N,N,N′,N′-Tetramethylformamidinium chloride explained

N,N,N′,N′-Tetramethylformamidinium chloride is the simplest representative of quaternary formamidinium cations of the general formula [R₂N−CH=NR₂]⁺ with a chloride as a counterion in which all hydrogen atoms of the protonated formamidine [HC(=NH₂)NH₂]⁺ are replaced by methyl groups.^[1]

Deprotonation results in the exceptionally basic bis(dimethylamino)carbene R₂N−C̈−NR₂.^[2]

Preparation

It is generated by protonation of (CH₃)₃COCH(N(CH₃)₂)₂ (Bredereck's reagent).^[3]

(CH₃)₃COCH(N(CH₃)₂)₂ + H⁺ → (CH₃)₃COH + [CH(N(CH₃)₂)₂]⁺

N,N,N′,N′-Tetramethylformamidinium chloride is also obtained in high yield (95%) in the reaction of dimethylformamide (DMF) with dimethylcarbamoyl chloride^[4] The conversion of DMF with thionyl chloride in a ratio of 3:1 obtains the product in a is significantly lower yield (72%) which appears, however, more realistic in view of the tricky handling of the chloride salt.^[5]

Properties

N,N,N′,N′-Tetramethylformamidinium chloride is a light yellow, strongly hygroscopic solid.^[6]

For drying, the salt is dissolved in dichloromethane and the solution is treated with solid anhydrous sodium sulfate. After several dissolutions in dichloromethane and acetone, and precipitations with tetrahydrofuran, a colorless solid is obtained, which is stable under air and moisture sealing.^[1]

The presumption of a mesomeric equilibrium between ionic formamidinium chloride and covalent bis(dimethylamino)chloromethane structure:

could be decided by reaction with germanium dichloride or tin(II) chloride in favour of the presence of N,N,N′,N′-tetramethylformamidinium chloride.^[7]

The hygroscopy of the chloride salt complicates the handling of the compound. Therefore, also syntheses of the much better processible salts N,N,N′,N′-tetramethylformamidinium methylsulfate^[6] (from the dimethylformamide–dimethylsulfate complex^[8]) and of N,N,N′,N′-tetramethylformamidinium p-toluenesulfonate (from dimethylformamide and p-toluenesulfonyl chloride) were investigated.^{[9] [10]}

Applications

N,N,N′,N′-Tetramethylformamidinium chloride is useful as a reagent for aminomethylenation (that is, to introduce a =CH−NR¹R² function to CH-acidic compounds). For example, ethyl cyanoacetate reacts with the formamidinium salt in the presence of solid sodium hydroxide to give ethyl (dimethylaminomethylene)cyanoacetate in practically quantitative yields.^[11]

The aminomethylenation provides intermediates for the synthesis of heterocycles such as indoles, pyrimidines, pyridines and quinolones.

N,N,N′,N′-Tetramethylformamidinium chloride reacts with alkali metal dimethylamides (such as lithium dimethylamide or sodium dimethylamide) to tris(dimethylamino)methane in yields of 55% to 84%.^{[12] [13] [14]}

The reaction product is suited as a reagent for formylation and aminomethylenation.

From N,N,N′,N′-tetramethylformamidinium chloride and sodium ethoxide in ethanol, dimethylformamide diethyl acetal is formed in 68% yield.^[15]

In aqueous sodium cyanide, N,N,N′,N′-tetramethylformamidinium reacts to bis(dimethylamino)acetonitrile.^[16]

From N,N,N′,N′-tetramethylformamidinium and anhydrous hydrogen cyanide, dimethylaminomalonic acid dinitrile is obtained in 92% yield.

N,N,N′,N′-Tetramethylformamidinium can be regaminated with cyclo-aliphatic amines to the corresponding heterocyclic formamidines.^[17]

N,N,N′,N′-tetramethylformamidinium is a catalyst in the preparation of acyl chlorides from carboxylic acids and phosgene has been reported.^[18]

Strong bases (such as phenyllithium) can abstract a proton from the formamidinium cation of N,N,N′,N′-tetramethylformamidinium forming bis(dimethylamino)carbene.^{[1] [2]}

See also

• Bis(dimethylamino)methane

Notes and References

1. R. W. . Alder . M. E. . Blake . S. . Bufali . C. P. . Butts . A. G. . Orpen . J. . Schütz . S. J. . Williams . Journal of the Chemical Society, Perkin Transactions 1. Preparation of tetraalkylformamidinium salts and related species as precursors to stable carbenes . 14. 1586–1593 . 2001 . 10.1039/B104110J.
2. A. M. . Magill . K. J. . Cavell . B. F. . Yates . Journal of the American Chemical Society . Basicity of nucleophilic carbenes in aqueous and nonaqueous solvents – theoretical predictions . 126 . 28 . 8717–24 . 2004 . 10.1021/ja038973x. 15250724 .
3. Book: 10.1002/9780470842898.rb350.pub2. T-Butoxybis(dimethylamino)methane. Encyclopedia of Reagents for Organic Synthesis. 2007. Kantlehner. Willi. Bowers. Albert. 978-0471936237.
4. Z. . Arnold . Collection of Czechoslovak Chemical Communications . The preparation of tetramethylformamidinium salts and their vinylogues . 24 . 3 . 760–765 . 1959 . 10.1135/cccc19590760.
5. W. . Kantlehner . P. . Speh . Chemische Berichte . Säureamid-Reaktionen. LI. Notiz zur Darstellung von N,N,N′,N′-Tetramethylformamidiniumchlorid . Acyl amide reactions. LI. Note on the presentation of N,N,N′,N′-tetramethylformamidinium chloride . 104 . 11 . 3714–3715 . 1971 . de . 10.1002/cber.19711041136.
6. DE. 1205528 . Verfahren zur Herstellung von N-substituierten Amidinen oder deren Vinylogen (Process for the preparation of N-substituted amidines or their vinylogues) . 1965-11-25 . 1962-02-08 . Bredereck, H. . Effenberger, F. . Simchen, G. . Bredereck, H..
7. X. . Tian . T. . Pape . N. W. . Mitzel . Zeitschrift für Naturforschung . Formamidinium Salts of Low Valent Metal Halide Anions (M = Ge, Sn) and (M = Ga, In) . 59b . 11–12 . 1524–1531 . 2004 . 10.1515/znb-2004-11-1224.
8. H. . Bredereck . F. . Effenberger . G. . Simchen . Chemische Berichte . Säureamid-Reaktionen. XXXII. Über Säureamid-Dialkylsulfat-Komplexe . Acyl amide reactions. XXXII. On acyl amide–dialkylsulfate complexes . 96 . 5 . 1350–1355 . 1963 . de . 10.1002/cber.19630960526.
9. US. 3707553 . Tetramethylformamidinium arenesulfonates and method of preparation . 1972-12-26 . 1965-8-24 . Bagley, G. E. . Poshkus A. C. . Armstrong Cork Co..
10. H. . Schindlbauer . Monatshefte für Chemie . Reaktionen mit Dimethylformamid. 3. (Mitt.) Die Umsetzung von Arylsulfochloriden und Arylsulfonsäuren mit Dimethylformamid . Reactions with dimethylformamide. 3. (Comm.) The reaction of arylsulfonyl chlorides and arylsulfonic acids with dimethylformamide . 100 . 5 . 1590–1595 . 1969 . de . 10.1007/BF00900174.
11. US. 5241099 . Process for the preparation of aminomethylene compounds . 1993-08-31 . 1992-03-16 . Blank, H.-U. . Kraus, H. . Bayer AG.
12. H. . Bredereck . F. . Effenberger . T. . Brendle . Angewandte Chemie . Synthese und Reaktionen von Trisdimethylaminomethan . Synthesis and reactions of tris(dimethylamino)methane . 78 . 2 . 147–148 . 1966 . de . 10.1002/ange.19660780212.
13. DE . 1217391 . Verfahren zur Herstellung von Tris-dimethylaminomethan (Process for the preparation of tris(dimethylamino)methane)) . 1966-12-08 . 1964-09-29 . Bredereck, H. . Effenberger, F. . T. . Brendle . Bredereck, H..
14. H. . Bredereck . F. . Effenberger . T. . Brendle . H. . Muffler . Chemische Berichte . Orthoamide. V. Synthese von Tris-dialkylamino-methanen . Orthoamides. V. Synthesis of tris(dialkylamino)methanes . 101 . 5 . 1885–1888 . 1968 . de . 10.1002/cber.19681010541.
15. H. . Gold . Angewandte Chemie . Die Reaktion von Cyanurchlorid mit Dimethylformamid . The reaction of cyanuric chloride with dimethylformamide . 72 . 24 . 956–959 . 1960 . de . 10.1002/ange.19600722406.
16. H. . Bredereck . G. . Simchen . W. . Kantlehner . Chemische Berichte . Orthoamide. XVI. Synthese von O.N- und N.N-Acetalen der α-Keto-carbonsäure-nitrile sowie von Iminoestern . Orthoamides. XVI. Synthesis of O,N- and N,N-acetals of α-keto-carboxylic acid nitriles as well as imino esters . 104 . 3 . 924–931 . 1971 . de . 10.1002/cber.19711040331.
17. H. . Gold . O. . Bayer . Chemische Berichte . Die Darstellung basisch substituierter Malonsäure-dinitrile . Presentation of base-substituted malonic acid dinitriles . 94 . 10 . 2594–2596 . 1961 . de . 10.1002/cber.19610941004.
18. EP . 1124783 . Method for producing carboxylic acid chlorides . 2001-08-22 . 1998-11-04 . Henkelmann, J. . Stamm, A. . BASF AG.