DIMETHYLFORMAMIDE

DIMETHYLFORMAMIDE

CAS No. : 68-12-2
EC No. : 200-679-5

Synonyms:
N,N-Dimethylformamide; Dimethylformamide; N,N-Dimethylmethanamide; DMF; N,N-Dimethylformamide; N,N-DIMETHYLFORMAMIDE; Dimethylformamide; 68-12-2; N,N-Dimethylmethanamide; Dimethyl formamide; N-Formyldimethylamine; Formamide, N,N-dimethyl-; Dimethylformamid; DMF; DMFA; Dimetilformamide; Dwumetyloformamid; Formyldimethylamine; N,N-Dimethyl formamide; Dimethylforamide; Dimetylformamidu; DMF (amide); NCI-C60913; dimethyl-Formamide; n,n,dimethylformamide; N,N-Dimethylformamid; Dimethylamid kyseliny mravenci; Caswell No. 366A; Dimetylformamidu [Czech]; Dimethylformamid [German]; Dimetilformamide [Italian]; Dwumetyloformamid [Polish]; UNII-8696NH0Y2X; CCRIS 1638; N,N-Dimetilformamida [Spanish]; n,n-dimethyl-Formamide; N, N-dimethylformamide; N,N'-Dimethylformamide; N,N- Dimethylformamide; N,N-Dimethylformaldehyde; NSC 5356; Formic acid, amide, N,N-dimethyl-; EINECS 200-679-5; UN2265; Dimethylamid kyseliny mravenci [Czech]; EPA Pesticide Chemical Code 366200; N,N Dimethylformamide; CAS-68-12-2; N,N-Dimethylformamide, 99+%, extra pure; N,N-Dimetilformamida; N,N-Dimethylformamide, 99.5%, for analysis; N,N-Dimethylformamide, for HPLC, >=99.9%; N,N-Dimethylformamide, 99.8+%, ACS reagent; N,N-Dimethylformamide, 99.8%, for spectroscopy; N,N-Dimethylformamide, ACS reagent, >=99.8%; N, N-dimethyl formamide; Dimethylformamide, N,N-; N,N-Dimethylformamide, 99.8%, for peptide synthesis; N,N-Dimethylformamide, 99.8+%, for spectroscopy ACS; N,N-Dimethylformamide, 99.8%, Extra Dry, AcroSeal(R); dimethlforamide; dimethlformamide; dimethyformamide; dimetylformamide; N,N-Dimethylformamide, 99.9%, for biochemistry, AcroSeal(R); dimehtylformamide; dimethlyformamide; dimethyiformamide; dimethy formamide; dimethyl foramide; dimethyl formamid; dimehtylformarnide; dimethylformarnide; dimethylforrnamide; dirnethylformamide; N,N-Dimethylformamide, 99.8%, Extra Dry over Molecular Sieve, AcroSeal(R); di-methylformamide; dimethylf ormamide; dimethylform amide; dimethylform-amide; dimethylformamid e; dimethylformamide-; dirnethylformarnide; N,N-Dimethylformamide, 99.8%, for molecular biology, DNAse, RNAse and Protease free; n-dimethylformamide; dimethyl form-amide; dimethyl- formamide; dimethylfor- mamide; DMF,SP Grade; N,n-dimethylforamide; formamide, dimethyl-; N,N-dimethlformamide; N,N-dimethyformamide; N,N-dimetylformamide; n,n.dimethylformamide; N,N'dimethylformamide; N,N-dimethvlformamide; N.N-dimethylformamide; HCONMe2; Formamide,N-dimethyl-; N, N-dimethylforamide; N, N-dimethylformaldehyde; bmse000709; EC 200-679-5; D.M.F; HCON(CH3)2; Dynasolve 100 (Salt/Mix); CHEMBL268291; D.M.F.; N,N-Dimethylformamide, 99.8%; N,N-Dimethylformamide HPLC grade; N,N-Dimethylformamide, ACS grade; ZINC901648; Dimethylformamide Reagent Grade ACS; N,N-Dimethylformamide, HPLC Grade; Tox21_201259; Tox21_300039; ANW-13584; s6192; STL264197; N,N-Dimethylformamide, LR, >=99%; AKOS000121096; FORMIN ACID,AMIDE,N,N-DIMETHYL; N,N-Dimethylformamide, p.a., 99.8%; N,N-Dimethylformamide, AR, >=99.5%; Dimethylformamide, n,n- Reagent Grade ACS; N,N-Dimethylformamide, analytical standard; N,N-Dimethylformamide, anhydrous, 99.8%; N,N-Dimethylformamide, 99.5%, for HPLC; N,N-Dimethylformamide, for HPLC, >=99.5%; N,N-Dimethylformamide, AldraSORB(TM), 99.8%; N,N-Dimethylformamide, ReagentPlus(R), >=99%; A836012; N,N-Dimethylformamide, biotech. grade, >=99.9%; Q409298; N,N-Dimethylformamide [UN2265] [Flammable liquid]; N,N-Dimethylformamide, p.a., ACS reagent, 99.8%; N,N-Dimethylformamide, SAJ first grade, >=99.0%, anhydrous, ZerO2(TM), 99.8%; N,N-Dimethylformamide, for molecular biology, >=99%; N,N-Dimethylformamide, JIS special grade, >=99.5%; N,N-Dimethylformamide, UV HPLC spectroscopic, 99.7%; N,N-Dimethylformamide, ACS spectrophotometric grade, >=99.8%; N,N-Dimethylformamide, B&J Brand (product of Burdick & Jackson); N,N-Dimethylformamide, Vetec(TM) reagent grade, anhydrous, >=99.8%; Dimethylformamide, Pharmaceutical Secondary Standard; Certified Reference Material; N,N-Dimethylformamide, 99.8%, Extra Dry, AcroSeal(R), package of 4x25ML bottles; N,N-Dimethylformamide, p.a., ACS reagent, reag. ISO, reag. Ph. Eur., 99.8%; N,N-Dimethylformamide, puriss. p.a., ACS reagent, reag. Ph. Eur., >=99.8% (GC); N,N-Dimethylformamide, suitable for neutral marker for measuring electroosmotic flow (EOF), ~99%

Dimethylformamide

Dimethylformamide is an organic compound with the formula (CH3)2NC(O)H. Commonly abbreviated as DMF (although this initialism is sometimes used for dimethylfuran, or dimethyl fumarate), this colourless liquid is miscible with water and the majority of organic liquids. DMF is a common solvent for chemical reactions. Dimethylformamide is odorless, but technical-grade or degraded samples often have a fishy smell due to impurity of dimethylamine. Dimethylamine degradation impurities can be removed by sparging degraded samples with an inert gas such as argon or by sonicating the samples under reduced pressure. As its name indicates, it is a derivative of formamide, the amide of formic acid. Dimethylformamide is a polar (hydrophilic) aprotic solvent with a high boiling point. It facilitates reactions that follow polar mechanisms, such as SN2 reactions.

Properties
Chemical formula C3H7NO
Molar mass 73.095 g·mol−1
Appearance Colourless liquid
Odor fishy, ammoniacal
Density 0.948 g/mL
Melting point −78 °C (−108 °F; 195 K)
Boiling point 153 °C (307 °F; 426 K)
Solubility in water Miscible
log P −0.829
Vapor pressure 516 Pa
Acidity (pKa) -0.3 (for the conjugate acid) (H2O)[3]
UV-vis (λmax) 270 nm
Absorbance 1.00
Refractive index (nD) 1.4305 (at 20 °C)
Viscosity 0.92 mPa s (at 20 °C)

Structure and properties
As for most amides, the spectroscopic evidence indicates partial double bond character for the C-N and C-O bonds. Thus, the infrared spectrum shows a C=O stretching frequency at only 1675 cm−1, whereas a ketone would absorb near 1700 cm−1.

Dimethylformamide is a classic example of a fluxional molecule.

DimethylformamideDNMR.png
The ambient temperature 1H NMR spectrum shows two methyl signals, indicative of hindered rotation about the (O)C-N bond.[6] At temperatures near 100 °C, the 500 MHz NMR spectrum of this compound shows only one signal for the methyl groups.

Dimethylformamide is miscible with water.[8] The vapour pressure at 20 °C is 3.5 hPa.[9] A Henry's law constant of 7.47 × 10−5 hPa m3 mol−1 can be deduced from an experimentally determined equilibrium constant at 25 °C.[10] The partition coefficient log POW is measured to −0.85.[11] Since the density of Dimethylformamide (0.95 g cm−3 at 20 °C[8]) is similar to that of water, significant flotation or stratification in surface waters in case of accidental losses is not expected.

Reactions
Dimethylformamide is hydrolyzed by strong acids and bases, especially at elevated temperatures. With sodium hydroxide, Dimethylformamide converts to formate and dimethylamine. Dimethylformamide undergoes decarbonylation near its boiling point to give dimethylamine. Distillation is therefore conducted under reduced pressure at lower temperatures.

In one of its main uses in organic synthesis, Dimethylformamide was a reagent in the Vilsmeier–Haack reaction, which is used to formylate aromatic compounds. The process involves initial conversion of Dimethylformamide to a chloroiminium ion, [(CH3)2N=CH(Cl)]+, known as a Vilsmeier reagent,[15] which attacks arenes.

Organolithium compounds and Grignard reagents react with Dimethylformamide to give aldehydes after hydrolysis in a reaction named after Bouveault.[16]

Dimethylformamide forms 1:1 adducts with a variety of Lewis acids such as the soft acid I2, and the hard acid phenol. It is classified as a hard Lewis base and its ECW model base parameters are EB= 2.19 and CB= 1.31. Its relative donor strength toward a series of acids, versus other Lewis bases, can be illustrated by C-B plots.

Production
Dimethylformamide was first prepared in 1893 by the French chemist Albert Verley (8 January 1867 – 27 November 1959), by distilling a mixture of dimethylamine hydrochloride and potassium formate.

Dimethylformamide is prepared by combining methyl formate and dimethylamine or by reaction of dimethylamine with carbon monoxide.
Although currently impractical, Dimethylformamide can be prepared from supercritical carbon dioxide using ruthenium-based catalysts.

Applications
The primary use of Dimethylformamide is as a solvent with low evaporation rate. Dimethylformamide is used in the production of acrylic fibers and plastics. It is also used as a solvent in peptide coupling for pharmaceuticals, in the development and production of pesticides, and in the manufacture of adhesives, synthetic leathers, fibers, films, and surface coatings.[8]

It is used as a reagent in the Bouveault aldehyde synthesis and in the Vilsmeier-Haack reaction, another useful method of forming aldehydes.
It is a common solvent in the Heck reaction.
It is also a common catalyst used in the synthesis of acyl halides, in particular the synthesis of acyl chlorides from carboxylic acids using oxalyl or thionyl chloride. The catalytic mechanism entails reversible formation of an imidoyl chloride:
Me2NC(O)H + (COCl)2 → CO + CO2 + [Me2N=CHCl]Cl
The iminium intermediate reacts with the carboxylic acid, abstracting an oxide, and regenerating the Dimethylformamide catalyst.

Reaction to give acyl chloride and Dimethylformamide.png
Dimethylformamide penetrates most plastics and makes them swell. Because of this property Dimethylformamide is suitable for solid phase peptide synthesis and as a component of paint strippers.

Dimethylformamide is used as a solvent to recover olefins such as 1,3-butadiene via extractive distillation.
It is also used in the manufacturing of solvent dyes as an important raw material. It is consumed during reaction.
Pure acetylene gas cannot be compressed and stored without the danger of explosion. Industrial acetylene is safely compressed in the presence of dimethylformamide, which forms a safe, concentrated solution. The casing is also filled with agamassan, which renders it safe to transport and use.
Proper uses
As a cheap and common reagent, Dimethylformamide has many uses in a research laboratory.

Dimethylformamide is effective at separating and suspending carbon nanotubes, and is recommended by the NIST for use in near infrared spectroscopy of such.
Dimethylformamide can be utilized as a standard in proton NMR spectroscopy allowing for a quantitative determination of an unknown compound.
In the synthesis of organometallic compounds, it is used as a source of carbon monoxide ligands.
Dimethylformamide is a common solvent used in electrospinning.
Dimethylformamide is commonly used in the solvothermal synthesis of Metal–Organic Frameworks.
Dimethylformamide-d7 in the presence of a catalytic amount of KOt-Bu under microwave heating is a reagent for deuteration of polyaromatic hydrocarbons.

Safety
Reactions including the use of sodium hydride in Dimethylformamide as a solvent are somewhat hazardous; exothermic decompositions have been reported at temperatures as low as 26 °C. On a laboratory scale any thermal runaway is (usually) quickly noticed and brought under control with an ice bath and this remains a popular combination of reagents. On a pilot plant scale, on the other hand, several accidents have been reported.[30]

On the 20 of June 2018, the Danish Environmental Protective Agency published an article about the Dimethylformamide's use in squishies. The density of the compound in the toy resulted in all squishes being removed from the Danish market. All squishies were recommended to be thrown out as household waste. 

Toxicity
The acute LD50 (oral, rats and mice) is 2.2–7.55 g/kg.[8] Hazards of Dimethylformamide have been examined.

Description
General description
N,N-Dimethylformamide (DMF) is the commonly employed solvent for chemical reactions. DMF is a useful solvent employed for the isolation of chlorophyll from plant tissues.[4] It is widely employed reagent in organic synthesis. It plays multiple roles in various reactions such as solvent, dehydrating agent, reducing agent as well as catalyst. It is a multipurpose building block for the synthesis of compounds containing O, -CO, -NMe2, -CONMe2, -Me, -CHO as functional groups.[1]

N,N-Dimethylformamide is a polar solvent commonly used in organic synthesis. It also acts as a multipurpose precursor for formylation, amination, aminocarbonylation, amidation and cyanation reactions.[1]

Application
N,N-Dimethylformamide (anhydrous) has been used as solvent for the synthesis of cytotoxic luteinizing hormone-releasing hormone (LH-RH) conjugate AN-152 (a chemotherapeutic drug) and fluorophore C625 [4-(N,N-diphenylamino)-4′-(6-O-hemiglutarate)hexylsulfinyl stilbene].[2] It may be employed as solvent medium for the various organic reduction reactions.[3]

Dimethylformamide has been used as a solvent in the following processes:
• Multi-step synthesis of L-azidohomoalanine (L-Aha) during the substitution of the mesylate by sodium azide.[5]
• Synthesis of phosphine-FLAG®, a detection reagent for metabolic labeling of glycans.[6]
• Synthesis of per-O-acetylated 6-azidofucose, a per-O-acetylated azido sugar.[6]
Solvent for many hydrophobic organic compounds.

Pure dimethylformamide is essentially noncorrosive to metals. However, copper, tin and their alloys should be avoided.
N,N-Dimethylformamide is adipolar aprotic solvent.

Dimethylformamide reached an average level of 2.8 ug/L in the blood of subjects exposed to 21 ppm of the vapor for 4 hr, and was undetectable at 4 hr after the exposure; the metabolite, methylformamide, averaged between 1 and 2 mg/L in the blood and this level was maintained for at least 4 hr after exposure. Maximal blood levels of about 14 and 8 ug/L were observed for dimethylformamide and methylformamide, respectively, at 0 and 3 hr, after a 4 hr exposure to 87 ppm of the vapor. Repeated daily exposures to 21 ppm of dimethylformamide did not result in accumulation of the chemical or its metabolite in blood. /Dimethylformamide and methylformamide/

Eight healthy male subjects were exposed to dimethylformamide (DMF) vapor at a concn of 8.79 + or - 0.33 ppm for 6 hr daily for 5 consecutive days. All urine voided by the subjects was collected from the beginning of the first exposure to 24 hr past the end of the last exposure and each sample was analyzed for monomethylformamide. Monomethylformamide was rapidly eliminated from the body with urine values peaking within a few hours following the end of each exposure period. The mean for the 7 hr (end of exposure) sample was 4.74 mg/mL.

The amount of N-methylformamide recovered in the urine represents only 2-6% of the dose of dimethylformamide inhaled. A substantial portion of an absorbed dose of DMF is excreted unchanged in the expired breath. The urinary concn of N-methylformamide is probably the best index of worker exponent dimethylformamide.

It is known that dimethylformamide is metabolized in man by sequential N-demethylation to methylformamide and formamide, which are largely eliminated in the urine.

Dimethylformamide is primarily used as an industrial solvent. Dimethylformamide solutions are used to process polymer fibers, films, and surface coatings; to permit easy spinning of acrylic fibers; to produce wire enamels, and as a crystallization medium in the pharmaceutical industry.

USES 
Dimethylformamide is used as an industrial solvent and in the production of fibers, films, and surface coatings. Acute (short-term) exposure to dimethylformamide has been observed to damage the liver in animals and in humans. Symptoms of acute exposure in humans include abdominal pain, nausea, vomiting, jaundice, alcohol intolerance, and rashes. Chronic (long-term) occupational exposure to dimethylformamide by inhalation has resulted in effects on the liver and digestive disturbances in workers. Human studies suggested a possible association between dimethylformamide exposure and testicular cancer, but further studies failed to confirm this relationship. EPA has not classified dimethylformamide with respect to its carcinogenicity.

This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. N,N,-Dimethylformamide is produced, as an intermediate or a final product, by process units covered under this subpart.

Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. N,N,-Dimethylformamide is included on this list. Effective date: 4/13/89; Sunset date: 12/19/95.

The determination of a dimethylformamide metabolite, methylformamide, in the urine of exposed workers has been recommended as a guide to monitoring worker exposure. The fluctuation in the rate of excretion of this metabolite requires that methylformamide determinations be carried out on 24 hr urine specimens. The 24 hr urinary excretion of 50 mg or less of methylformamide is consistent with occupational exposure to 20 ppm of dimethylformamide vapor.

Dimethylformamide exposure to air concn of 3500 ppm is considered immediately dangerous to life or health (IDLH).

N,N-Dimethylformamide's production and use as a solvent, in pharmaceutical intermediate, in acrylic fibers and in plastics may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 3.87 mm Hg at 25 °C indicates N,N-dimethylformamide will exist solely as a vapor in the atmosphere. Vapor-phase N,N-dimethylformamide will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 20 hours. N,N-Dimethylformamide contains chromophores that absorb at wavelengths >290 nm and, therefore, may be susceptible to direct photolysis by sunlight. If released to soil, N,N-dimethylformamide is expected to have very high mobility based upon an estimated Koc of 1. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 7.39X10-8 atm-cu m/mole. N,N-Dimethylformamide may volatilize from dry soil surfaces based upon its vapor pressure. Utilizing the Japanese MITI test, 4.4% of the theoretical BOD was reached in 2 weeks, however, 100% of N,N-dimethylformamide was biodegraded in 9 days using a river die-away test. These results indicate that biodegradation may be an important environmental fate process. If released into water, N,N-dimethylformamide is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's Henry's Law constant. BCFs of 0.3 to 1.2, in carp, suggests bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since neutral hydrolysis rate constants for amides are <10-9/sec under environmental conditions (pH 5 to 9). Occupational exposure to N,N-dimethylformamide may occur through inhalation and dermal contact with this compound at workplaces where N,N-dimethylformamide is produced or used. Monitoring data indicate that the general population may be exposed to N,N-dimethylformamide via inhalation of ambient air and dermal contact with consumer products containing N,N-dimethylformamide. 

N,N-Dimethylformamide's production and use as a solvent, in pharmaceuticals, in acrylic fibers and in plastics(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1(SRC), determined from a structure estimation method(2), indicates that N,N-dimethylformamide is expected to have very high mobility in soil(SRC). Volatilization of N,N-dimethylformamide from moist soil surfaces is not expected to be an important fate process(SRC) given a Henry's Law constant of 7.39X10-8 atm-cu m/mole(3). N,N-Dimethylformamide is expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 3.87 mm Hg at 25 °C(4). N,N-Dimethylformamide may biodegrade in soil based upon river die-away tests (100% in 6 days)(5), however, utilizing the Japanese MITI test, only 4.4% of the theoretical BOD was reached in 2 weeks(6).

Aerobic unacclimated and acclimated river die-away tests showed that N,N-dimethylformamide at an initial concentration of 30 mg/L completely disappeared within 6 and 3 days, respectively(1). However, 24 to 48 hours was required before any degradation was observed among unacclimated samples(1). N,N-Dimethylformamide, present at 100 mg/L, reached 4.4% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 30 mg/L in the Japanese MITI test(2). Aerobic grab sample data for N,N-dimethylformamide in sea water showed a mineralization rate of <3% in 24 hours for initial concentration of 10 ug/L and 100 ug/L(3). However, 20% of N,N-dimethylformamide at a concentration of 0.1 ug/L was mineralized in 24 hrs(3). All samples were adjusted to sterilized controls(3). Aqueous screening test data demonstrated that dimethylformamide was easily removed by sewage treatment facilities upon acclimation(4). Wastewater from a polyimide synthesis operation at Kansas City, MO contained N,N-dimethylformamide at a concentration of 65,500 mg/L before entering a bench scale biological treatment system(5). At feed rates of 90 lb/day/1000 cu ft, effluent from the biological reactor contained N,N-dimethylformamide at a concentration of <10 mg/L(5). The concentration of N,N-dimethylformamide in the reactor sludge was not documented(5).

The rate constant for the vapor-phase reaction of N,N-dimethylformamide with photochemically-produced hydroxyl radicals has been estimated as 1.8X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 20 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Hydrolysis is not expected to be an important environmental fate process since neutral hydrolysis rate constants for amides are <10-9/sec under environmental conditions (pH 5 to 9)(2). N,N-Dimethylformamide contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Dimethylformamide is stable. It is hygroscopic and easily absorbs water form a humid atmosphere and should therefore be kept under dry nitrogen. High purity Dimethylformamide, required for acrylic fibers, is best stored in aluminum tanks. Dimethylformamide dose not change under light or oxygen and does not polymerize spontaneously. Temperatures >350 °C may cause decomposition to form dimethylamine and carbon dioxide, with pressure developing in closed containers.

N,N-Dimethylformamide is metabolized by the microsomal cytochrome p-450 into mainly N-hydroxymethyl- N-methylformamide (HMMF), which further breaks down to N-methyformamide (NMF). However, the detailed mechanism of its toxicity remains unclear. We investigated the metabolism and the toxicity of Dimethylformamide using the isolated perfused liver model. Dimethylformamide was added to the recirculating perfusate of the isolated perfused rat liver at concentrations of 0, 10 and 25 mM. Samples were collected from the inferior vena cava at 0, 30, 45, 60, 75, and 90 minutes following addition of the Dimethylformamide. The metabolites of Dimethylformamide were analyzed using Gas-chromatography (GC). The changes in the rate of oxygen consumption by the Dimethylformamide were monitored during perfusion. The enzyme activities (aspartic aminotransferase:AST, alanine aminotransferase:ALT, and lactic dehydrogenase:LDH)) in the perfusate were monitored to see if Dimethylformamide caused hepatotoxicity. As the perfusion progressed, the Dimethylformamide concentration in the perfusate decreased, but the level of NMF increased to a maximum of 1.16 mM. The rate of oxygen consumption increased at Dimethylformamide concentrations of 10 mM and 25 mM. However, when a known inhibitor of cytochrome P-450, SKF 525A (300 uM), was used to pretreat the perfusate prior to the addition of the Dimethylformamide, the rate of oxygen consumption was significantly inhibited, indicating the cytochrome P-450 system was responsible for the conversion of Dimethylformamide to NMF. On addition of the Dimethylformamide, the activities of the enzymes AST, ALT and LDH were significantly increased a time and dose dependent manner. However, following pretreatment with SKF 525A, their releases were inhibited.

Blood and urine samples of rats and dogs which had been exposed to Dimethylformamide were examined by GLC analysis and N-methylformamide(NMF) and formamide were detected in addition to Dimethylformamide. These metabolites were eliminated faster in rats than in dogs. It has been suggested recently that the major metabolite of Dimethylformamide which has been characterized an NMF by GLC is no NMF but N-hydroxymethyl-N-methylformamide (HMMF). HMMF is the immediate product of methyl C-hydroxylation of Dimethylformamide and is a relatively stable carbinolamide in aqueous soln. It is, however thermally labile so that it decomposes quantitatively to NMF and presumably formaldehyde on the GLC column. The evidence that the metabolite which has been characterized as NMF is really HMMF is based on three studies. /One study/ found a formaldehyde precursor in the urine of mice which had received Dimethylformamide. This metabolite liberated formaldehyde only after alkaline hydrolysis. In aqueous soln, authentic HMMF also decomposed to formaldehyde only on alkaline hydrolysis. /Another study/ isolated a urinary metabolite of Dimethylformamide in rats by HPLC and subjected it to mass spectrometric analysis. The observed fragmentation pattern suggested the presence of HMMF, even though the mass fragments, including the one corresponding to the molecular ion, were also detected in control urine samples. Unequivocal evidence for the contention that HMMF and not NMF is the major metabolite of Dimethylformamide was recently obtained by high-field proton NMF spectroscopy of urine samples of mice which had received Dimethylformamide. HMMF exists in 2 rotameric forms and the methyl and formyl protons in the two rotamers are not equivalent. The resonance frequencies corresponding to the methyl and formyl protons of both rotamers were prominent signals in the NMR spectrum of the urine. However, at the resonance frequency of the methyl protons of NMF only a minute signal was observed. In this study dimethylamine and methylamine were found to be minor urinary metabolites of Dimethylformamide in mice.

In mice, 56% of the dose of 400 mg/kg Dimethylformamide given ip was metabolized to HMMF. However, C-hydroxylation occurred at a very slow rate when Dimethylformamide was incubated with liver fractions. The metabolic oxidation of Dimethylformamide in vitro has been suggested to be mediated, at least in part, by hydroxyl radicals and hydrogen peroxide, as this metabolic route measured in rat liver microsomes was reduced in the presence of catalase, superoxide dismutase, and the radical scavengers DMSO, t-butanol, aminopyrine and hydroquinone. Dimethylformamide itself inhibited the oxidation of DMSO, t-butanol and aminopyrine.

The major pathway of dimethylformamide metabolism is hydroxylation of one of the methyl groups, giving N-hydroxymethyl-N-methylformamide, which is unstable in many analytical manipulations and readily decomposes to N-methylformamide. N-Hydroxymethyl-N- methylformamide was underestimated, or not detected at all, in a number of early studies for this reason. The formation of N-hydroxymethyl-N-methylformamide is a cytochrome p450 dependent reaction mediated by CYP2EI in rat liver microsomes. The reaction mediated by human liver microsomes was inhibited by a monospecific antibody against rat liver.

The primary metabolic product and major urinary excretion product of Dimethylformamide /Dimethylformamide/ has been identified as N-(hydroxymethyl-N-methyl formamide (HMMF) which rapidly decomposes to MMF. The oxidation Dimethylformamide to HMMF is mediated by cytochrome P-450. Secondary metabolites of Dimethylformamide have been identified, including formamide, a product formed by the oxidation of the formyl group yielding N-acetyl-S-(N)methylcarbamoyl cysteine (AMCC), and an unidentified reactive intermediate.

Only a small amount of Dimethylformamide administered to animals is excreted unchanged in the urine. The demethylated product (NMF) was identified in the urine of rats treated with Dimethylformamide. Both NMF and hydroxylated-Dimethylformamide were found in mouse urine but separation by standard techniques is difficult. Blood levels of Dimethylformamide were low following oral doses to rats but were somewhat proportional to the given dose.

N,N-Dimethylformamide is an organic solvent extensively used in industries such as synthetic leather, fibers and films, and induces liver toxicity and carcinogenesis. Despite a series of experimental and clinical reports on Dimethylformamide-induced liver failure, the mechanism of toxicity is yet unclear. This study investigated whether Dimethylformamide in combination with a low dose of hepatotoxicant enhances hepatotoxicity, and if so, on what mechanistic basis. Treatment of rats with either Dimethylformamide (50-500 mg/kg/day, for 3 days) or a single low dose of CCl(4) (0.2mL/kg) alone caused small increases in plasma transaminases and lactate dehydrogenase activities. However, combinatorial treatment of Dimethylformamide with CCl(4) markedly increased blood biochemical changes. Histopathology confirmed the synergism in hepatotoxicity. Moreover, Dimethylformamide+CCl(4) caused PARP cleavage and caspase-3 activation, but decreased the level of Bcl-xL, all of which confirmed apoptosis of hepatocytes. Consistently, Dimethylformamide+CCl(4) treatment markedly increased lipid peroxidation. By contrast, treatment of Dimethylformamide in combination with lipopolysaccharide, acetaminophen or d-galactosamine caused no enhanced hepatotoxicity. Given the link between endoplasmic reticulum (ER) dysfunction and cell death, ER stress response was monitored after Dimethylformamide and/or CCl(4) treatment. Whereas either Dimethylformamide or CCl(4) treatment alone marginally changed the expression levels of glucose-regulated protein 78 and 94 and phosphorylated PKR-like ER-localized eIF2alpha kinase, concomitant treatment with Dimethylformamide and CCl(4) synergistically induced them with increases in glucose-regulated protein 78 and C/EBP homologous protein mRNAs. /These/ results demonstrate that Dimethylformamide treatment in combination with CCl(4) synergistically increases hepatocyte death, which may be associated with the induction of severe ER stress.

The direct or one-step synthesis of Dimethylformamide begins with either pure carbon monoxide or a gas stream containing carbon monoxide. This is reacted in a continuous process with N,N-dimethylamine, by using a solution of alkali alkoxide (usually sodium methoxide) in methanol as catalyst. Methyl formate is presumably formed as an intermediate. The reaction mixture passes over an external heat exchanger to remove the excess heat generated and to ensure thorough mixing of the components. The reaction is conducted between 0.5 and 11 MPa at 50 - 200 °C. The reaction mixture exits the reactor through a decompression chamber. In addition to N,N-dimethylformamide, the crude product contains methanol, a certain amount of unreacted N,N-dimethylamine, dissolved carbon monoxide, and residual catalyst. The addition of acid or water deactivates any catalyst present, resulting in the formation of sodium formate. Dissolved carbon monoxide, together with inert gases, escapes from the mixture during decompression, and the off-gases are removed by combustion. Preliminary distillation is followed by a second distillation in a separate column; here, dimethylformamide is separated from methanol which contains traces of N,N-dimethylamine. Further distillation results in a product of 99.9%purity.

/The aim of this study is/ to assess the suitability of different methods for biological monitoring of internal dose to N,N-Dimethylformamide in occupational settings. The determination of urinary metabolites of Dimethylformamide, N-hydroxymethyl- N-methylformamide (HMMF), N-methylformamide (NMF) and N-acetyl- S-(N-methylcarbamoyl) cysteine (AMCC) was carried out by four selected analytical procedures. Two methods solely measured total NMF (HMMF and NMF). The other two methods measured both total NMF and AMCC in one analytical run. All four methods were tested on 34 urine samples from workers exposed to Dimethylformamide. Comparison of the four methods for determination of total NMF in urine showed that results were similar for three methods, while the remaining one provided NMF levels significantly lower (by 22%) than the other methods. Thus, all but one of the tested methods for the determination of total NMF can be considered to be suitable for biological monitoring of internal dose to Dimethylformamide. The two tested methods for the determination of AMCC afforded results that showed high correlation but differed significantly (by 10%). The choice of the biomonitoring method depends mainly on the purpose for which the measurement is conducted. For evaluation of acute exposures or to assess safety measures in the working area, an updated version of the traditional method of Kimmerle and Eben (1975)for the determination of total NMF in urine is sufficient. For risk assessment after exposure to Dimethylformamide, the determination of AMCC should be carried out, since AMCC, but not total NMF, is supposed to be related to the toxicity of Dimethylformamide. However, there is still a need to develop an easier, more sensitive and more selective method for the determination of AMCC in urine until AMCC can be considered for regulatory purposes in occupational settings.

N-Hydroxymethyl-N-methylformamide (HMMF) and N-methylformamide (NMF) in urine samples from workers exposed to N,N-Dimethylformamide cannot be distinguished by a gas chromatographic method because HMMF is converted to NMF at the injection port of gas chromatography (GC). Total NMF (HMMF+NMF) has been measured instead. Also, the determination of N-acetyl-S-(N-methylcarbamoyl)cystein (AMCC), which is supposed to be related to the toxicity of Dimethylformamide, needs multiple treatments to convert to a volatile compound before GC analysis. There is no previous report of a simultaneous determination of three major metabolites of Dimethylformamide in urine. The aim of this study is to develop a simple and selective method for the determination of Dimethylformamide metabolite in urine. By using a liquid chromatography-tandem mass spectrometry, we can directly distinguish these three major metabolites of Dimethylformamide in a single run. The diluted urine samples were analyzed on Capcell Pak MF SG80 column with the mobile phase of methanol in 2mM formic acid (10:90, v/v). The analytes were detected by an electrospray ionization tandem mass spectrometry in the multiple-reaction-monitoring mode. The standard curves were linear (r>0.999) over the concentration ranges of 0.004-8 microg/mL. The precision and accuracy of quality control samples for inter-batch (n=6) analyses were in the range of 1.3-9.8% and 94.7-116.8, respectively. The sum of each HMMF and NMF concentration determined by LC-MS/MS method shows high correlation (r=0.9927 with the slope of 1.0415, p<0.0001) with NMF included HMMF concentration determined by GC method for 13 urine samples taken from workers exposed to Dimethylformamide. The excretion ratio of HMMF:NMF:AMCC is approximately 4:1:1 in molar concentration.

After a thermal runaway reaction during chlorination in Dimethylformamide solution, investigation revealed that saturated solutions of chlorine in Dimethylformamide are hazardous, and will self-heat and erupt under either adiabatic or non-adiabatic conditions.

Bromine and dimethylformamide interaction is extremely exothermic and under confinement in an autoclave the internal temperature and pressure exceeded 100 °C and 135 bar, causing failure of the bursting disc.

Addition of potassium permanganate to Dimethylformamide to give a 20% (approx saturated) solution led to an explosion after 5 min. Subsequent tests on 1 g of oxidant with 5 g of solvent showed a rapid exotherm after 3-4 min, accompanied by popping noises from undissolved oxidant.

A veterinary euthanasia drug containing embutramide, mebezonium, tetracaine, and dimethylformamide (Dimethylformamide; T-61 or Tanax) may cause serious manifestations or even fatalities after self-poisoning. Immediate toxicity is mainly due to a general anesthetic and due to a neuromuscular blocking agent, while delayed hepatotoxicity seems related to the solvent Dimethylformamide. The protective role of N-acetylcysteine (NAC) administration remains debatable. Two male veterinarians (50- and 44-year-old) attempted suicide by injecting T-61 in the precordial area for the first one, and by ingesting 50 mL for the second. Both received NAC (for 14 days in the first case and only for 20 hr in the second). Urine was collected for the serial determination of Dimethylformamide, N-methylformamide (NMF), and N-acetyl-S-(N-methylcarbamoyl)cysteine (AMCC). Both patients developed only mild signs of liver injury. The metabolite of Dimethylformamide, NMF, appeared rapidly in the urine, while a further delay was necessary for AMCC excretion. The kinetics of elimination of Dimethylformamide and Dimethylformamide metabolites were slightly slower than those reported in exposed workers. While both patients had a favorable outcome, there is no clear evidence that NAC could directly influence NMF and AMCC excretion.

Dimethylformamide ... is an organic solvent produced in large quantities through-out the world. It is used in the chemical industry as a solvent, an intermediate & an additive. Dimethylformamide is a colorless liquid with an unpleasant slight odor that ... has poor warning properties & individuals may be exposed through the inhalation of vapor. Occupational exposure occurs via skin contact with dimethylformamide liquid & vapors. ... Toxic amounts of dimethylformamide may be absorbed by inhalation & through the skin. Absorbed dimethylformamide is distributed uniformily. The /metabolism/ of dimethylformamide takes place mainly in the liver, with the aid of microsomal enzyme systems. In animals & humans, the main product of dimethylformamide biotransformation is N-hydroxymethyl-N-methylformamide. This metabolite is converted during gas chromatographic analysis to N-methylformamide, which itself (together with N-hydroxymethylformamide & formamide) a minor metabolite. ... In metabolic studies & biological monitoring, urinary concentration are expressed as N-hydroxymethylformamide. ... The determination of the /metabolites/ ... in the urine may be a suitable biological indicator of total dimethylformamide exposure. In experimental animals, it has been demonstrated that dimethylformamide metabolism is saturated at high levels &, at very high levels, dimethylformamide inhibits its own metabolism. Metabolic interaction occurs between dimethylformamide & ethanol. ... The effects of dimethylformamide on the environment have not been well studied. The toxicity for aquatic organisms appears to be low ... The acute toxicity of dimethylformamide in a variety of species is low ... . It is a slight to moderate skin & eye irritant. One study on guinea pigs indicated no sensitization potential. Dimethylformamide can facilitate the absorption of other chemical substances through the skin. Exposure of experimental animals to dimethylformamide via all routes of exposure may cause dose related liver injury. ... In some studies, signs of toxicity in the myocardium & kidneys have been /noted/. Dimethylformamide was ... found to be inactive, both in vitro & in vivo, in an extensive set of short term tests for genetic & related effects. No adequate long term carcinogenicity studies on experimental animals have been reported. ... Skin irritation & conjunctivitis have been reported after direct contact with dimethylformamide in /humans/. After accidental exposure to high levels of /this cmpd/, abdominal pain, nausea, vomiting, dizziness & fatigue occur within 48 hr. Liver function may be disturbed, & blood pressure changes, tachycardia & ECG abnormalities have been reported. ... Following long-term repeated exposure, symptoms include headache, loss of appetite & fatigue. Biochemical signs of liver dysfunction may be observed. Exposure to dimethylformamide, even at concn below 30 mg/cu m may cause alcohol intolerance. Symptoms may include a sudden facial flush, tightness of the chest, & dizziness sometimes accompanied by nausea & dypsnea. ... There is limited evidence that dimethylformamide is carcinogenic for human beings. An incr in testicular tumors was reported in one study, whereas another study showed incr incidence of tumors of the buccal cavity & pharynx, but not the testes. In two studies with limited details, an incr frequency of miscarriages was reported in women exposed to dimethylformamide among other chemicals.

The assessment of dimethylformamide exposure can be accomplished through measurement of the metabolites, N-methylformamide or N-acetyl-S-(N-methylcarbamoyl) cysteine. Studies have found that there is a linear relationship between dimethylformamide in air & N-methylformamide levels in urine, with the highest correlation from samples collected the end of the shift, for assessing exposure from that day. The determination of N-methylformamide in the urine actually represents the sum of N-(hydroxymethyl)-N-methylformamide & N-methylformamide. Measurement of N-acetyl-S-(N-methylcarbamoyl) cysteine is found to be an index for assessing exposure during several preceding days since its peak in the urine occurs between 16-40 hr post-exposure, but is not as useful for assessing exposure for a particular day only. Urine Reference Ranges: Normal-None detected; Exposed- BEI (sampling time is end of shift, measured as the metabolite, N-methylformamide): 40 mg/g creatinine (Notice of Intent to Establish or Change: BEI (sampling time is end of shift, measured as the metabolite, N-methylformamide) 15 mg/g creatinine, (Notice of Intent to Establish: BEI (sampling time is prior to last shift of workweek, measured as the metabolite, N-acetyl-S-(N-methylcarbamoyl cysteine) 40 mg/l), BAT (sampling time is end of exposure or end of shift, measured as the metabolite, N-methylformamide): 15 mg/l; Toxic- Not established.

/HUMAN EXPOSURE STUDIES/ N,N-Dimethylformamide could be readily absorbed via skin and inhalation routes. It is difficult, however, to separate the internal dose contribution from skin vapor and inhalation exposure. This study attempts to quantitatively determine the separate skin vapor and inhalation exposure contributions using a semi-actual exposure approach. Six volunteers were tailgated by Dimethylformamide-exposed employees completely for two exposure scenarios: with and without wearing a respirator. Individual airborne Dimethylformamide (A-Dimethylformamide) exposure was evaluated by integrating real-time Dimethylformamide monitoring and time-activity log. Urinary N-methylformamide (U-NMF) concentrations in 4-hr and 8-hr one urine sample plus 24-hr consecutive urine sample were determined to evaluate the internal Dimethylformamide exposure dose. The average A-Dimethylformamide concentrations for all participants were 8.10 (2.75) and 9.52 (3.47) ppm, respectively, for with respirator and without respirator scenarios. Area under the curve of U-NMF throughout 24-hr showed 71% and 29% contribution from skin and inhalation exposure, respectively, indicates that the absorbed dose of Dimethylformamide via skin vapor exposure was much greater than inhalation. In conclusion, the semi-actual approach provides a novel measure to accurately determine the relative skin vapor and inhalation exposure contributions to the internal dose. The skin vapor exposure deserves more attention in the prevention of chemical hazards in the exposed environment.

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1(SRC), determined from a structure estimation method(2), indicates that N,N-dimethylformamide is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon a Henry's Law constant of 7.39X10-8 atm-cu m/mole(4). According to a classification scheme(5), BCFs of 0.3-1.2(6), suggest bioconcentration in aquatic organisms is low(SRC). Hydrolysis is not expected to be an important environmental fate process since neutral hydrolysis rate constants for amides are <10-9/sec under environmental conditions (pH 5 to 9)(7). N,N-Dimethylformamide may biodegrade in the aqueous environment based on river die-away tests (100% in 6 days)(8); however, utilizing the Japanese MITI test, only 4.4% of the theoretical BOD was reached in 2 weeks(6).

According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), N,N-dimethylformamide, which has a vapor pressure of 3.87 mm Hg at 25 °C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase N,N-dimethylformamide is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 20 hours(SRC), calculated from its rate constant of 1.8X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). N,N-Dimethylformamide contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of N,N-dimethylformamide can be estimated to be 1(SRC). According to a classification scheme(2), this estimated Koc value suggests that N,N-dimethylformamide is expected to have very high mobility in soil.

The Henry's Law constant for N,N-dimethylformamide is reported as 7.39X10-8 atm-cu m/mole(1). This Henry's Law constant indicates that N,N-dimethylformamide is expected to be essentially nonvolatile from moist soil and water surfaces(2). The potential for volatilization of N,N-dimethylformamide from dry soil surfaces may exist based upon a vapor pressure of 3.87 mm Hg(3).

N,N-Dimethylformamide was detected in the air over a hazardous waste site in Lowell, MA and a neighboring industry at 2.18 and >50 ppb, respectively(1). N,N-Dimethylformamide was detected in 1 of 63 industrial wastewater effluents at <10 ug/L(2). N,N-Dimethylformamide was detected in the waste effluent of a plastics manufacturer at 28,378 ng/uL of extract(3). Effluent from a New Jersey publically owned treatment works in a rural area with no industrial contribution contained 32 ppb of N,N-dimethylformamide(4). The specific mass emission of N,N-dimethylformamide from a sponge rubber carpet cushion was <1 ug/cu m hr after a 96 hour period in a 52 liter environmental chamber(5). N,N-Dimethylformamide was given off of an operating complete television set and an operating printed circuit board(6).

The mean atmospheric concentration of N,N-dimethylformamide in a synthetic leather factory was 16.5 mg/cu m (range, 3-27 mg/cu m)(1). Workers at leather, polyurethane, and shoe-sole production facilities were exposed to N,N-dimethylformamide concentrations (mean value) in air of 9.1 ppm, 3.9 ppm, and 0.7 ppm, respectively(2).

The specific mass emission of N,N-dimethylformamide from a sponge rubber carpet cushion was <1 ug/cu m hr after a 96 hour period in a 52 liter environmental chamber(1). N,N-Dimethylformamide was reported as a component in tobacco smoke(2).

NIOSH (NOES Survey 1981-1983) has statistically estimated that 124,683 workers (16,011 of these were female) were potentially exposed to N,N-dimethylformamide in the US(1). Occupational exposure to N,N-dimethylformamide may occur through inhalation and dermal contact with this compound at workplaces where N,N-dimethylformamide is produced or used. Monitoring data indicate that the general population may be exposed to N,N-dimethylformamide via inhalation of ambient air and dermal contact with consumer products containing N,N-dimethylformamide(SRC).

The mean environmental concentration of N,N-dimethylformamide in a synthetic leather factory was 16.5 mg/cu m (range, 3-27 mg/cu m)(1). Workers at leather, polyurethane, and shoe-sole production facilities were exposed to N,N-dimethylformamide concentrations (mean value) in air of 9.1 ppm, 3.9 ppm, and 0.7 ppm, respectively(2).

N,N-Dimethylformamide was detected in the urine of synthetic leather factory workers(1); the ave and range of concentrations at the end of shift were 449 ug/L and 100-990 ug/L, respectively, for workers exposed to N,N-dimethylformamide in the workplace(1). Urinary levels of N,N-dimethylformamide (detected as N-monomethylformamide) for workers at leather, polyurethane, and shoe-sole production facilities were 19.7 ppm, 7.8 ppm, and 2.6 ppm, respectively(2).