N -Methyl- N - (trimethylsilyl) trifluoroacetamide

Structural formula
General
Surname	N -Methyl- N - (trimethylsilyl) trifluoroacetamide
other names	2,2,2-trifluoro- N -methyl- N - (trimethylsilyl) acetamide ( IUPAC ) MSTFA
Molecular formula	C 6 H 12 F 3 NOSi
Brief description	clear, colorless liquid
External identifiers / databases
CAS number 24589-78-4 EC number 246-331-6 ECHA InfoCard 100.042.104 PubChem 32510 Wikidata Q27158313
properties
Molar mass	199.25 g mol −1
Physical state	liquid
density	1.075 g cm −3 (25 ° C )
boiling point	78-79 ° C (130 mmHg ) 130-132 ° C (760 mmHg )
Vapor pressure	11.7 hPa (27 ° C)
solubility	soluble in dimethylformamide (DMF) and tetrahydrofuran (THF)
Refractive index	1.4720 (25 ° C, 589 nm)
safety instructions
GHS labeling of hazardous substances Caution H and P phrases H: 226-315-319-335 P: 261-305 + 351 + 338
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . Refractive index: Na-D line , 20 ° C

N -Methyl- N - (trimethylsilyl) trifluoroacetamide (MSTFA) is a silylation reagent forthe introduction of the trimethylsilyl group TMS as a protective group for H-acidic functional groups, especially for hydroxyl groups . MSTFA forms particularly volatile reaction products during silylation and is therefore suitable for the derivatization of low molecular weight compounds for gas chromatographic GC and mass spectrometric MS analyzes.

Occurrence and representation

Manfred Donike synthesized MSTFA the first time in 1969 as a reagent for the production of O -, N - and S -Trimethylsilylderivaten. N -methyl trifluoroacetamide (MTFA) and trimethylchlorosilane react in benzene in the presence of triethylamine to form MSTFA (yield 90–95%).

To isolate the end product, the resulting hygroscopic triethylamine hydrochloride must be filtered off with exclusion of moisture, and the carcinogenic solvent benzene must be distilled off.

Industrially, N -methyl- N - (trimethylsilyl) trifluoroacetamide by reaction of N -Methyltrifluoracetamid and N , O prepared bis- (trimethylsilyl) acetamide (BSA).

The starting compound N -methyltrifluoroacetamide is easily accessible from trifluoroacetic anhydride TFAA or trifluoroacetic acid ethyl ester and methylamine , N , O- bis (trimethylsilyl) acetamide (BSA) from acetamide and trimethylchlorosilane in the presence of triethylamine.

With optimized process management - reaction without solvent, temperature between 40 and 130 ° C. - MSTFA can be obtained in 94% yield in addition to the by-product N- trimethylsilylacetamide (TMS-acetamide), which can also be used as a silylating agent .

properties

N -Methyl- N - (trimethylsilyl) trifluoroacetamide is a clear, colorless and moisture-sensitive liquid.

Applications

The conversion of a para-carboxy group into a nitrile group proceeds quantitatively by dehydration with a copper salt and N- methyl- N - (trimethylsilyl) trifluoroacetamide MSTFA in toluene at 100 ° C.

MSTFA is hydrolyzed to N -methyltrifluoroacetamide and hexamethyldisiloxane .

The most important application for N -Methyl- N - (trimethylsilyl) trifluoroacetamide is the preparation of trimethylsilyl derivatives of compounds that carry hydroxy, carboxy , primary and secondary amino and thiol groups for GC and GC / MS analysis. The trimethylsilyl (TMS) derivatives formed are more volatile, less polar and more thermally stable than the starting substances. In the trimethylsilylation, MSTFA in turn produces N- methyltrifluoroacetamide, which, due to its high volatility, appears before the TMS derivatives in the gas chromatogram, which avoids the undesired overlaying of measurement substance peaks.

The foundations for this were laid by Manfred Donike, who later became known as the “ doping pope”, in several early publications, e. B. for the detection of the catecholamines adrenaline , noradrenaline and dopamine and the phenylalkylamines used as stimulants amphetamine , methamphetamine and ephedrine .

For trimethylsilylation of the less reactive indole alkylamines, such as. B. tryptamine , melatonin and serotonin , mixtures of MSTFA with N- methyltrifluoroacetamide MTFA and imidazole are used.

The reaction can also be accelerated by adding trimethylchlorosilane TMCS, trimethylsilylimidazole (TMS-imidazole) or the very reactive iodotrimethylsilane TMIS.

Also, sex hormones , such as for contraception used ethinyl estradiol or anabolic steroids such as testosterone can in biological samples after derivatization with MSTFA by GC / MS to be determined quantitatively.

Derivatization with MSTFA and subsequent GC / MS is also suitable for determining the structure of organic compounds with active hydrogen atoms.

Individual evidence

1. ↑ ^{a b c d e f} data sheet N-Methyl-N-trimethylsilyltrifluoroacetamide from Sigma-Aldrich , accessed on September 28, 2019 ( PDF ).
2. ↑ ^{a b} M. Donike: N-Methyl-N-trimethylsilyl-trifluoroacetamide, a new silylating agent from the series of silylated amides . In: J. Chromatogr. A . tape 42 , 1969, p. 103-104 , doi : 10.1016 / S0021-9673 (01) 80592-6 .
3. ↑ Ellen M. Leahy: 1,3-Dimethyl-2-imidazolidinone . In: e-EROS Encyclopedia of Reagents for Organic Synthesis . 2001, doi : 10.1002 / 047084289X.rd342 .
4. ↑ Entry on N-Methyl-N-trimethylsilyltrifluoroacetamide at TCI Europe, accessed on September 28, 2019.
5. ↑ ^{a b} D. Urbach: MSTFA and MSTFA-D9 - indispensable tools for the structure determination by mass spectrometry . In: Toxichem Krimtech . tape 79 , no. 3 , 2012, p. 137-146 ( gtfch.org [PDF]).
6. ↑ Patent US4663471 : Method for the preparation of N-methyl-N-trimethylsilyl trifluoroacetamide. Applied on August 14, 1986 , published on May 5, 1987 , Applicant: Shin-Etsu Chemical Co., Ltd., Inventor: T. Shinohara, Y. Inoue. ‌
7. ^ EN Gate et al .: Structural studies on bioactive compounds. 4. A structure-antitumor activity study on analogs of N-methylformamide . In: J. Med. Chem. Volume 29 , no. 6 , 1986, pp. 1046-1052 , doi : 10.1021 / jm00156a024 .
8. ↑ ER Bissell, M. Finger: Fluorine-containing nitrogen compounds. I. Trifluoroethylamines . In: J. Org. Chem. Band 24 , no. 9 , 1959, pp. 1256-1259 , doi : 10.1021 / jo01091a024 .
9. ↑ L. Birkofer, A. Ritter, W. Gießler: Bis-silylated carboxamides . In: Angew. Chem. Band 75 , no. 1 , 1963, p. 93-94 , doi : 10.1002 / anie.19630750127 .
10. ↑ Patent US3397220 : Silylating process and agent. Applied on September 23, 1964 , published August 13, 1968 , applicant: General Electric Co., inventor: JF Klebe. ‌
11. ↑ S. Enthaler, M. Weidauer: Copper-catalyzed dehydration of primary amides to nitriles . In: Catal. Lett. tape 141 , 2014, pp. 1079-1085 , doi : 10.1007 / s10562-011-0660-9 .
12. ↑ Improved Detection & Identification using MSTFA / MSTFA-d ₉ Derivatization - GC / MS Case Study of Amphetamines. In: Contributed Article. Merck KGaA, accessed October 1, 2019 . 
13. ↑ DIED: Manfred Donike . In: Der Spiegel . No. 35 , 1995 ( online - Aug. 28, 1995 ).
14. ↑ M. Donike: N-Trifluoroacetyl-O-trimethylsilyl-phenolalkylamine, representation and mass-specific gas chromatographic detection . In: J. Chromatogr. A . tape 103 , no. 1 , 1975, p. 91-112 , doi : 10.1016 / S0021-9673 (00) 83805-4 .
15. ↑ G. Forsdahl, G. Gmeiner: Investigation of the silylation of ephedrines using N-methyl-N-trimethylsilyl-trifluoroacetamide . In: J. Chromatogr. B . tape 811 , no. 2 , 2004, p. 201–208 , doi : 10.1016 / j.chromb.2004.09.002 .
16. ↑ German Sport University Cologne, Institute for Biochemistry: Stimulant Analysis .
17. ↑ M. Donike, R. Gola, L. Jaenicke: Detection of indole alkylamines after selective derivatization . In: J. Chromatogr. A . tape 134 , no. 2 , 1977, p. 385-395 , doi : 10.1016 / S0021-9673 (00) 88537-4 .
18. ↑ Y.-Q. Zhou, Z.-J. Wang, N. Jia: Formation of multiple trimethylsilyl derivatives in the derivatization of 17α-ethinylestradiol with BSTFA or MSTFA followed by gas chromatography-mass spectrometry determination . In: J. Environm. Sci. tape 19 , no. 7 , 2007, p. 879-884 , doi : 10.1016 / S1001-0742 (07) 60146-6 .
19. ↑ German Sport University Cologne, Institute for Biochemistry: Anabolic androgenic steroid hormones (anabolic steroids)