TCFH (''N'',''N'',''N''’,''N''’-tetramethylchloroformamidinium hexafluorophosphate) is an

electrophilic In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carr ...

amidine Amidines are organic compounds with the functional group RC(NR)NR2, where the R groups can be the same or different. They are the imine derivatives of amides (RC(O)NR2). The simplest amidine is formamidine, HC(=NH)NH2. Examples of amidines includ ...

reagent In chemistry, a reagent ( ) or analytical reagent is a substance or compound added to a system to cause a chemical reaction, or test if one occurs. The terms ''reactant'' and ''reagent'' are often used interchangeably, but reactant specifies a ...

used to activate a number of

functional groups In organic chemistry, a functional group is any substituent or moiety (chemistry), moiety in a molecule that causes the molecule's characteristic chemical reactions. The same functional group will undergo the same or similar chemical reactions r ...

for reaction with nucleophilies. TCFH is most commonly used to activate

carboxylic acids In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...

for reaction with

amines In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...

in the context of amide bond formation and

peptide synthesis In organic chemistry, peptide synthesis is the production of peptides, compounds where multiple amino acids are linked via amide bonds, also known as peptide bonds. Peptides are chemically synthesized by the condensation reaction of the carboxyl ...

. __TOC__

Preparation

TCFH is commercially available. It may be prepared from

tetramethylurea Tetramethylurea is the organic compound with the formula (Me2N)2CO. It is a substituted ureas, urea. This colorless liquid is used as an Protic solvent, aprotic-polar solvent, especially for aromatic compounds and is used e. g. for Grignard reag ...

using a chlorinating agent such as

oxalyl chloride Oxalyl chloride is an organic chemical compound with the formula . This colorless, sharp-smelling liquid, the diacyl chloride of oxalic acid, is a useful reagent in organic synthesis. Preparation Oxalyl chloride was first prepared in 1892 by the ...

thionyl chloride Thionyl chloride is an inorganic compound with the chemical formula . It is a moderately Volatility (chemistry), volatile, colourless liquid with an unpleasant acrid odour. Thionyl chloride is primarily used as a Halogenation, chlorinating reagen ...

phosphorus oxychloride Phosphoryl chloride (commonly called phosphorus oxychloride) is a colourless liquid with the formula . It hydrolyses in moist air releasing phosphoric acid and fumes of hydrogen chloride. It is manufactured industrially on a large scale from phos ...

followed by salt exchange.

Uses

TCFH itself is a common reagent used in the preparation of uronium and guanidinium salts used for amide bond formation and peptide synthesis, such as

HATU HATU (Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium) is a reagent used in peptide coupling chemistry to generate an active ester from a carboxylic acid. HATU is used along with Hünig's base (''N,N''-diisopropylethylamine), or trieth ...

. Amide bond formation with TCFH can be performed in a wide range of organic solvents, most commonly

acetonitrile Acetonitrile, often abbreviated MeCN (methyl cyanide), is the chemical compound with the formula and structure . This colourless liquid is the simplest organic nitrile (hydrogen cyanide is a simpler nitrile, but the cyanide anion is not class ...

, but also water and in the solid state. Reactions typically require an added Brønsted base, and a wide range can be employed including ''N,N''-diisopropylethylamine (DIPEA). In reactions of carboxylic acids with TCFH and a weakly Lewis basic amine like DIPEA, formation of an

acid chloride In organic chemistry, an acyl chloride (or acid chloride) is an organic compound with the functional group . Their formula is usually written , where R is a side chain. They are reactive derivatives of carboxylic acids (). A specific example o ...

anhydride An acid anhydride is a type of chemical compound derived by the removal of water molecules from an acid (chemistry), acid. In organic chemistry, organic acid anhydrides contain the functional group . Organic acid anhydrides often form when one ...

as the active acylating agent occurs. Use of ''N''-methylimidazole (NMI) as a base, with both Brønsted and Lewis basic properties, provides some unique advantages. Reactions of carboxylic acids with TCFH and a strongly Lewis basic amine like NMI lead to ''in situ'' formation of an ''N''-acyl imidazolium ion (NAI) as the active acylating agent. TCFH mechanism2

These strongly electrophilic NAIs allow for reactions with a wide range of nitrogen nucleophiles, including hindered and electron-deficient amines. An added benefit of the use of NMI as the base, due to its low p''K''_a(H₂O) of 7, is that the epimerization of labile stereogenic centers is minimized. The reaction by-products have high water solubility, facilitating reaction workup and isolation. TCFH Examples1

TCFH can also be used in other reactions involving activation of carboxylic acids from reactions with oxygen-, sulfur- and carbon-

nucleophiles In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...

for the preparation of

esters In chemistry, an ester is a chemical compound, compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds c ...

thioesters In organic chemistry, thioesters are organosulfur compounds with the molecular structure . They are analogous to carboxylate esters () with the sulfur in the thioester replacing oxygen in the carboxylate ester, as implied by the thio- prefix. ...

and

ketones In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...

. Extending beyond reactions with carboxylic acids, TCFH has been shown to be an activator for other oxygen centered nucleophiles, including heterocyclic alcohols, ketooximes, and even

alcohols In chemistry, an alcohol (), is a type of organic compound that carries at least one hydroxyl () functional group bound to a Saturated and unsaturated compounds, saturated carbon atom. Alcohols range from the simple, like methanol and ethanol ...

. Reactivity with sulfur centered nucleophiles like

thioureas In organic chemistry, thioureas are members of a family of organosulfur compounds with the formula and structure . The parent member of this class of compounds is thiourea (). Substituted thioureas are found in several commercial chemicals. Stru ...

has also been demonstrated. TCFH4

Safety

TCFH does not exhibit dermal corrosion or irritation but irritates eyes. The sensitization potential of TCFH was shown to be low compared to other common amide bond forming agents (non-sensitizing at 1% in LLNA testing according to OECD 429). The by-product of the reactions of TCFH is

, which has demonstrated

embryotoxic Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology caused by ...

and

teratogenic Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology caused by ...

activity in several animal species.

References

{{Reflist Reagents for organic chemistry Amidines Hexafluorophosphates