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Piperazines are organic compound with the formula (CH2CH2NH)2.
In term of its structure, Piperazines can be described as cyclohexane with the 1- and 4-CH2 groups replaced by NH.
Piperazines exists as deliquescent solid with a saline taste.
CAS: 110-85-0
MF: C4H10N2
MW: 86.14
EINECS: 203-808-3
Synonyms
PIPERAZINE;1,4-DIAZACYCLOHEXANE;AKOS 90646;AKOS BBS-00004315;HEXAHYDRO-1,4-DIAZINE;HEXAHYDROPYRAZINE;DIETHYLENEDIAMINE;Anhydrous Piperazine (PIP)
Piperazines are freely soluble in water and ethylene glycol, but poorly soluble in diethyl ether.
Piperazines are commonly available industrially is as the hexahydrate, (CH2CH2NH)2·6H2O, which melts at 44 °C and boils at 125–130 °C.
Substituted derivatives of piperazine are a broad class of chemical compounds.
Many piperazines have useful pharmacological properties, prominent examples include viagra, ciprofloxacin, and ziprasidone.
Piperazines are important pharmaceutical intermediate, is mainly used for the production of anthelmintic piperazine phosphate, piperazine citrate and fluphenazine, strong pain, rifampicin, adipic acid piperazine, piperazine guanidine methyl tetracycline, quinoline piperazine phosphate, piperazine thiazole nitrate, enoxacin, hydroxyzine hydrochloride, trifluoperazine, diethylcarbamazine citrate, cinnarizine, flunarizine, decloxizine strong carbamazepine, prednisolone sodium phosphate, dexamethasone sodium phosphate, PPA, norfloxacin, ciprofloxacin, easy to cough piperazine, a piperazine Lee vancomycin, trimethoprim-triazine and other drugs.
Piperazines are also used for the production of surfactants products such as wetting agents, emulsifying agents,and dispersing agents ,and the production of plastic additives such as antioxidants, preservatives, stabilizers and rubber additives.
Piperazines are derived from Dichloroethane by alcohol solution of ammonia.
Needle-like white or colorless crystals.
Shipped as a solid or suspended in a liquid medium.
Very corrosive to skin, eyes and mucous membranes.
Solid turns dark when exposed to light.
Flash point 190°F. Used as a corrosion inhibitor and as an insecticide.
Origin and naming
Piperazines were originally named because of their chemical similarity with piperidine, part of the structure of piperine in the black pepper plant (Piper nigrum).
The -az- infix added to "piperazine" refers to the extra nitrogen atom, compared to piperidine.
Piperazines is important to note, however, that piperazines are not derived from plants in the Piper genus.
Piperazines Chemical Properties
Melting point: 109-112 °C (lit.)
Boiling point: 145-146 °C (lit.)
Density: 1,1 g/cm3
Bulk density: 400kg/m3
Vapor pressure: 0.8 mm Hg ( 20 °C)
FEMA: 4250 | PIPERAZINE
Refractive index: 1.4460
Fp: 65 °C
Storage temp.: Store below +30°C.
Solubility H2O: 0.1 M at 20 °C, clear, colorless
Pka: 9.83(at 23℃)
Form: Crystalline Flakes
Color: White to slightly yellow
Odor: at 0.10 % in dipropylene glycol. ammoniacal
PH: 11.0-12.5 (25℃, 0.1M in H2O)
Explosive limit: 14%
Odor Type: ammoniacal
Biological source: rabbit
Water Solubility :150 g/L (20 ºC)
Sensitive: Air Sensitive & Hygroscopic
λmax λ: 260 nm Amax: 0.035
λ: 280 nm Amax: 0.010
JECFA Number: 1615
Merck: 14,7464
BRN: 102555
Exposure limits ACGIH: TWA 0.03 ppm
Stability: Stable. Hygroscopic. Light sensitive. Flammable. Incompatible with strong oxidizing agents.
InChIKey: GLUUGHFHXGJENI-UHFFFAOYSA-N
LogP: -1.24 at 20-25℃
CAS DataBase Reference: 110-85-0(CAS DataBase Reference)
NIST Chemistry Reference: Piperazine(110-85-0)
EPA Substance Registry System: Piperazine (110-85-0)
Uses
As an anthelmintic
Piperazines was marketed by Bayer as an anthelmintic in the early 20th century, and was featured in print ads alongside other popular Bayer products at the time, including heroin.
In fact, a large number of piperazine compounds have an anthelmintic action.
Their mode of action is generally by paralysing parasites, which allows the host body to easily expel the invasive organism.
The neuromuscular effects are thought to be caused by blocking acetylcholine at the myoneural junction.
This action is mediated by its agonist effects upon the inhibitory GABA (γ-aminobutyric acid) receptor.
Piperazines's selectivity for helminths is because vertebrates use GABA only in the CNS, and the GABA receptor of helminths is of a different isoform from that of vertebrates.
Piperazine hydrate, piperazine adipate and piperazine citrate (used to treat ascariasis and enterobiasis) are the most common anthelmintic piperazine compounds.
These drugs are often referred to simply as "piperazine" which may cause confusion between the specific anthelmintic drugs, the entire class of piperazine-containing compounds, and the compound itself.
Two common salts in the form of which piperazine is usually prepared for pharmaceutical or veterinary purposes are the citrate, 3C4H10N2·2C6H8O7 (i.e. containing 3 molecules of piperazine to 2 molecules of citric acid), and the adipate, C4H10N2·C6H10O4 (containing 1 molecule each of piperazine and adipic acid).
Piperazines derivatives as drugs
See also: Substituted piperazine
Many notable drugs contain a piperazine ring as part of their molecular structure.
They may be used as antiparasitic drugs.
Other examples include: Diethylcarbamazine, a derivative of piperazine, is used to treat some types of filariasis.
Most of these agents can be classified as either phenylpiperazines, benzylpiperazines, diphenylmethylpiperazines (benzhydrylpiperazines), pyridinylpiperazines, pyrimidinylpiperazines, or tricyclics (with the piperazine ring attached to the heterocyclic moiety via a side chain).
Other uses
Piperazines also a fluid used for CO2 and H2S scrubbing in association with methyl diethanolamine (MDEA).
Pharmacology and mechanism of action
Piperazines are a heterocyclic organic base widely used as an anthelminthic.
Piperazines was originally developed for the treatment of gout.
Piperazines's first successful use in helminthiasis was reported by Mouriquand et al. in 1951.
Presently the drug is used in the treatment of infections caused by Ascaris lumbricoides and Enterobius vermicularis.
The drug causes flaccid paralysis in susceptible worms and the parasites lose their attachment to the intestinal wall, and are swept away by the normal bowel peristalsis.
The biochemical mechanism behind this action is uncertain.
Piperazine causes hyperpolarization of the Ascaris muscle rendering it unresponsive to acetylcholine.
Synthesis and structure
Piperazines is formed by the ammoniation of 1,2-dichloroethane or ethanolamine.
This reaction is mainly used for production of ethylene diamine, but piperazine is a side product.
Piperazines is separated from the product stream, which, in addition to ethylenediamine, also contains various derivatives containing CH2CH2NH subunits, e.g. diethylenetriamine, aminoethylpiperazine, and other related linear and cyclic chemicals of this type.
Piperazines can also be synthesized by reduction of pyrazine with sodium in ethanol.
As confirmed by X-ray crystallography, piperidine is a centrosymmetric molecule.
The ring adopts a chair conformation and the two N-H groups are equatorial.
Clinical Use
Hexahydropyrazine or diethylenediamine (Arthriticine,Dispermin) occurs as colorless, volatile crystals of the hexahydratethat are freely soluble in water.
After the discoveryof the anthelmintic properties of a derivative diethylcarbamazine,the activity of piperazine itself was established.
Piperazines is still used as an anthelmintic for the treatmentof pinworm (Enterobius [Oxyuris] vermicularis) and roundworm(Ascaris lumbricoides) infestations.
Piperazines is available invarious salt forms, including the citrate (official in the USP)in syrup and tablet forms.
Piperazines blocks the response of the ascaris muscleto acetylcholine, causing flaccid paralysis in the worm,which is dislodged from the intestinal wall and expelled inthe feces.
Reactions
Piperazines's basicity is that of a typical amine.
The pH of a 10% aqueous solution of piperazine is 10.8–11.8.
The two pKb's are 5.35 and 9.73 at 25 °C.
Piperazines readily absorbs water and carbon dioxide from the air.
Carbon dioxide produce a series of carbamates.
Some of the relevant equilibria are:
HN(CH2CH2)2NH + CO2 ⇌ H2N+(CH2CH2)2NCO−22 HN(CH2CH2)2NH + CO2 ⇌ HN(CH2CH2)2NCO−2 +(CH2CH2)2NH+2H2N+(CH2CH2)2NCO−2+ CO2 ⇌ HO2CN(CH2CH2)2NCO2H
As a basic amine, piperazines forms a variety of coordination complexes, usually binding to metals as a unidentate ligand (bidentate binding would require the boat conformation).
One example is the polymer [CoCl2(piperazine)]n, which features tetrahedral cobalt centers linked by bridging piperazine ligands.
Piperazine is easily N-alkylated.
Depending on conditions mono- or dialkyl derivatives are obtained.
Side effects
Side effects commonly encountered with the recommended doses of piperazines are nausea, vomiting, abdominal cramps and diarrhoea which are usually mild and self-limiting.
Although absolute incidence is unknown, severe side effects reported in the literature are rare.
They can be classified into:
1. Allergic reactions such as urticaria, exantema, hypersensitivity, lacrimation, rhinorrea, productive cough, and bronchospasm.
2. Neuro-psychological reactions:
(a) cerebral type such as vertigo, dizziness, tremor, incoordination, ataxia and hypotonia with EEG changes;
(b) psychic type such as depersonalization, hallucination and paranoic reactions;
(c) miscellaneous such as headache, visual disturbances, somnolence, coma and an increase in the number of petit mal attacks.
Neuro-psychological reactions are rare.
Most cases reported concern children with pre disposing factors like neurological symptoms, renal diseases or those who have been treated with high doses of piperazine.
One case of haemolytic anaemia in a patient with G6PD deficiency, and one case of toxic hepatitis have also been reported.
However, no causal relationships can be established from these cases.
Nitrosation of piperazines to the potential carcinogen N-mononitrosopiperazine in the stomach of patients treated with normal therapeutic doses has been reported.
However, carcinogenicity related to the use of piperazines has not been reported despite the use of the drug over many years.
In any case, Piperazines are unlikely to have any clinical implications with the short treatment period of nematodes.
