illegal to buy, sell, or possess.


2,5-Dimethoxy-4-chloroamphetamine, Drug prohibition laws, United Nations
In December 2019, the UNODC announced scheduling recommendations placing DOC into Schedule I alongside another several research chemicals.


2,5-Dimethoxy-4-ethoxyamphetamine
2,5-Dimethoxy-4-ethoxyamphetamine (MEM) is a psychedelic drug of the phenethylamine and amphetamine chemical classes. It was first synthesized by Alexander Shulgin. In his book PiHKAL, he lists the active dose range as 20–50 mg, and the duration as 10–14 hours. According to Shulgin, MEM produces color enhancement, visual phenomena, and pattern movement, among other effects.


2,5-Dimethoxy-4-ethoxyamphetamine
MEM possesses affinity (Ki) for the 5-HT2A (3,948 nM), 5-HT2B (64.5 nM), 5-HT7 (7,156 nM), and σ1 (5,077 nM) receptors. It behaves as a partial agonist at the 5-HT2A receptor. MEM is relatively selective for these sites and displays low/negligible (> 10,000 nM) affinity for a wide array of other targets.


2,5-Dimethoxy-4-ethylamphetamine
2,5-Dimethoxy-4-ethylamphetamine (DOET, DOE, Hecate, "'3-CE'") is a psychedelic drug of the phenethylamine and amphetamine chemical classes. It was first synthesized by Alexander Shulgin, and was described in his book PiHKAL (Phenethylamines i Have Known And Loved).


2,5-Dimethoxy-4-ethylamphetamine, Chemistry
DOET is in a class of compounds commonly known as substituted amphetamines; its full chemical name is 4-ethyl-2,5-dimethoxy-alpha-methylbenzeneethanamine, or 1-(2,5-dimethoxy-4-ethylphenyl)propan-2-amine. It has an active stereocenter and (R)-DOET is the more active enantiomer. DOET is an extremely rare compound and reports of its effects and toxicology in humans are sparse. However, like the more common 2,5-dimethoxy-amphetamine analogues DOB, DOI and DOM, it is a potent and long-acting psychedelic. Removal of the alpha-methyl moiety yields the 2-carbon analogue, commonly known as 2C-E, another psychedelic compound first synthesized by Dr. Alexander Shulgin.


2,5-Dimethoxy-4-ethylamphetamine, Pharmacology
Similarly to related drugs like DOM, DOET likely acts as a 5-HT2A, 5-HT2B, and 5-HT2C receptor partial agonist. It is an agonist of human TAAR1.


2,5-Dimethoxy-4-ethylamphetamine, Effects
DOET produces psychedelic effects that last up 14–20 hours. In PiHKAL, Shulgin lists the dosage of DOET as being 2–7 mg orally, with 6–7 mg being the dosage for full, desired effects.


2,5-Dimethoxy-4-ethylamphetamine, Legal Status
Internationally, DOET is a Schedule I controlled drug under the Convention on Psychotropic Substances it's legal only for medical uses or scientific research:.


2,5-Dimethoxy-4-ethylamphetamine, Legal Status, United States
DOET is classified as a Schedule I substance in the United States and is similarly controlled in other parts of the world.


2,5-Dimethoxy-4-ethylamphetamine, Legal Status, Australia
DOET is considered a Schedule 9 prohibited substance in Australia under the Poisons Standard (October 2015). A Schedule 9 substance is a substance which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities.


2,5-Dimethoxy-4-fluoroamphetamine
2,5-Dimethoxy-4-fluoroamphetamine (DOF) is a psychedelic drug of the phenethylamine and amphetamine classes. Alexander Shulgin briefly describes DOF in his book PiHKAL:


2,5-Dimethoxy-4-fluoroamphetamine
Animal studies that have compared DOF to the highly potent DOI and DOB imply that the human activity will be some four to six times less than these two heavier halide analogues.


2,5-Dimethoxy-4-fluoroamphetamine
DOF showed some stimulating effects in humans, but no psychedelic activity, after three doses of 6 mg spaced by one hour. Daniel Trachsel further suspected that the molar refraction of the important 4-substituent in DOF and 2C-F may be too low to activate the  5-HT2A receptor sufficiently. DOF more closely mimics the effects of the 4-unsubstituted 2,5-dimethoxyamphetamine than the effects of DOC, DOB, and DOI.


2,5-Dimethoxy-4-iodoamphetamine
2,5-Dimethoxy-4-iodoamphetamine (DOI) is a psychedelic drug and a substituted amphetamine. Unlike many other substituted amphetamines, however, it is not primarily a stimulant. DOI has a stereocenter and R-(−)-DOI is the more active stereoisomer. In neuroscience research, [125I]-R-(−)-DOI is used as a radioligand and indicator of the presence of 5-HT2A serotonin receptors. DOI's effects have been compared to LSD, although there are differences that experienced users can distinguish. Besides the longer duration, the trip tends to be more energetic than an LSD trip, with more body load and a different subjective visual experience.


2,5-Dimethoxy-4-iodoamphetamine
The after effects include residual stimulation and difficulty sleeping, which, depending on the dose, may persist for days. While rare, it is sometimes sold as a substitute for LSD, or even sold falsely as LSD, which may be dangerous because DOI does not have the same established safety profile as LSD.


2,5-Dimethoxy-4-iodoamphetamine, Research
Research suggests that administration of (R)-DOI blocks pulmonary inflammation, mucus hyper-production, airway hyper-responsiveness and turns off key genes in in-lung immune response. These effects block the development of allergic asthma in a mouse model.


2,5-Dimethoxy-4-iodoamphetamine, Research
Several 5-HT2A agonist hallucinogens including (R)-2,5-dimethoxy-4-iodoamphetamine DOI, TCB-2, LSD and LA-SS-Az have unexpectedly also been found to act as potent inhibitors of TNF, with DOI being the most active, showing TNF inhibition in the picomolar range, an order of magnitude more potent than its action as a hallucinogen.


2,5-Dimethoxy-4-iodoamphetamine, Pharmacology
DOI has been shown to be an extremely potent inhibitor of tumour necrosis factor-alpha inflammation at picomolar concentrations in cell studies. TNF-alpha is an important target for research into degenerative conditions such as rheumatoid arthritis and Alzheimer's disease, where the disease process involves tissue damage through chronic inflammation. This could make DOI and other 5-HT2A agonists an entirely new area for development of novel treatments for these conditions.


2,5-Dimethoxy-4-iodoamphetamine, Pharmacology
DOI has also been shown to induce rapid growth and reorganization of dendritic spines and synaptic connections with other neurons, processes known to underlie neuroplasticity.


2,5-Dimethoxy-4-iodoamphetamine, History
DOI was first synthesized by Alexander Shulgin. The radioactive iodine-125 form of DOI  for PET imaging was first developed in the lab of David E. Nichols.


2,5-Dimethoxy-4-iodoamphetamine, History
In January 2007, British police reported that three young men had fallen ill, reportedly, after taking DOI at a rave in Biggleswade, near Milton Keynes, and warned others who had taken it to seek medical attention. This would appear to be the first indication that DOI has found more widespread use as a recreational drug in the UK.


2,5-Dimethoxy-4-iodoamphetamine, Legal status, Australia
The Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) of Australia does not list DOI as a prohibited substance.


2,5-Dimethoxy-4-iodoamphetamine, Legal status, Canada
Listed as a Schedule 1 as it is an analogue of amphetamine. The CDSA was updated as a result of the Safe Streets Act changing amphetamines from Schedule 3 to Schedule 1.


2,5-Dimethoxy-4-iodoamphetamine, Legal status, Sweden
Sveriges riksdag added DOI to schedule I ("substances, plant materials and fungi which normally do not have medical use") as narcotics in Sweden as of August 30, 2007,  published by Medical Products Agency in their regulation LVFS 2007:10 listed as DOI, 4-jod-2,5-dimetoxi-amfetamin.


2,5-Dimethoxy-4-iodoamphetamine, Legal status, United States
DOI is not scheduled in the United States, but it is likely that DOI would be considered an analog (of DOB), in which case, sales or possession could be prosecuted under the Federal Analogue Act. DOI is occasionally used in animal and in vitro research. Scheduling DOI could cause problems for medical researchers.


2,5-Dimethoxy-4-iodoamphetamine, Legal status, United States, US State of Florida
DOI is a Schedule I controlled substance in the state of Florida.


2,5-Dimethoxy-4-isopropylamphetamine
2,5-Dimethoxy-4-isopropylamphetamine (also known as DOiP and DOiPr) is a psychedelic drug of the phenethylamine and amphetamine chemical classes. It was first synthesized by Alexander Shulgin, and was described in his book PiHKAL (Phenethylamines i Have Known And Loved). Shulgin described DOiPR as being at least an order of magnitude weaker than DOPr, with doses of 20–30 mg required to produce valid changes in mental state. Very little data exists about the pharmacological properties, metabolism, and toxicity of DOiPR.


2,5-Dimethoxy-4-methylamphetamine
2,5-Dimethoxy-4-methylamphetamine (DOM; known on the street as STP, standing for "Serenity, Tranquility and Peace") is a psychedelic and a substituted amphetamine. It was first synthesized by Alexander Shulgin, and later reported in his book PiHKAL: A Chemical Love Story. DOM is classified as a Schedule I substance in the United States, and is similarly controlled in other parts of the world. Internationally, it is a Schedule I drug under the Convention on Psychotropic Substances. It is generally taken orally.


2,5-Dimethoxy-4-methylamphetamine
The belief the name "STP" actually comes from the motor oil additive is untrue. STP was a street name given to DOM by hippies in the 60s when "underground chemist" Owsley made a few batches of the drug and handed them out at shows, only to stop, upon realising that the drug was not popular among new users, due to the greater length and intensity of the 'high' it produced, compared with that evoked by his beloved LSD.


2,5-Dimethoxy-4-methylamphetamine, History
STP was first synthesized and tested in 1963 by Alexander Shulgin, who was investigating the effect of 4-position substitutions on psychedelic amphetamines.


2,5-Dimethoxy-4-methylamphetamine, History
In mid-1967, tablets containing 20 mg (later 10 mg) of STP were widely distributed in the Haight-Ashbury District of San Francisco under the name of STP, having been manufactured by underground chemists Owsley Stanley and Tim Scully. This short-lived appearance of STP on the black market proved disastrous for several reasons. First, the tablets contained an excessively high dose of the chemical.


2,5-Dimethoxy-4-methylamphetamine, History
This, combined with DOM's slow onset of action (which encouraged some users, familiar with drugs that have quicker onsets, such as LSD, to re-dose) and its remarkably long duration, caused many users to panic and sent some to the emergency room. Second, treatment of such overdoses was complicated by the fact that no one at the time knew that the tablets called STP were, in fact, DOM.


2,5-Dimethoxy-4-methylamphetamine, Effects
Effects of this drug include substantial perceptual changes such as blurred vision, multiple images, vibration of objects, visual alterations, distorted shapes, enhancement of details, slowed passage of time, increased sexual drive and pleasure, and increased contrasts. It may cause mystical experiences and changes in consciousness. It may also cause pupillary dilation and a rise in systolic blood pressure.


2,5-Dimethoxy-4-methylamphetamine, Pharmacology
DOM is a selective 5-HT2A, 5-HT2B, and 5-HT2C receptor partial agonist. Its psychedelic effects are mediated by its agonistic properties at the 5-HT2A receptor. Due to its selectivity, DOM is often used in scientific research when studying the 5-HT2 receptor subfamily. DOM is a chiral molecule, and R-(−)-DOM is the more active enantiomer, functioning as a potent agonist of the serotonin 5-HT family of receptors; mainly of the 5-HT2 subtype.


2,5-Dimethoxy-4-methylamphetamine, Pharmacology, Analogues and derivatives
The 2,6-dimethoxy positional isomer of DOM, known as Ψ-DOM, is also mentioned in PiHKAL as being active, as is the alpha-ethyl homologue Ariadne. Analogues where the methoxy groups at the 2,5- positions of the aromatic ring have been altered have also been synthesised and tested as part of an effort to identify the binding mode of DOM at the 5-HT2A receptor. Both the 2- and 5- O-desmethyl derivatives 2-DM-DOM and 5-DM-DOM, and the 2- and 5- ethyl analogues 2-Et-DOM and 5-Et-DOM have been tested, but in all cases were significantly less potent than the corresponding methoxy compound, showing the importance of the oxygen lone pairs in 5-HT2A binding.


2,5-Dimethoxy-4-methylamphetamine, Pharmacology, Analogues and derivatives
The tranylcypromine-DOM compound is fully one-third the potency of DOM proper according to page 72 of monograph 22. This would mean that the ED50 for 1 tablet should be approximately 30 mg.


2,5-Dimethoxy-4-methylamphetamine, Toxicity
Very little is known about the toxicity of DOM. According to Alexander Shulgin, the effects of DOM typically last 14 to 20 hours, though other clinical trials indicate a duration of 7 to 8 hours.


2,5-Dimethoxy-4-methylamphetamine, Legal status, Canada
Listed as a Schedule 1, as it is an analogue of amphetamine.


2,5-Dimethoxy-4-methylamphetamine, Legal status, United States
DOM is Schedule I in the United States. This means it is illegal to manufacture, buy, possess, or distribute (make, trade, own or give) without a DEA license.


2,5-Dimethoxy-4-methylamphetamine, Legal status, Australia
DOM is schedule 9 under the Australia Poisons standard. A schedule 9 substance is a "Substances which may be abused or misused, the manufacture, possession, sale or use of which should be prohibited by law except when required for medical or scientific research, or for analytical, teaching or training purposes with approval of Commonwealth and/or State or Territory Health Authorities."


2,5-Dimethoxy-4-methylphenylcyclopropylamine
2,5-Dimethoxy-4-methylphenylcyclopropylamine (DMCPA) is a lesser-known psychedelic drug and a substituted amphetamine. DMCPA was first synthesized by Alexander Shulgin. In his book PiHKAL, the dosage range is listed as 15–20 mg and the duration is listed as 4–8 hours. DMCPA produces open-eye visuals, anorexia, and psychedelic dreams. Shulgin gives it a +++ on the Shulgin Rating Scale.


2,5-Dimethoxy-4-methylphenylcyclopropylamine, Legality, United Kingdom
This substance is a Class A drug in the Drugs controlled by the UK Misuse of Drugs Act.


2,5-Dimethoxy-4-methylphenylcyclopropylamine, Pharmacology
Very little data exists about the pharmacological properties, metabolism, and toxicity of DMCPA.


2,5-Dimethoxy-4-nitroamphetamine
2,5-Dimethoxy-4-nitroamphetamine (DON) is a recreational drug and amphetamine. It is an analog of DOM and DOB. It is also closely related to 2C-N.


2,5-Dimethoxy-4-nitroamphetamine, Chemistry
DON is in a class of compounds commonly known as alpha-methyl phenethylamines, or amphetamines and the full chemical name is 1-(2,5-dimethoxy-4-nitrophenyl)propan-2-amine. It has a stereocenter.


2,5-Dimethoxy-4-nitroamphetamine, Effects
In his book PiHKAL, Alexander Shulgin lists a dosage of DON as being 3-4.5 mg orally with amphetamine-like stimulation lasting 8–15 hours.


2,5-Dimethoxy-4-nitroamphetamine, Legality
DON is unscheduled in the United States, but because of its close similarity in structure and effects to DOM and DOB, possession and sale of DON may be subject to prosecution under the Federal Analog Act. DON is listed as a Class A drug in the Drugs controlled by the UK Misuse of Drugs Act after the table of contents of PiHKAL and TiHKAL were added to the schedules.


2,5-Dimethoxy-4-propylamphetamine
2,5-Dimethoxy-4-propylamphetamine (DOPR) is a psychedelic drug of the phenethylamine and amphetamine chemical classes. It was first synthesized by Alexander Shulgin, and was described in his book PiHKAL (Phenethylamines i Have Known And Loved). Shulgin described DOPR is a "heavy duty psychedelic", complete with alterations of the thought process and visual distortion. Very little data exists about the pharmacological properties, metabolism, and toxicity of DOPR.


2,5-Dimethoxy-4-propylamphetamine
The alternative structural isomer DOIP, with a 4-isopropyl substitution, is also known but is around ten times weaker than DOPR, with an active dose of some 20–30 mg (as compared to 2–5 mg for DOPR).


2,5-Dimethoxy-4-trifluoromethylamphetamine
2,5-Dimethoxy-4-trifluoromethylamphetamine (DOTFM) is a psychedelic drug of the phenethylamine and amphetamine chemical classes. It was first synthesized in 1994 by a team at Purdue University led by David E. Nichols. DOTFM is the alpha-methylated analogue of 2C-TFM, and is around twice as potent in animal studies. It acts as an agonist at the 5HT2A and 5HT2C receptors. In drug-substitution experiments in rats, DOTFM fully substituted for LSD and was slightly more potent than DOI.


2,5-Dimethoxy-p-cymene
2,5-Dimethoxy-p-cymene, or thymohydroquinone dimethyl ether, is a phytochemical found in the essential oils of plants within the family Asteraceae. These essential oils, which contain the compound as a major component of the oil, have antifungal, antibacterial,  and insecticidal properties.


2,5-Dimethoxy-p-cymene, Natural occurrence
2,5-Dimethoxy-p-cymene occurs in a variety of different plants' essential oils. Examples include:


2,5-Dimethoxy-p-cymene, Chemical synthesis
2,5-Dimethoxy-p-cymene can be synthesized from carvacrol by aromatic halogenation followed by nucleophilic substitution with sodium methoxide and Williamson ether synthesis using methyl iodide.


2,5-Dimethoxybenzaldehyde
2,5-Dimethoxybenzaldehyde is an organic compound and a benzaldehyde derivative. One of its uses is the production of 2,5-dimethoxyphenethylamine, also known as 2C-H. 2C-H is used to produce many other substituted phenethylamines such as 2C-B, 2C-I and 2C-C.


2,5-Dimethylfuran
2,5-Dimethylfuran is a heterocyclic compound with the formula (CH3)2C4H2O. Although often abbreviated DMF, it should not be confused with dimethylformamide. A derivative of furan, this simple compound is a potential biofuel, being derivable from cellulose.


2,5-Dimethylfuran, Production
Fructose can be converted into 2,5-dimethylfuran in a catalytic biomass-to-liquid process. The conversion of fructose to DMF proceeds via hydroxymethylfurfural.


2,5-Dimethylfuran, Production
Fructose is obtainable from glucose, a building block in cellulose.


2,5-Dimethylfuran, Potential as a biofuel
DMF has a number of attractions as a biofuel. It has an energy density 40% greater than that of ethanol, making it comparable to gasoline (petrol). It is also chemically stable and, being insoluble in water, does not absorb moisture from the atmosphere. Evaporating dimethylfuran during the production process also requires around one third less energy than the evaporation of ethanol, although it has a boiling point some 14 °C higher, at 92 °C, compared to 78 °C for ethanol.


2,5-Dimethylfuran, Potential as a biofuel
The ability to efficiently and rapidly produce dimethylfuran from fructose, found in fruit and some root vegetables, or from glucose, which can be derived from starch and cellulose - all widely available in nature - adds to the attraction of dimethylfuran, although safety issues must be examined. Bioethanol and biodiesel are currently the leading liquid biofuels.


2,5-Dimethylfuran, Potential as a biofuel
The stoichiometric air/fuel ratio of dimethylfuran is 10.72, compared to ethanol at 8.95 and gasoline at 14.56. This means that burning dimethylfuran requires approximately 33% less air than the same quantity of gasoline, but approximately 20% more air than the same quantity of ethanol.


2,5-Dimethylfuran, Potential as a biofuel
The calorific value of liquid dimethylfuran is 33.7 MJ/kg, compared to 26.9 MJ/kg for ethanol and 43.2 MJ/kg for gasoline. The research octane number (RON) of dimethylfuran is 119. The latent heat of vaporization at 20 °C is 31.91 kJ/mol. Recent tests in a single-cylinder gasoline engine found that the thermal efficiency of burning dimethylfuran is similar to that of gasoline.


2,5-Dimethylfuran, Other uses
2,5-Dimethylfuran serves as a scavenger for singlet oxygen, a property which has been exploited for the determination of singlet oxygen in natural waters. The mechanism involves a Diels-Alder reaction followed by hydrolysis, ultimately leading to diacetylethylene and hydrogen peroxide as products. More recently, furfuryl alcohol has been used for the same purpose.


2,5-Dimethylfuran, Other uses
2,5-Dimethylfuran has also been proposed as an internal standard for NMR spectroscopy. 2,5-Dimethylfuran has singlets in its 1H NMR spectrum at δ 2.2 and 5.8; the singlets give reliable integrations, while the positions of the peaks do not interfere with many analytes. The compound also has an appropriate boiling point of 92 °C which prevents evaporative losses, yet is easily removed.


2,5-Dimethylfuran, Role in food chemistry
2,5-Dimethylfuran forms upon thermal degradation of some sugars and has been identified in trace amounts as a component of caramelized sugars.


2,5-Dimethylfuran, Toxicology
2,5-Dimethylfuran plays a role in the mechanism for the neurotoxicity of hexane in humans. Together with hexane-2,5-dione and 4,5-dihydroxy-2-hexanone, it is one of the main metabolites of hexane.


2,5-Dimethylfuran, Toxicology
2,5-Dimethylfuran has been identified as one of the components of cigar smoke with low ciliary toxicity (ability to adversely affect the cilia in the respiratory tract that are responsible for removing foreign particles). Its blood concentration can be used as a biomarker for smoking.


2,5-Dimethylfuran, Toxicology
Comparison of Safety Data Sheets shows that human handling of 2,5-dimethylfuran is approximately as hazardous as handling gasoline.


2,5-Dimethylhexane
2,5-Dimethylhexane is a branched alkane used in the aviation industry in low revolutions per minute helicopters. As an isomer of octane, the boiling point is very close to that of octane, but can in pure form be slightly lower. 2,5-Dimethylhexane is moderately toxic.


2,5-Dimethylthiophene
2,5-Dimethylthiophene is an organosulfur compound with the formula C4H2(CH3)2S. It is one of four isomers of dimethylthiophene. A colorless liquid, it is prepared by sulfurization of hexane-2,5-dione. It is approved as a food flavouring additive in Europe.


2,5-Diphenyloxazole
2,5-Diphenyloxazole (PPO) is an organic scintillator. It is used as a wavelength shifter (also called a "primary shifter" or "fluor"), which means that it converts shorter wavelength light to longer wavelength light. Its output spectrum peaks at 385 nm, which is in the range of UV light.


2,5-Furandicarboxylic acid
2,5-Furandicarboxylic acid (FDCA) is an organic chemical compound consisting of two carboxylic acid groups attached to a central furan ring. It was first reported as dehydromucic acid by Rudolph Fittig and Heinzelmann in 1876, who produced it via the action of concentrated hydrobromic acid upon mucic acid. It can be produced from certain carbohydrates and as such is a renewable resource, it was identified by the US Department of Energy as one of 12 priority chemicals for establishing the “green” chemistry industry of the future. Furan-2,5-dicarboxylic acid (FDCA) has been suggested as an important renewable building block because it can substitute for terephthalic acid (PTA) in the production of polyesters and other current polymers containing an aromatic moiety.


2,5-Furandicarboxylic acid, Synthesis of FDCA
Methods for the synthesis of the FDCA may be divided into four groups:


2,5-Furandicarboxylic acid, Synthesis of FDCA, Dehydration of hexose derivatives
First group is based on the acid-promoted triple dehydration of aldaric (mucic) acids. This reaction requires severe conditions (highly concentrated acids, temp > 120 °C, React time > 20h) and all the methods were non-selective with yields < 50%. The process has also been patented by the French company Agro Industrie Recherches et Developpements. This is also the process which DuPont and ADM are using according to patent literature.


2,5-Furandicarboxylic acid, Synthesis of FDCA, Oxidation of 2,5-disubstituted furans
The second class of synthesis routes include the oxidation reactions of various 2,5-disubstituted furans utilizing a variety of inorganic oxidants. Several routes to FDCA via oxidation of hydroxymethylfurfural (HMF) with air over different catalysts have been reported. Oxidation of HMF under strongly alkaline conditions over noble metal catalysts gives almost quantitative formation of FDCA. HMF and methoxymethylfurfural (MMF) oxidation was also studied with a series of conventional metal bromide catalysts (Co, Mn, Br) used for the oxidation of para-xylene to terephthalic acid. Also, the direct, one pot dehydration and oxidation of fructose to FDCA via intermediate HMF has been investigated with good selectivities, unfortunately this system does not work in water.


2,5-Furandicarboxylic acid, Synthesis of FDCA, Catalytic conversions of various furan derivatives
The third class includes reactions describing the synthesis of FDCA from furfural. Furfural can be oxidized to 2-furoic acid with nitric acid and the latter was subsequently converted to its methyl ester. The ester was then converted via chloromethylation at position 5 to give 5-chloromethylfuroate. The latter was oxidized with nitric acid to form dimethyl 2,5-furandicarboxylate, which, after the alkaline hydrolysis gave FDCA in 50% yield. Andrisano reported that potassium 2-furoate, when heated up to 300 °C in a nitrogen atmosphere, underwent decarboxylation to furan with simultaneous carboxylation at position 5 to di-potassium 2,5-furandicarboxylate.


2,5-Furandicarboxylic acid, Synthesis of FDCA, Biological conversion of HMF
FDCA has also been detected in human urine. A healthy human produces 3–5 mg/day. Numerous studies were undertaken to establish the metabolism of this compound and to determine the quantity, which is produced depending on the healthiness of the human. It was demonstrated that the individual quantity of produced FDCA increased after the injection of fructose. FDCA was also detected in blood plasma. Recently, the enzyme furfural/HMF oxidoreductase was isolated from the bacterium Cupriavidus basilensis HMF14. This enzyme might be able to convert HMF to FDCA using molecular oxygen, although an aldehyde dehydrogenase might also play a role.


2,5-Furandicarboxylic acid, Synthesis of FDCA, Biological conversion of HMF
A Pseudomonas putida strain that was genetically engineered to express this enzyme can completely and selectively convert HMF to FDCA. This biocatalysis is performed in water, at ambient temperature and pressure, without toxic or polluting chemicals, making it very environmentally friendly. Several other enzymes have been described later, including HMFO. This flavin dependent oxidase catalyzes the three consecutive oxidations to form FDCA from HMF.


2,5-Furandicarboxylic acid, Synthesis of FDCA, Industrial production
DuPont has announced the production of FDCA for use in PTF. In 2011, Avantium was the first company to build a FDCA pilot plant in Geleen, the Netherlands. Avantium has fully proven its technology to produce FDCA in this pilot plant and the company now plans to open the world’s first commercial FDCA plant. Currently Avantium is in the process of making an investment decision for this 5kt FDCA commercial plant, which is slated to start up in 2023 in Delfzijl, the Netherlands.


2,5-Furandicarboxylic acid, Properties and conversions
FDCA is a very stable compound. Its physical properties, such as insolubility in most of common solvents and a very high melting point (it melts at 342 °C) seem to indicate intermolecular hydrogen bonding. Despite its chemical stability, FDCA undergoes reactions typical for carboxylic acids, such as halogen substitution to give carboxylic dihalides, the di-ester formation and the formation of amides. All these reactions were elaborated at the end of 19th and in the beginning of 20th century.